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1
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Michalakis NP, Patel A, Awais M. A Case Report of a 61-Year-Old Woman With Jaundice and Cholelithiasis Presenting With Autoimmune Hepatitis. Cureus 2025; 17:e80829. [PMID: 40255774 PMCID: PMC12007933 DOI: 10.7759/cureus.80829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2025] [Indexed: 04/22/2025] Open
Abstract
Autoimmune hepatitis (AIH) is a complex disease with a chronic cell-mediated immunologic process against healthy liver cells. The clinical presentation can vary since the exact cause of AIH is multifactorial. Here, we report a case of a 61-year-old woman with a past medical history of post-traumatic stress disorder and hypothyroidism who presented clinically with diffuse abdominal distention, nausea, vomiting, jaundice, rash on the torso and legs, and tea-burnt orange urine. The patient underwent an initial workup with a complete blood count (CBC), comprehensive metabolic panel (CMP), and gamma-glutamyl transpeptidase (GGT), with results leading towards a mixed intra- and extrahepatic process. This report will show various findings related to AIH to improve the detection and treatment of these patients early on.
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Affiliation(s)
| | - Archit Patel
- Internal Medicine, Piedmont Macon Medical Center, Macon, USA
| | - Muhammad Awais
- Graduate Medical Education, Piedmont Macon Medical Center, Macon, USA
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2
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Zhang Q, Chan DXH, Ho KY. Efficacy and Safety of Fixed-Dose Combinations for Pain in Older Adults. Drugs Aging 2024; 41:873-879. [PMID: 39453601 DOI: 10.1007/s40266-024-01156-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/06/2024] [Indexed: 10/26/2024]
Abstract
Pain is common in older adults and managing pain in this population can be challenging owing to altered pharmacokinetics, multimorbidity, polypharmacy, cognitive impairment, and physical frailty. A fixed-dose combination (FDC) analgesic contains two or more pharmaceutical ingredients in a single pill and may offer more benefits when compared with loose-dose formulations. The benefits include reduced pill burden and better adherence, a broader analgesic spectrum well-suited to multimechanistic pain conditions and more predictable pharmacokinetic and pharmacodynamic properties. These advantages may outweigh disadvantages such as reduced flexibility in dose adjustment. Most of the commonly used FDC analgesics are made up of a combination of paracetamol, muscle relaxant, nonsteroidal anti-inflammatory drug or opioid. They have been shown to have better efficacy and similar safety profiles compared with individual drugs. Adverse effects from the use of FDC analgesics in older patients were comparable with that observed in younger populations. With proper patient selection and continuous surveillance, FDC analgesics will likely benefit older adults by simplifying dosing regimen and improving compliance.
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Affiliation(s)
- Qianpian Zhang
- Division of Anaesthesiology, Singapore General Hospital, Singapore, Singapore
| | - Diana Xin Hui Chan
- Division of Anaesthesiology, Singapore General Hospital, Singapore, Singapore
| | - Kok-Yuen Ho
- The Pain Clinic, Mount Alvernia Hospital, Singapore, Singapore.
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Duffy M, Zhang G, Ariyawansa C, Anstey MH. Niacin (Vitamin B3)-Induced Acute Fulminant Hepatic Failure in a 24-Year-Old Female. Cureus 2024; 16:e69518. [PMID: 39416578 PMCID: PMC11481423 DOI: 10.7759/cureus.69518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/08/2024] [Indexed: 10/19/2024] Open
Abstract
Acute liver failure (ALF) is a rare, life-threatening condition characterized by acute severe liver injury, encephalopathy, and coagulopathy in the absence of prior liver disease. The causes of ALF are broad and varied worldwide, commonly including triggers such as drugs (predominantly paracetamol) in developed countries and viral infections in developing nations. Prompt diagnosis and management are crucial in acute fulminant liver failure as highlighted in this case of a 24-year-old female with ALF secondary to vitamin B3 overdosing. This study further highlights the need for a high degree of clinical suspicion that physicians need to ascertain the cause of acute liver failure, the complexity of its management, and the significant harm unnecessary dietary supplementation can result in. This is a crucial example of why healthcare professionals need to educate their patients about the potential adverse consequences of dietary supplements.
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Affiliation(s)
- Michael Duffy
- Intensive Care Medicine, Sir Charles Gairdner Hospital, Perth, AUS
| | - Gary Zhang
- Intensive Care Medicine, Sir Charles Gairdner Hospital, Perth, AUS
| | | | - Matthew H Anstey
- Intensive Care Medicine, The University of Western Australia, Perth, AUS
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4
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Sehrawat SS, Premkumar M. Critical care management of acute liver failure. Indian J Gastroenterol 2024; 43:361-376. [PMID: 38578565 DOI: 10.1007/s12664-024-01556-8] [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: 12/12/2023] [Accepted: 02/12/2024] [Indexed: 04/06/2024]
Abstract
The management of acute liver failure (ALF) in modern hepatology intensive care units (ICU) has improved patient outcomes. Critical care management of hepatic encephalopathy, cerebral edema, fluid and electrolytes; prevention of infections and organ support are central to improved outcomes of ALF. In particular, the pathogenesis of encephalopathy is multifactorial, with ammonia, elevated intra-cranial pressure and systemic inflammation playing a central role. Although ALF remains associated with high mortality, the availability of supportive care, including organ failure support such as plasma exchange, timely mechanical ventilation or continuous renal replacement therapy, either conservatively manages patients with ALF or offers bridging therapy until liver transplantation. Thus, appropriate critical care management has improved the likelihood of patient recovery in ALF. ICU care interventions such as monitoring of cerebral edema, fluid status assessment and interventions for sepsis prevention, nutritional support and management of electrolytes can salvage a substantial proportion of patients. In this review, we discuss the key aspects of critical care management of ALF.
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Affiliation(s)
- Surender Singh Sehrawat
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Madhumita Premkumar
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India.
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5
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Wang S, Argikar UA, Cheruzel L, Cho S, Crouch RD, Dhaware D, Heck CJS, Johnson KM, Kalgutkar AS, King L, Liu J, Ma B, Maw H, Miller GP, Seneviratne HK, Takahashi RH, Wei C, Khojasteh SC. Bioactivation and reactivity research advances - 2022 year in review‡. Drug Metab Rev 2023; 55:267-300. [PMID: 37608698 DOI: 10.1080/03602532.2023.2244193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 06/05/2023] [Indexed: 08/24/2023]
Abstract
With the 50th year mark since the launch of Drug Metabolism and Disposition journal, the field of drug metabolism and bioactivation has advanced exponentially in the past decades (Guengerich 2023).This has, in a major part, been due to the continued advances across the whole spectrum of applied technologies in hardware, software, machine learning (ML), and artificial intelligence (AI). LC-MS platforms continue to evolve to support key applications in the field, and automation is also improving the accuracy, precision, and throughput of these supporting assays. In addition, sample generation and processing is being aided by increased diversity and quality of reagents and bio-matrices so that what is being analyzed is more relevant and translatable. The application of in silico platforms (applied software, ML, and AI) is also making great strides, and in tandem with the more traditional approaches mentioned previously, is significantly advancing our understanding of bioactivation pathways and how these play a role in toxicity. All of this continues to allow the area of bioactivation to evolve in parallel with associated fields to help bring novel or improved medicines to patients with urgent or unmet needs.Shuai Wang and Cyrus Khojasteh, on behalf of the authors.
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Affiliation(s)
- Shuai Wang
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA
| | - Upendra A Argikar
- Non-clinical Development, Bill and Melinda Gates Medical Research Institute, Cambridge, MA, USA
| | - Lionel Cheruzel
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA
| | - Sungjoon Cho
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA
| | - Rachel D Crouch
- Department of Pharmacy and Pharmaceutical Sciences, Lipscomb University College of Pharmacy, Nashville, TN, USA
| | | | - Carley J S Heck
- Medicine Design, Pfizer Worldwide Research, Development and Medical, Groton, CT, USA
| | - Kevin M Johnson
- Drug Metabolism and Pharmacokinetics, Inotiv, Maryland Heights, MO, USA
| | - Amit S Kalgutkar
- Medicine Design, Pfizer Worldwide Research, Development and Medical, Cambridge, MA, USA
| | - Lloyd King
- Quantitative Drug Discovery, UCB Biopharma UK, Slough, UK
| | - Joyce Liu
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA
| | - Bin Ma
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA
| | - Hlaing Maw
- Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
| | - Grover P Miller
- Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Herana Kamal Seneviratne
- Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD, USA
| | | | - Cong Wei
- Drug Metabolism and Pharmacokinetics, Biogen Inc., Cambridge, MA, USA
| | - S Cyrus Khojasteh
- Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA
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6
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Kong X, Liu W, Zhang X, Zhou C, Sun X, Cheng L, Lin J, Xie Z, Li J. HIF-1α inhibition in macrophages preserves acute liver failure by reducing IL-1β production. FASEB J 2023; 37:e23140. [PMID: 37584647 DOI: 10.1096/fj.202300428rr] [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: 03/07/2023] [Revised: 07/13/2023] [Accepted: 08/01/2023] [Indexed: 08/17/2023]
Abstract
The development of acute liver failure (ALF) is dependent on its local inducer. Inflammation is a high-frequency and critical factor that accelerates hepatocyte death and liver failure. In response to injury stress, the expression of the transcription factor hypoxia-inducible factor-1α (HIF-1α) in macrophages is promoted by both oxygen-dependent and oxygen-independent mechanisms, thus promoting the expression and secretion of the cytokine interleukin-1β (IL-1β). IL-1β further induces hepatocyte apoptosis or necrosis by signaling through the receptor (IL-1R) on hepatocyte. HIF-1α knockout in macrophages or IL-1R knockout in hepatocytes protects against liver failure. However, whether HIF-1α inhibition in macrophages has a protective role in ALF is unclear. In this study, we revealed that the small molecule HIF-1α inhibitor PX-478 inhibits the expression and secretion of IL-1β, but not tumor necrosis factor α (TNFα), in bone marrow-derived macrophages (BMDMs). PX-478 pretreatment alleviates liver injury in LPS/D-GalN-induced ALF mice by decreasing the hepatic inflammatory response. In addition, preventive or therapeutic administration of PX-478 combined with TNFα neutralizing antibody markedly improved LPS/D-GalN-induced ALF. Taken together, our data suggest that PX-478 administration leads to HIF-1α inhibition and decreased IL-1β secretion in macrophages, which represents a promising therapeutic strategy for inflammation-induced ALF.
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Affiliation(s)
- Xiangrong Kong
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Wei Liu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China
- University of Chinese Academy of Sciences, Beijing, P.R. China
| | - Xinwen Zhang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China
| | - Chendong Zhou
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China
| | - Xinyu Sun
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China
| | - Long Cheng
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China
- University of Chinese Academy of Sciences, Beijing, P.R. China
| | - Jinxia Lin
- Zhangzhou Pien Tze Huang Pharmaceutical Co., Ltd, Zhangzhou, P.R. China
| | - Zhifu Xie
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China
| | - Jingya Li
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, P.R. China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P.R. China
- University of Chinese Academy of Sciences, Beijing, P.R. China
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7
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Shionoya K, Kako M, Masuda S, Makazu M, Koizumi K. Acute liver failure due to herpes simplex viral hepatitis diagnosed by skin lesions and blood tests: a case report. J Med Case Rep 2023; 17:338. [PMID: 37559160 PMCID: PMC10413703 DOI: 10.1186/s13256-023-04083-w] [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: 06/21/2022] [Accepted: 07/16/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND The incidence of acute liver failure from herpes simplex virus is rare. CASE PRESENTATION A 71-year-old Japanese man was diagnosed with acute liver failure and was transferred to our hospital. Steroid therapy, plasma exchange, and hemodiafiltration were started for liver failure, and antimicrobial therapy was initiated for pneumonia. Staphylococcus epidermidis was detected in blood culture. Skin rash appeared; a positive anti-herpes simplex virus result led to the diagnosis of acute liver failure from herpes simplex virus. Hence, acyclovir was started. After blood tests improved, treatments for acute liver failure were discontinued. Antimicrobial therapy was continued; however, he died. In this case, persistent bacteremia and drug-induced liver damage due to acyclovir may have contributed to his death. CONCLUSIONS Acute liver failure can lead to complications and death. Thus, careful observation is crucial, even if the patient has shown some improvements.
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Affiliation(s)
- Kento Shionoya
- Shonan Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Okamoto 1370-1, Kamakura-Shi, Kanagawa, 247-8533, Japan.
| | - Makoto Kako
- Shonan Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Okamoto 1370-1, Kamakura-Shi, Kanagawa, 247-8533, Japan
| | - Sakue Masuda
- Shonan Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Okamoto 1370-1, Kamakura-Shi, Kanagawa, 247-8533, Japan
| | - Makomo Makazu
- Shonan Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Okamoto 1370-1, Kamakura-Shi, Kanagawa, 247-8533, Japan
| | - Kazuya Koizumi
- Shonan Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Okamoto 1370-1, Kamakura-Shi, Kanagawa, 247-8533, Japan
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8
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Shingina A, Mukhtar N, Wakim-Fleming J, Alqahtani S, Wong RJ, Limketkai BN, Larson AM, Grant L. Acute Liver Failure Guidelines. Am J Gastroenterol 2023; 118:1128-1153. [PMID: 37377263 DOI: 10.14309/ajg.0000000000002340] [Citation(s) in RCA: 71] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 04/04/2023] [Indexed: 06/29/2023]
Abstract
Acute liver failure (ALF) is a rare, acute, potentially reversible condition resulting in severe liver impairment and rapid clinical deterioration in patients without preexisting liver disease. Due to the rarity of this condition, published studies are limited by the use of retrospective or prospective cohorts and lack of randomized controlled trials. Current guidelines represent the suggested approach to the identification, treatment, and management of ALF and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence was reviewed using the Grading of Recommendations, Assessment, Development and Evaluation process to develop recommendations. When no robust evidence was available, expert opinions were summarized using Key Concepts. Considering the variety of clinical presentations of ALF, individualization of care should be applied in specific clinical scenarios.
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Affiliation(s)
- Alexandra Shingina
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Nizar Mukhtar
- Department of Gastroenterology, Kaiser Permanente, San Francisco, California, USA
| | - Jamilé Wakim-Fleming
- Department of Gastroenterology, Hepatology & Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, Cleveland Ohio, USA
| | - Saleh Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, USA
- Liver Transplantation Unit, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Robert J Wong
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, Gastroenterology Section, Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA
| | | | - Anne M Larson
- Division of Gastroenterology and Hepatology, University of Washington, Seattle, Washington, USA
| | - Lafaine Grant
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas, USA
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9
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Deacon AJ, Goetz NN, Weber N, Clouston A, Gonsalkorala E, Baskerville C, Leggett B. Relapsed nodular lymphocyte-predominant Hodgkin lymphoma presenting as severe paraneoplastic hepatitis: a case report. J Med Case Rep 2023; 17:269. [PMID: 37386640 DOI: 10.1186/s13256-023-04014-9] [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: 12/08/2022] [Accepted: 05/27/2023] [Indexed: 07/01/2023] Open
Abstract
BACKGROUND Hematological malignancies are an infrequent but important cause of liver dysfunction. There are several mechanisms by which this can occur, including direct malignant infiltration of the hepatic parenchyma and/or vasculature, vanishing bile duct syndrome, and paraneoplastic hepatitis. Paraneoplastic hepatitis is an extremely rare mechanism by which a hematological malignancy can cause liver dysfunction, and we present the first case, to our knowledge, of paraneoplastic hepatitis caused by nodular lymphocyte-predominant Hodgkin lymphoma in the literature. CASE PRESENTATION A 28-year-old Caucasian male presented with 3 weeks of fatigue, epigastric pain, and jaundice. His medical history was significant for early stage nodular lymphocyte-predominant Hodgkin lymphoma in the cervical region in remission for 5 years after primary treatment with involved-field radiotherapy. Liver biochemistry was normal at the time of treatment for lymphoma and there was no known liver disease before the current presentation. On physical examination, there was scleral icterus and ecchymoses, but no evidence of hepatic encephalopathy, other stigmata of chronic liver disease, or lymphadenopathy. A computed tomography scan of his neck, chest, abdomen, and pelvis showed heterogeneous enhancement of the liver, multiple enlarged upper abdominal lymph nodes, and an enlarged spleen with multiple rounded lesions. Portal and hepatic veins were patent. Initial workup for viral, autoimmune-, toxin-, and medication-related hepatitis was negative. A transjugular liver biopsy was performed with histology showing a predominantly T-cell mediated hepatitis with very extensive multiacinar hepatic necrosis, but no evidence of lymphoma within the liver. Retroperitoneal lymph node biopsy revealed nodular lymphocyte-predominant Hodgkin lymphoma. The patient's symptoms, bilirubin, and transaminases improved significantly after treatment with oral prednisolone and a staged introduction of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy. CONCLUSIONS Nodular lymphocyte-predominant Hodgkin lymphoma may cause paraneoplastic hepatitis. Physicians should be aware of the possibility of this life-threatening presentation and the importance of early liver biopsy and treatment before acute liver failure occurs. Interestingly, paraneoplastic hepatitis did not occur when nodular lymphocyte-predominant Hodgkin lymphoma was first diagnosed and confined to the cervical region, but was the presenting feature of the recurrence below the diaphragm.
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Affiliation(s)
- Anthony J Deacon
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Australia.
- Faculty of Medicine, University of Queensland, Brisbane, Australia.
| | - Naeman N Goetz
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Australia
- Faculty of Medicine, University of Queensland, Brisbane, Australia
| | - Nicholas Weber
- Department of Haematology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | - Andrew Clouston
- Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | - Enoka Gonsalkorala
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Australia
| | - Catherine Baskerville
- Department of Internal Medicine and Aged Care, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | - Barbara Leggett
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Australia
- Faculty of Medicine, University of Queensland, Brisbane, Australia
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10
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Özbilgin M, Egeli T, Ağalar C, Özkardeşler S, Saatli B, Ellidokuz H, Akarsu M, Ünek T, Karademir S, Astarcıoğlu İ. Evaluation of the Effects of Immunosuppressive Drugs Following Liver Transplantation on Pregnancy Outcomes: A Retrospective Study. Transplant Proc 2023; 55:1245-1251. [PMID: 37230900 DOI: 10.1016/j.transproceed.2023.04.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 04/05/2023] [Accepted: 04/14/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND Liver transplantations can be safely performed in women of reproductive age. Women with chronic liver disease may have infertility for various reasons, although fertility returns after recovering >90% of sexual disorders following liver transplantation. The present study examined the effects of immunosuppressive drugs used by women of reproductive age undergoing liver transplantation in our clinic on pregnancy and pregnancy outcomes and evaluated mortality and morbidity in this patient population. METHODS Among the patients undergoing liver transplantation in our clinic between 1997 and 2020, those conceiving after liver transplantation were evaluated in the present study. Demographic data on maternal and newborn health, as well as mortality and morbidity, were recorded. Maternal transplant indications, graft type, the interval between transplantation and pregnancy, maternal age at pregnancy and the number of pregnancies, the number of living children, complications, delivery mode, immunosuppressive drugs, and blood levels were investigated. RESULTS A total of 615 liver transplantations (353 from a living donor, 262 from a cadaveric donor) were performed in our clinic. Furthermore, 33 pregnancies occurred in 22 women following transplantation (17 living donor liver transplantations, 5 deceased donor liver transplantations), and the data of these patients were recorded. Tacrolimus and mycophenolate mofetil were used as immunosuppressive therapy. CONCLUSIONS Liver transplantations can be safely performed in women of reproductive age if indicated, and these patients can be safely followed up throughout the pregnancy and during labor by a multidisciplinary team.
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Affiliation(s)
- Mücahit Özbilgin
- Department of General Surgery, Hepatobiliary Surgery and Liver Transplantation Unit, Dokuz Eylül University Hospital, Izmir, Turkey.
| | - Tufan Egeli
- Department of General Surgery, Hepatobiliary Surgery and Liver Transplantation Unit, Dokuz Eylül University Hospital, Izmir, Turkey
| | - Cihan Ağalar
- Department of General Surgery, Hepatobiliary Surgery and Liver Transplantation Unit, Dokuz Eylül University Hospital, Izmir, Turkey
| | - Sevda Özkardeşler
- Department of Anesthesiology and Reanimation, Dokuz Eylül University Hospital, Izmir, Turkey
| | - Bahadır Saatli
- Department of Gynecology and Obstetrics, Dokuz Eylül University Hospital, Izmir, Turkey
| | - Hülya Ellidokuz
- Department of Preventive Oncology, Dokuz Eylül University Hospital, Izmir, Turkey
| | | | - Tarkan Ünek
- Department of General Surgery, Hepatobiliary Surgery and Liver Transplantation Unit, Dokuz Eylül University Hospital, Izmir, Turkey
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11
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Xue Y, Zhang D, Wei Y, Guo C, Song B, Cui Y, Zhang C, Xu D, Zhang S, Fang J. Polymeric nano-micelle of carbon monoxide donor SMA/CORM2 ameliorates acetaminophen-induced liver injury via suppressing HMGB1/TLR4 signaling pathway. Eur J Pharm Sci 2023; 184:106413. [PMID: 36863618 DOI: 10.1016/j.ejps.2023.106413] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 02/10/2023] [Accepted: 02/25/2023] [Indexed: 03/04/2023]
Abstract
Acetaminophen (APAP) overdose-induced hepatotoxicity is the most common cause of acute liver failure. Excessive generation of reactive oxygen species (ROS) and inflammatory responses are the major causes of necrosis and/or necroptosis of the liver cells. Currently, the treatment options for APAP-induced liver injury are very limited, N-acetylcysteine (NAC) is the only approved drug to treat APAP overdose patients. It is of great necessity to develop new therapeutic strategies. In a previous study, we focused on the anti-oxidative, anti-inflammatory signal molecule carbon monoxide (CO), and developed a nano-micelle encapsulating CO donor, i.e., SMA/CORM2. Administration of SMA/CORM2 to the mice exposed to APAP significantly ameliorated the liver injury and inflammatory process, in which modulating macrophage reprogramming plays a critical role. Along this line, in this study, we investigated the potential effect of SMA/CORM2 on toll-like receptor 4 (TLR4) and high mobility group protein B1 (HMGB1) signaling pathways that are known to be closely involved in many inflammatory responses and necroptosis. In a mouse APAP-induced liver injury model, similar to the previous study, SMA/CORM2 at 10 mg/kg remarkably improved the condition of the liver after injury as evidenced by histological examination and liver function. During the process of liver injury triggered by APAP, TLR4 expression gradually increased over time, and it was significantly upregulated as early as 4 h after APAP exposure, whereas, an increase of HMGB1 was a late-stage event. Notably, SMA/CORM2 treatment suppressed significantly both TLR4 and HMGB1, consequently inhibiting the progression of inflammation and liver injury. Compared to CORM2 without SMA modification (native CORM2) of 1 mg/kg that is equivalent to 10 mg/kg of SMA/CORM2 (the amount of CORM2 in SMA/CORM2 is 10% [w/w]), SMA/CORM2 exhibited a much better therapeutic effect, indicating its superior therapeutic efficacy to native CORM2. These findings revealed that SMA/CORM2 protects against APAP-induced liver injury via mechanisms involving the suppression of TLR4 and HMGB1 signaling pathways. Taking together the results in this study and previous studies, SMA/CORM2 exhibits great therapeutic potential for APAP overdose-induced liver injury, we thus anticipate the clinical application of SMA/CORM2 for the treatment of APAP overdose, as well as other inflammatory diseases.
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Affiliation(s)
- Yanni Xue
- Department of Maternal, Child and Adolescent Health, School of Public Health, and MOE Key Laboratory of Population Health Across Life Cycle/ Anhui Provincial Key Laboratory of Population Health and Aristogenics, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
| | - Daoxu Zhang
- State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 MeiLong Road, Shanghai 200237, China
| | - Yanyan Wei
- Department of Infectious Disease, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Chunyu Guo
- Department of Toxicology, School of Public Health, and Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
| | - Bingdong Song
- Department of Toxicology, School of Public Health, and Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
| | - Yingying Cui
- Department of Toxicology, School of Public Health, and Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
| | - Cheng Zhang
- Department of Toxicology, School of Public Health, and Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
| | - Dexiang Xu
- Department of Toxicology, School of Public Health, and Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China
| | - Shichen Zhang
- School of Public Health and Health Management, Anhui Medical College, No 632 Furong Road, Hefei 230601, China; MOE Key Laboratory of Population Health Across Life Cycle, No 81 Meishan Road, Hefei 230032, China.
| | - Jun Fang
- Department of Toxicology, School of Public Health, and Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, Anhui Medical University, No 81 Meishan Road, Hefei 230032, China; MOE Key Laboratory of Population Health Across Life Cycle, No 81 Meishan Road, Hefei 230032, China; Faculty of Pharmaceutical Science, Sojo University, Ikeda 4-22-1, Kumamoto 860-0082, Japan.
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12
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Muacevic A, Adler JR, Coombes K, Moin K, Joseph BM, Funk CM. Remdesivir-Associated Acute Liver Failure in a COVID-19 Patient: A Case Report and Literature Review. Cureus 2023; 15:e34221. [PMID: 36852363 PMCID: PMC9960027 DOI: 10.7759/cureus.34221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2023] [Indexed: 01/27/2023] Open
Abstract
There is a broad classification of the causes of acute liver failure (ALF) that include drug-induced liver injury (DILI). In this report, we aim to discuss the association between remdesivir, a novel therapeutic drug for hypoxic coronavirus disease 2019 (COVID-19) pneumonia, and DILI with subsequent ALF in a patient who was recently treated with the drug in question. Remdesivir, which is a direct-acting nucleoside RNA polymerase inhibitor, is one of the only FDA-approved drugs on the market for COVID-19 pneumonia associated with hypoxia. Our case describes a patient with an extensive past medical history who was treated for COVID-19 pneumonia with remdesivir and subsequently developed ALF in the absence of all other possible etiologies. This association has only been highlighted in anecdotal case reports in the past and to a lesser degree in the safety documentation of remdesivir.
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13
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Liu Y, Xue Y, Zhang Z, Ji J, Li C, Zheng K, Lu J, Gao Y, Gong Y, Zhang Y, Shi X. Wolfberry enhanced the abundance of Akkermansia muciniphila by YAP1 in mice with acetaminophen-induced liver injury. FASEB J 2023; 37:e22689. [PMID: 36468767 DOI: 10.1096/fj.202200945r] [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: 06/17/2022] [Revised: 10/18/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022]
Abstract
Drug-induced liver injury (DILI) by acetaminophen (APAP) was one of the most challenging liver diseases. Wolfberry (Lycium barbarum L.), a traditional Chinese medicinal material and food supplement, has a potential effect on increasing the abundance of Akkermansia muciniphila (A. muciniphila) in mice colons. However, the effect and mechanism of wolfberry remain unclear in APAP-induced DILI. In this study, wolfberry promoted the proliferation of activated-A. muciniphila in vitro and in vivo. For the first time, we detected that the activated-A. muciniphila but not the killed-A. muciniphila increased the expression level of Yes-associated protein 1 (YAP1) in the liver and alleviated liver injury in APAP-induced DILI mice. Mechanically, A. muciniphila improved the intestinal mucosal barrier and reduced lipopolysaccharide (LPS) content in the liver, leading to the increased expression level of YAP1. Furthermore, wolfberry increased the A. muciniphila abundance in the colon and YAP1 expression in the liver from APAP-induced DILI mice, which promoted the recovery of APAP-induced liver injury. Meanwhile, wolfberry combination with A. muciniphila synergistically increased AKK abundance and YAP1 expression in the liver. Our research provides an innovative strategy to improve DILI.
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Affiliation(s)
- Yiwei Liu
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Yu Xue
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Zhiqin Zhang
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Jingmin Ji
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Caige Li
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Kangning Zheng
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Junlan Lu
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Yuting Gao
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Yi Gong
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Yuman Zhang
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Xinli Shi
- Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China
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14
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Zhou Y, Li Z, Xu M, Zhang D, Ling J, Yu P, Shen Y. O-GlycNacylation Remission Retards the Progression of Non-Alcoholic Fatty Liver Disease. Cells 2022; 11:cells11223637. [PMID: 36429065 PMCID: PMC9688300 DOI: 10.3390/cells11223637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/04/2022] [Accepted: 11/10/2022] [Indexed: 11/18/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease spectrum associated with insulin resistance (IR), from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). O-GlcNAcylation is a posttranslational modification, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Abnormal O-GlcNAcylation plays a key role in IR, fat deposition, inflammatory injury, fibrosis, and tumorigenesis. However, the specific mechanisms and clinical treatments of O-GlcNAcylation and NAFLD are yet to be elucidated. The modification contributes to understanding the pathogenesis and development of NAFLD, thus clarifying the protective effect of O-GlcNAcylation inhibition on liver injury. In this review, the crucial role of O-GlcNAcylation in NAFLD (from NAFL to HCC) is discussed, and the effect of therapeutics on O-GlcNAcylation and its potential mechanisms on NAFLD have been highlighted. These inferences present novel insights into the pathogenesis and treatments of NAFLD.
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Affiliation(s)
- Yicheng Zhou
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Zhangwang Li
- The Second Clinical Medical College of Nanchang University, Nanchang 330031, China
| | - Minxuan Xu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Deju Zhang
- Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Jitao Ling
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Peng Yu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
- Correspondence: (P.Y.); (Y.S.)
| | - Yunfeng Shen
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
- Correspondence: (P.Y.); (Y.S.)
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15
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Hefler J, Hatami S, Thiesen A, Olafson C, Durand K, Acker J, Karvellas CJ, Bigam DL, Freed DH, Shapiro AMJ. Model of Acute Liver Failure in an Isolated Perfused Porcine Liver-Challenges and Lessons Learned. Biomedicines 2022; 10:biomedicines10102496. [PMID: 36289758 PMCID: PMC9598959 DOI: 10.3390/biomedicines10102496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/29/2022] [Accepted: 10/02/2022] [Indexed: 11/16/2022] Open
Abstract
Acute liver failure (ALF) is a rare but devastating disease associated with substantial morbidity and a mortality rate of almost 45%. Medical treatments, apart from supportive care, are limited and liver transplantation may be the only rescue option. Large animal models, which most closely represent human disease, can be logistically and technically cumbersome, expensive and pose ethical challenges. The development of isolated organ perfusion technologies, originally intended for preservation before transplantation, offers a new platform for experimental models of liver disease, such as ALF. In this study, female domestic swine underwent hepatectomy, followed by perfusion of the isolated liver on a normothermic machine perfusion device. Five control livers were perfused for 24 h at 37 °C, while receiving supplemental oxygen and nutrition. Six livers received toxic doses of acetaminophen given over 12 h, titrated to methemoglobin levels. Perfusate was sampled every 4 h for measurement of biochemical markers of injury (e.g., aspartate aminotransferase [AST], alanine aminotransferase [ALT]). Liver biopsies were taken at the beginning, middle, and end of perfusion for histological assessment. Acetaminophen-treated livers received a median dose of 8.93 g (8.21–9.75 g) of acetaminophen, achieving a peak acetaminophen level of 3780 µmol/L (3189–3913 µmol/L). Peak values of ALT (76 vs. 105 U/L; p = 0.429) and AST (3576 vs. 4712 U/L; p = 0.429) were not significantly different between groups. However, by the end of perfusion, histology scores were significantly worse in the acetaminophen treated group (p = 0.016). All acetaminophen treated livers developed significant methemoglobinemia, with a peak methemoglobin level of 19.3%, compared to 2.0% for control livers (p = 0.004). The development of a model of ALF in the ex vivo setting was confounded by the development of toxic methemoglobinemia. Further attempts using alternative agents or dosing strategies may be warranted to explore this setting as a model of liver disease.
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Affiliation(s)
- Joshua Hefler
- Division of General Surgery, Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Sanaz Hatami
- Department of Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Canadian Donation & Transplantation Research Program, Edmonton, AB T6G 2R3, Canada
| | - Aducio Thiesen
- Department of Laboratory Medicine & Pathology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Carly Olafson
- Department of Laboratory Medicine & Pathology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Canadian Blood Services, Edmonton, AB T6G 2R3, Canada
| | - Kiarra Durand
- Department of Laboratory Medicine & Pathology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Canadian Blood Services, Edmonton, AB T6G 2R3, Canada
| | - Jason Acker
- Department of Laboratory Medicine & Pathology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Canadian Blood Services, Edmonton, AB T6G 2R3, Canada
| | - Constantine J. Karvellas
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Department of Critical Care Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - David L. Bigam
- Division of General Surgery, Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Darren H. Freed
- Canadian Donation & Transplantation Research Program, Edmonton, AB T6G 2R3, Canada
- Division of Cardiac Surgery, Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
| | - Andrew Mark James Shapiro
- Division of General Surgery, Department of Surgery, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Canadian Donation & Transplantation Research Program, Edmonton, AB T6G 2R3, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB T6G 2R3, Canada
- Correspondence:
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16
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Saraf N, Dhampalwar S, Kute V, Bansal SB. Expert Group Opinion for Diagnosis and Management Viral Hepatitis in Solid Organ Transplant Recipients in South Asia. INDIAN JOURNAL OF TRANSPLANTATION 2022; 16:S77-S81. [DOI: 10.4103/ijot.ijot_89_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/18/2023] Open
Abstract
Viral hepatitis is endemic in the South Asia region and is mainly caused by four hepatotropic viruses: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis E virus (HEV). South Asia region consists of developing countries and HAV and HEV infections are common because of poor sanitary conditions and hygiene practices. HAV and HEV are transmitted person-to-person by fecal[FIGURE DASH]oral route. HBV and HCV are transmitted via permucosal or percutaneous exposure. It is important to know the impact of these viral infections in the setting of transplantation including evaluation and management in pre, peri, and posttransplant periods. This review summarizes the epidemiology, preventive practices, and advisory for travelers to these endemic regions. Furthermore, recommendations for screening donors and recipients in transplant settings are discussed.
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17
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Hilscher MB. Neutrophil Extracellular Traps Enhance Liver Inflammation and Fibrin Deposition in Fulminant Viral Hepatitis. Cell Mol Gastroenterol Hepatol 2022; 14:1172-1173. [PMID: 36084749 PMCID: PMC9606834 DOI: 10.1016/j.jcmgh.2022.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 08/23/2022] [Accepted: 08/23/2022] [Indexed: 01/31/2023]
Affiliation(s)
- Moira B. Hilscher
- Correspondence Address correspondence to: Moira Hilscher, MD, Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 914 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104.
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18
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RIPK1 in Liver Parenchymal Cells Limits Murine Hepatitis during Acute CCl4-Induced Liver Injury. Int J Mol Sci 2022; 23:ijms23137367. [PMID: 35806372 PMCID: PMC9266426 DOI: 10.3390/ijms23137367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 06/28/2022] [Accepted: 06/29/2022] [Indexed: 12/10/2022] Open
Abstract
Some life-threatening acute hepatitis originates from drug-induced liver injury (DILI). Carbon tetrachloride (CCl4)-induced acute liver injury in mice is the widely used model of choice to study acute DILI, which pathogenesis involves a complex interplay of oxidative stress, necrosis, and apoptosis. Since the receptor interacting protein kinase-1 (RIPK1) is able to direct cell fate towards survival or death, it may potentially affect the pathological process of xenobiotic-induced liver damage. Two different mouse lines, either deficient for Ripk1 specifically in liver parenchymal cells (Ripk1LPC-KO) or for the kinase activity of RIPK1 (Ripk1K45A, kinase dead), plus their respective wild-type littermates (Ripk1fl/fl, Ripk1wt/wt), were exposed to single toxic doses of CCl4. This exposure led in similar injury in Ripk1K45A mice and their littermate controls. However, Ripk1LPC-KO mice developed more severe symptoms with massive hepatocyte apoptosis as compared to their littermate controls. A pretreatment with a TNF-α receptor decoy exacerbated liver apoptosis in both Ripk1fl/fl and Ripk1LPC-KO mice. Besides, a FasL antagonist promoted hepatocyte apoptosis in Ripk1fl/fl mice but reduced it in Ripk1LPC-KO mice. Thus, the scaffolding properties of RIPK1 protect hepatocytes from apoptosis during CCl4 intoxication. TNF-α and FasL emerged as factors promoting hepatocyte survival. These protective effects appeared to be independent of RIPK1, at least in part, for TNF-α, but dependent on RIPK1 for FasL. These new data complete the deciphering of the molecular mechanisms involved in DILI in the context of research on their prevention or cure.
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19
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Xu L, Chen W, Chen J, Jin Y, Ma W, Qi G, Sun X, Luo J, Li C, Zhao K, Zheng Y, Yu D. PIWI-interacting RNA-23210 protects against acetaminophen-induced liver injury by targeting HNF1A and HNF4A. Biochem Pharmacol 2021; 197:114897. [PMID: 34968487 DOI: 10.1016/j.bcp.2021.114897] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 11/19/2022]
Abstract
Acetaminophen (APAP) overdose is one of the leading causes of acute liver failure in the US and other developed countries, the molecular mechanisms of APAP-induced hepatotoxicity remain speculative. PIWI-interacting RNAs (piRNAs), a novel class of small non-coding RNAs, have been identified as epigenetic regulators of transposon silencing, mRNA deadenylation, and elimination. However, the functional role of piRNAs in APAP-induced liver injury remains unclear. In the current study, the piRNA profiles were constructed in HepaRG cells after APAP exposure, and the roles of piR-23210 in regulating nuclear receptors (NRs) expression, metabolizing enzymes expression, and consequently APAP-induced liver injury were systematically investigated. As a result, 57 upregulated piRNAs were identified after APAP exposure, indicating the stress-response characteristic of piRNA molecules. Subsequent in vitro and in vivo experiments proved that piR-23210 is a novel self-protective molecule that targets HNF1A and HNF4A transcripts by interacting with RNA binding protein Nucleolin (NCL), suppresses downstream CYPs (CYP2E1, CYP3A4, and CYP1A2) expression, and protects against APAP-induced liver injury. In conclusion, our findings provided new mechanistic clues revealing potential protective role of a piRNA against the hepatoxicity of APAP.
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Affiliation(s)
- Lin Xu
- School of Public Health, Qingdao University, Qingdao, China
| | - Wendi Chen
- School of Public Health, Qingdao University, Qingdao, China
| | - Jing Chen
- School of Public Health, Qingdao University, Qingdao, China
| | - Yuan Jin
- School of Public Health, Qingdao University, Qingdao, China
| | - Wanli Ma
- School of Public Health, Qingdao University, Qingdao, China
| | - Guangshuai Qi
- School of Public Health, Qingdao University, Qingdao, China
| | - Xueying Sun
- School of Public Health, Qingdao University, Qingdao, China
| | - Jiao Luo
- School of Public Health, Qingdao University, Qingdao, China
| | - Chuanhai Li
- School of Public Health, Qingdao University, Qingdao, China
| | - Kunming Zhao
- School of Public Health, Qingdao University, Qingdao, China
| | - Yuxin Zheng
- School of Public Health, Qingdao University, Qingdao, China
| | - Dianke Yu
- School of Public Health, Qingdao University, Qingdao, China.
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20
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Clemens MM, Kennon-McGill S, Vazquez JH, Stephens OW, Peterson EA, Johann DJ, Allard FD, Yee EU, McCullough SS, James LP, Finck BN, McGill MR. Exogenous phosphatidic acid reduces acetaminophen-induced liver injury in mice by activating hepatic interleukin-6 signaling through inter-organ crosstalk. Acta Pharm Sin B 2021; 11:3836-3846. [PMID: 35024310 PMCID: PMC8727922 DOI: 10.1016/j.apsb.2021.08.024] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/26/2021] [Accepted: 08/17/2021] [Indexed: 12/11/2022] Open
Abstract
We previously demonstrated that endogenous phosphatidic acid (PA) promotes liver regeneration after acetaminophen (APAP) hepatotoxicity. Here, we hypothesized that exogenous PA is also beneficial. To test that, we treated mice with a toxic APAP dose at 0 h, followed by PA or vehicle (Veh) post-treatment. We then collected blood and liver at 6, 24, and 52 h. Post-treatment with PA 2 h after APAP protected against liver injury at 6 h, and the combination of PA and N-acetyl-l-cysteine (NAC) reduced injury more than NAC alone. Interestingly, PA did not affect canonical mechanisms of APAP toxicity. Instead, transcriptomics revealed that PA activated interleukin-6 (IL-6) signaling in the liver. Consistent with that, serum IL-6 and hepatic signal transducer and activator of transcription 3 (Stat3) phosphorylation increased in PA-treated mice. Furthermore, PA failed to protect against APAP in IL-6-deficient animals. Interestingly, IL-6 expression increased 18-fold in adipose tissue after PA, indicating that adipose is a source of PA-induced circulating IL-6. Surprisingly, however, exogenous PA did not alter regeneration, despite the importance of endogenous PA in liver repair, possibly due to its short half-life. These data demonstrate that exogenous PA is also beneficial in APAP toxicity and reinforce the protective effects of IL-6 in this model.
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21
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Abstract
This article reviews the incidence of acute hepatitis B virus (HBV) infection, its clinical course, strategies to prevent acute HBV infection in susceptible individuals, and the management of patients with acute HBV.
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Affiliation(s)
- Simone E Dekker
- Department of Medicine, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
| | - Ellen W Green
- Department of Medicine, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA
| | - Joseph Ahn
- Division of Gastroenterology and Hepatology, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, MNP 4112, Portland, OR 97239, USA.
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22
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Geczo A, Giannakoudakis DA, Triantafyllidis K, Elshaer MR, Rodríguez-Aguado E, Bashkova S. Mechanistic insights into acetaminophen removal on cashew nut shell biomass-derived activated carbons. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:58969-58982. [PMID: 31925698 DOI: 10.1007/s11356-019-07562-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 12/29/2019] [Indexed: 05/20/2023]
Abstract
Activated carbons prepared from cashew nut shells by chemical activation with phosphoric acid were tested for the removal of acetaminophen. It was found that an increase in carbonization temperature resulted in increased pore volume and decreased amount of surface functional groups. Potentiometric titration analysis indicated that the majority of surface groups on carbons are acidic. Detailed surface characterization by FT-IR, XPS, and thermal analyses indicated the involvement of surface functional groups in the removal of acetaminophen either via hydrogen bonding or by acid hydrolysis. The carbon obtained at 600 °C, which contains high amount of carboxylic groups and high pore volume, exhibited the highest adsorption capacity. For this carbon, the removal of acetaminophen took place mostly via acid hydrolysis with the formation of p-aminophenol and acetic acid adsorbed on the surface. Carbon obtained at 400 °C was found to have the highest density of acidic functional groups, which resulted in dimerization reactions and pore blockage. No direct correlation was observed between the adsorption capacities of carbons and their textural or surface characteristics. This suggests the complexity of acetaminophen removal by the cashew nut shell-derived activated carbons, governed by their surface chemistry and supported by high surface area accessible via micro/mesopores.
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Affiliation(s)
- Alexandra Geczo
- Department of Chemistry and Biochemistry, Fairleigh Dickinson University, Madison, NJ, 07940, USA
| | | | | | - Mohammed Ragab Elshaer
- Department of Chemistry and Biochemistry, Fairleigh Dickinson University, Madison, NJ, 07940, USA
| | - Elena Rodríguez-Aguado
- Departamento de Química Inorgánica, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071, Málaga, Spain
| | - Svetlana Bashkova
- Department of Chemistry and Biochemistry, Fairleigh Dickinson University, Madison, NJ, 07940, USA.
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23
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Cheng X, Zhu JL, Li Y, Luo WW, Xiang HR, Zhang QZ, Peng WX. Serum biomarkers of isoniazid-induced liver injury: Aminotransferases are insufficient, and OPN, L-FABP and HMGB1 can be promising novel biomarkers. J Appl Toxicol 2021; 42:516-528. [PMID: 34494278 DOI: 10.1002/jat.4236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/24/2021] [Accepted: 08/26/2021] [Indexed: 11/06/2022]
Abstract
Isoniazid (INH)-induced liver injury is a great challenge for tuberculosis treatment. Existing biomarkers cannot accurately determine the occurrence of this injury in the early stage. Therefore, developing early specific sensitive biomarkers of INH-induced liver injury is urgent. A rat model of liver injury was established with gastric infusion of INH or INH plus rifampicin (RFP). We examined seven potential novel serum biomarkers, namely, glutamate dehydrogenase (GLDH), liver-fatty acid-binding protein (L-FABP), high-mobility group box-1 (HMGB1), macrophage colony-stimulating factor receptor (MCSF1R), osteopontin (OPN), total cytokeratin 18 (K18), and caspase-cleaved cytokeratin-18 (ccK18), to evaluate their sensitivity and specificity on INH-induced liver injury. With the increase of drug dosage, combining with RFP and prolonging duration of administration, the liver injury was aggravated, showing as decreased weight of the rats, upgraded liver index and oxidative stress level, and histopathological changes of liver becoming marked. But the activity of serum aminotransferases decreased significantly. The area under the curve (AUC) of receiver-operating characteristic (ROC) curve of OPN, L-FABP, HMGB1, MCSF1R, and GLDH was 0.88, 0.87, 0.85, 0.71, and 0.70 (≥0.7), respectively, and 95% confidence interval of them did not include 0.5, with statistical significance, indicating their potential abilities to become biomarkers of INH-induced liver injury. In conclusion, we found traditional biomarkers ALT and AST were insufficient to discover the INH-induced liver injury accurately and OPN, L-FABP, and HMGB1 can be promising novel biomarkers.
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Affiliation(s)
- Xuan Cheng
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Jia-Lian Zhu
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yun Li
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Wen-Wen Luo
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Huai-Rong Xiang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Qi-Zhi Zhang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Wen-Xing Peng
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
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Chávez SM, Poniachik JM, Urzua ÁM, Roblero JP, Cattaneo MJ, Jimenez AP, Carreño LE, Cornejo RA. Acute liver failure due to herpes simplex virus: diagnostic clues and potential role of plasmapheresis: A case report. Medicine (Baltimore) 2021; 100:e27139. [PMID: 34477166 PMCID: PMC8416005 DOI: 10.1097/md.0000000000027139] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 08/03/2021] [Accepted: 08/18/2021] [Indexed: 01/05/2023] Open
Abstract
INTRODUCTION Acute liver failure (ALF) is a life-threatening condition that remains challenging for physicians despite several advances in supportive care. Etiologies vary worldwide, with herpes simplex virus (HSV) hepatitis representing less than 1% of cases. Despite its low incidence, ALF is a lethal cause of acute necrotizing hepatitis and has a high mortality. Early antiviral treatment is beneficial for survival and decreased liver transplantation necessity. However, plasmapheresis, despite its theoretical potential benefit, is scarcely reported. PATIENT CONCERNS A 25-year-old woman with no known disease presented with painful pharynx ulcers, increased transaminases and impaired liver function. DIAGNOSIS ALF due to a disseminated HSV-2 primary infection was diagnosed with a positive polymerase chain reaction for HSV-2 in the biopsied liver tissue and blood. INTERVENTIONS Empiric antiviral treatment was initiated. After clinical deterioration, plasmapheresis was also initiated. OUTCOMES After 6 cycles of plasmapheresis and supportive care, the patient's condition improved without undergoing liver transplantation. CONCLUSIONS ALF is a life-threatening condition, and HSV as an etiology must be suspected based on background, clinical manifestation, and laboratory information. The potential role of plasmapheresis in HSV hepatitis should be considered.
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Affiliation(s)
- Sebastián M. Chávez
- Unidad de Pacientes Críticos, Departamento de Medicina, Hospital Clínico Universidad de Chile. Santiago, Chile
| | - Jaime M. Poniachik
- Sección Gastroenterología, Departamento de Medicina, Hospital Clínico Universidad de Chile. Santiago, Chile
| | - Álvaro M. Urzua
- Sección Gastroenterología, Departamento de Medicina, Hospital Clínico Universidad de Chile. Santiago, Chile
| | - Juan P. Roblero
- Sección Gastroenterología, Departamento de Medicina, Hospital Clínico Universidad de Chile. Santiago, Chile
| | - Máximo J. Cattaneo
- Sección Gastroenterología, Departamento de Medicina, Hospital Clínico Universidad de Chile. Santiago, Chile
| | - Andrea P. Jimenez
- Sección Gastroenterología, Departamento de Medicina, Hospital Clínico Universidad de Chile. Santiago, Chile
| | - Laura E. Carreño
- Departamento de Anatomía patológica, Hospital Clínico Universidad de Chile. Santiago, Chile
| | - Rodrigo A. Cornejo
- Unidad de Pacientes Críticos, Departamento de Medicina, Hospital Clínico Universidad de Chile. Santiago, Chile
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Reznik EV, Yudin DV, Gudilova YY, Baikova IE, Karmanova SE, Nikitin IG. A medicinal liver injury with an immunomodulatory drug of natural origin. Case report. TERAPEVT ARKH 2021; 93:932-935. [PMID: 36286888 DOI: 10.26442/00403660.2021.08.200975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 09/04/2021] [Indexed: 11/22/2022]
Abstract
As practice shows, there are many alternative drugs that cause drug damage to the liver. A case of medicinal damage to the liver with an immunomodulatory herbal preparation Immunostimulating collection, which included St. John's wort, Elecampane, Kopeichnik, Echinacea, Licorice, Rosehip, is presented. A 39-year-old patient came to the clinic with complaints of yellowing of the skin, whites of the eyes, heaviness in the epigastrium after eating, lightening of feces, dark urine, sour taste in the mouth, bloating, pruritus, decreased appetite, pronounced general weakness, drowsiness 10 days after you start taking herbal immunostimulant. The diagnosis of drug damage to the liver was made taking into account the history and laboratory parameters, since the patient had negative markers of viral hepatitis and increasing of biochemical blood tests: alanine transferase up to 2800 U/l (norm up to 32 U/L), aspartate transferase up to 1776 U/l (norm up to 31 U/l), total bilirubin up to 577 U/l (norm up to 21 U/l), direct bilirubin up to 116 U/l (norm up to 4.3 U/l), alkaline phosphatase up to 112 U/l (norm up to 98 U/l). After the withdrawal of the immunomodulator and the appointment of therapy, including diet, enzyme replacement therapy, drugs clinical and laboratory manifestations of liver drug damage completely disappeared. This confirms the leading role of the immunoactive drug, which the patient took in the toxic effect on the liver.
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Kamal T, Haboubi N. Epstein-Barr virus and acute liver failure: an exceedingly rare amalgamation. J R Coll Physicians Edinb 2021; 51:46-48. [PMID: 33877134 DOI: 10.4997/jrcpe.2021.111] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Epstein-Barr virus (EBV) associated acute liver failure (ALF) is an exceedingly uncommon event. Despite this, EBV-associated ALF has a very high fatality rate. When looking at the number of reported cases of EBV-associated ALF requiring an emergency liver transplant, we see even fewer numbers. This presents challenges to clinicians in the diagnosis, awareness and appropriate case management. There is limited information in the medical literature about the hepatic demonstration and complications of EBV. We therefore report a case of EBV-associated ALF in a 17-year-old immunocompetent female who was treated successfully with an orthotopic liver transplantation.
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Affiliation(s)
- Tom Kamal
- Nevill Hall Hospital, Abergavenny NP7 7EG, Wales, UK,
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Wang Q, Liu S, Wang H, Liu L, Zhang S, Ming Y, Zhao Y, Cheng K. Silencing long noncoding RNA NEAT1 alleviates acute liver failure via the EZH2-mediated microRNA-139/PUMA axis. Aging (Albany NY) 2021; 13:12537-12551. [PMID: 33901015 PMCID: PMC8148447 DOI: 10.18632/aging.202927] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 07/30/2020] [Indexed: 12/17/2022]
Abstract
This study aimed to investigate the role of long noncoding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) in the development of ALF. We collected blood samples from patients with acute liver failure (ALF) and established an ALF mouse model induced by D-galactosamine/Lipopolysaccharide (D-GalN/LPS) for in vivo studies. Peripheral blood mononuclear cells (PMBCs) induced with LPS were isolated for in vitro experiments. Survival tests, histological analysis, and biochemical indicator assays were conducted. Luciferase assay was performed to determine the binding affinity between microRNA-139 (miR-139) and p53-upregulated modulator of apoptosis (PUMA). Expression of lncRNA NEAT1, enhancer of zeste homolog 2 (EZH2), and PUMA was upregulated, while the expression of miR-139 was downregulated in clinical samples and D-GalN/LPS induced ALF mouse model. LncRNA NEAT1 promoted the enrichment of H3K27me3 on the promoter region of miR-139 via EZH2, which led to suppression of miR-139. The inhibition of miR-139 resulted in the upregulation of its downstream target PUMA. The NEAT1/miR-139/PUMA pathway upregulated the production of pro-inflammatory cytokines, tumor necrosis factor alpha, interleukin (IL)-6, and IL-1β, thereby mediating the progression of ALF. In conclusion, silencing lncRNA NEAT1 upregulated the expression of miR-139 through EZH2, leading to the downregulation of PUMA, which alleviated the development of ALF.
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Affiliation(s)
- Qiang Wang
- Transplantation Center, The Third Xiangya Hospital of Central South University, Changsha 410013, P.R. China
| | - Shu Liu
- Transplantation Center, The Third Xiangya Hospital of Central South University, Changsha 410013, P.R. China
| | - Huan Wang
- Transplantation Center, The Third Xiangya Hospital of Central South University, Changsha 410013, P.R. China
| | - Lian Liu
- Transplantation Center, The Third Xiangya Hospital of Central South University, Changsha 410013, P.R. China
| | - Sheng Zhang
- Transplantation Center, The Third Xiangya Hospital of Central South University, Changsha 410013, P.R. China
| | - Yingzi Ming
- Transplantation Center, The Third Xiangya Hospital of Central South University, Changsha 410013, P.R. China
| | - Yujun Zhao
- Transplantation Center, The Third Xiangya Hospital of Central South University, Changsha 410013, P.R. China
| | - Ke Cheng
- Transplantation Center, The Third Xiangya Hospital of Central South University, Changsha 410013, P.R. China
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28
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Kim JE, Chun S, Sinn DH, Kim NJ, Kim S, Kang W, Kim JM, Choi GS, Joh JW, Cho D. Initial experience with high-volume plasma exchange in patients with acute liver failure. J Clin Apher 2021; 36:379-389. [PMID: 33400840 DOI: 10.1002/jca.21873] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 12/24/2020] [Accepted: 12/27/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND/AIMS High-volume plasma exchange (HVPE), defined as an exchange of 8 to 12 L per day per procedure or 15% of the ideal body weight with fresh frozen plasma, has shown promising results in improving the survival of patients with acute liver failure (ALF). However, clinical evidence is limited. The aim of this study was to report our initial experience using HVPE as a bridge treatment in patients with ALF. METHODS We retrospectively reviewed 32 consecutive patients awaiting liver transplantation (LT) due to ALF between 2013 and 2020 at Samsung Medical Center in Korea. HVPE has been used for patients with ALF since May 2016 at our institution. RESULTS During the study period, 16 patients received HVPE. After HVPE, coagulopathies (INR, 4.46 [2.32-6.02] vs 1.48 [1.33-1.76], P < .05), total bilirubin (22.6 [9.1-26.4] vs 8.9 [5.6-11.3], P < .05), alanine aminotransferase (506 [341-1963] vs 120 [88-315], P < .05), and ammonia levels (130.6 [123.7-143.8] vs 98.2 [84.2-116.5], P < .05) were improved. Improvement in the hepatic encephalopathy grade was observed in four patients. Among 16 patients who received HVPE, 12 patients were bridged to LT, and three patients recovered spontaneously. The overall survival was 94% and 69%, respectively at 30 days in patients who received and did not receive HVPE (P = .068). Among 18 patients with high chronic liver failure-sequential organ failure assessment scores (≥13), the overall survival was significantly better for those who received HVPE than for those who did not (91% vs 29%, respectively, at 30 days, P < .05). CONCLUSIONS Our initial clinical experience with HVPE suggests that HVPE can be a viable option in improving the outcomes of patients presenting with ALF.
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Affiliation(s)
- Ji Eun Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Sejong Chun
- Department of Laboratory Medicine, Chonnam National University Medical School & Hospital, Gwangju, South Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | | | - Semi Kim
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Wonseok Kang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Gyu-Seong Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Duck Cho
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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29
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Krishnamoorthy S, Gayathri P, Chandra S, K Pillai MG, Menon R, Iyer S. Prognostic markers in acute liver failure - Alpha feto protein. ARCHIVES OF MEDICINE AND HEALTH SCIENCES 2021. [DOI: 10.4103/amhs.amhs_14_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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30
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Zhang P, Chen S, Tang H, Fang W, Chen K, Chen X. CoQ10 protects against acetaminophen-induced liver injury by enhancing mitophagy. Toxicol Appl Pharmacol 2020; 410:115355. [PMID: 33271250 DOI: 10.1016/j.taap.2020.115355] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/11/2020] [Accepted: 11/26/2020] [Indexed: 12/24/2022]
Abstract
Coenzyme Q10 (CoQ10), which is a key cofactor of the electron transport chain in the mitochondria has shown many beneficial effects on liver diseases. However, the mechanisms of CoQ10 protective role on the acetaminophen (APAP)-induced liver injury are elusive and unclear. In this study, we further investigated the CoQ10 therapeutic effects on APAP-overdose liver injury. C57BL/6 J mice were intraperitoneally treated with APAP to induce liver injury. CoQ10 (5 mg/kg) was given to mice at 1.5 h after APAP treatment. The results showed that hepatic CoQ10 levels were decreased during the APAP-induced hepatotoxicity and preceded serum ALT elevation. Treatment of CoQ10 significantly improved the liver injury induced by APAP. Moreover, CoQ10 treatment decreased the ROS levels and promoted the antioxidative related gene expression in APAP overdose mice. Importantly, results showed that even though CoQ10 had no effects on the mtDNA copy number and the expression of genes related to mitochondrial biogenesis, it significantly improved the mitochondrial complex I and V activities and promoted the mitophagy in APAP-overdose mice. To further authenticate mitophagy role in CoQ10-mediated improved liver injury in vivo, we administrated APAP-overdose mice with chloroquine 1 h prior to APAP treatment and found that chloroquine treatment functionally abrogated the CoQ10 protective role on APAP overdose mice. To conclude, this study provides evidence that CoQ10 activates mitophagy to protect against APAP-induced liver injury. Therefore, CoQ10 may represent a novel therapeutic option for the prevention and treatment of drug-induced liver injury.
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Affiliation(s)
- Peiwen Zhang
- Department of Nutrition, School of Public Health, Guangdong Medical University, People's Republic of China; School of Public Health, Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, People's Republic of China
| | - Shen Chen
- Department of Nutrition, School of Public Health, Guangdong Medical University, People's Republic of China; Department of Toxicology, School of Public Health, Sun Yat-sen University, People's Republic of China
| | - Huanwen Tang
- School of Public Health, Dongguan Key Laboratory of Environmental Medicine, Guangdong Medical University, People's Republic of China
| | - Wanjun Fang
- Department of Clinical Nutrition, Ningbo Women and Children's Hospital, Ningbo, People's Republic of China
| | - Ke Chen
- Department of Clinical Nutrition, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, People's Republic of China; Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Xu Chen
- Department of Nutrition, School of Public Health, Guangdong Medical University, People's Republic of China; Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China.
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31
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Ishitsuka Y, Kondo Y, Kadowaki D. Toxicological Property of Acetaminophen: The Dark Side of a Safe Antipyretic/Analgesic Drug? Biol Pharm Bull 2020; 43:195-206. [PMID: 32009106 DOI: 10.1248/bpb.b19-00722] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) is the most popular analgesic/antipyretic agent in the world. APAP has been regarded as a safer drug compared with non-steroidal anti-inflammatory drugs (NSAIDs) particularly in terms of lower risks of renal dysfunction, gastrointestinal injury, and asthma/bronchospasm induction, even in high-risk patients such as the elderly, children, and pregnant women. On the other hand, the recent increasing use of APAP has raised concerns about its toxicity. In this article, we review recent pharmacological and toxicological findings about APAP from basic, clinical, and epidemiological studies, including spontaneous drug adverse events reporting system, especially focusing on drug-induced asthma and pre-and post-natal closure of ductus arteriosus. Hepatotoxicity is the greatest fault of APAP and the most frequent cause of drug-induced acute liver failure in Western countries. However, its precise mechanism remains unclear and no effective cure beyond N-acetylcysteine has been developed. Recent animal and cellular studies have demonstrated that some cellular events, such as c-jun N-terminal kinase (JNK) pathway activation, endoplasmic reticulum (ER) stress, and mitochondrial oxidative stress may play important roles in the development of hepatitis. Herein, the molecular mechanisms of APAP hepatotoxicity are summarized. We also discuss the not-so-familiar "dark side" of APAP as an otherwise safe analgesic/antipyretic drug.
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Affiliation(s)
- Yoichi Ishitsuka
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
| | - Yuki Kondo
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
| | - Daisuke Kadowaki
- Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Sojo University
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32
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Saleh M, Taher M, Sohrabpour AA, Vaezi AA, Nasiri Toosi M, Kavianpour M, Ghazvinian Z, Abdolahi S, Verdi J. Perspective of placenta derived mesenchymal stem cells in acute liver failure. Cell Biosci 2020; 10:71. [PMID: 32483484 PMCID: PMC7245988 DOI: 10.1186/s13578-020-00433-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 05/16/2020] [Indexed: 02/07/2023] Open
Abstract
Acute Liver failure (ALF) is a life-threatening disease and is determined by coagulopathy (with INR ≥ 1.5) and hepatic encephalopathy as a result of severe liver injury in patients without preexisting liver disease. Since there are problems with liver transplantation including lack of donors, use of immunosuppressive drugs, and high costs of this process, new therapeutic approaches alongside current treatments are needed. The placenta is a tissue that is normally discarded after childbirth. On the other hand, human placenta is a rich source of mesenchymal stem cells (MSCs), which is easily available, without moral problems, and its derived cells are less affected by age and environmental factors. Therefore, placenta-derived mesenchymal stem cells (PD-MSCs) can be considered as an allogeneic source for liver disease. Considering the studies on MSCs and their effects on various diseases, it can be stated that MSCs are among the most important agents to be used for novel future therapies of liver diseases. In this paper, we will investigate the effects of mesenchymal stem cells through migration and immigration to the site of injury, cell-to-cell contact, immunomodulatory effects, and secretory factors in ALF.
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Affiliation(s)
- Mahshid Saleh
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taher
- 2Gastroenterology and Hepatology, Tehran University of Medical Sciences, Imam Hospital Complex, Tehran, Iran
| | - Amir Ali Sohrabpour
- 3Gastroenterology and Hepatology, School of Medicine Shariati Hospital, Tehran University of Medical Science, Tehran, Iran
| | - Amir Abbas Vaezi
- 4Department of Internal Medicine, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Mohsen Nasiri Toosi
- 5Internal Medicine, School of Medicine Liver Transplantation Research Center Imam, Khomeini Hospital Tehran University of Medical Sciences, Tehran, Iran
| | - Maria Kavianpour
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zeinab Ghazvinian
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahrokh Abdolahi
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Javad Verdi
- 1Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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33
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Bhushan B, Gunewardena S, Edwards G, Apte U. Comparison of liver regeneration after partial hepatectomy and acetaminophen-induced acute liver failure: A global picture based on transcriptome analysis. Food Chem Toxicol 2020; 139:111186. [PMID: 32045647 DOI: 10.1016/j.fct.2020.111186] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 02/05/2020] [Accepted: 02/06/2020] [Indexed: 12/19/2022]
Abstract
Liver regenerates following surgical removal and after drug-induced liver injury (DILI). However, most of the mechanisms of liver regeneration were identified using partial hepatectomy (PHX) model rather than using DILI models. We compared mechanisms of liver regeneration following PHX and after acetaminophen (APAP) overdose, a DILI model, using transcriptomic approach. Kinetics of hepatocyte proliferation and global gene expression profiles were studied in male C57BL/6J mice either subjected to PHX or following APAP overdose. Liver regeneration was much more synchronized after PHX as compared to APAP overdose. Transcriptomics analysis revealed activation of common upstream regulators in both models including growth factors HGF, EGF and VEGF; and cytokines IL6 and TNFα. However, magnitude of activation and temporality was significantly differed between the two models. HGF and VEGF showed similar activation between PHX and APAP but activation of EGF was significantly stronger in the APAP model. Activation of IL6 and TNFα transcriptional programs was delayed but remarkably higher in APAP. These dissimilarities could be attributed to inherent differences in the two models including significant injury and inflammation exclusively in the APAP model. This study highlights need to study mechanisms of liver regeneration after DILI separately from the mechanisms of regeneration PHX.
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Affiliation(s)
- Bharat Bhushan
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Genea Edwards
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
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Ren Y, Xu Y, Lee WM, Di Bisceglie AM, Fan X. In-depth serum virome analysis in patients with acute liver failure with indeterminate etiology. Arch Virol 2020; 165:127-135. [PMID: 31741097 PMCID: PMC6957702 DOI: 10.1007/s00705-019-04466-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 10/12/2019] [Indexed: 11/26/2022]
Abstract
In clinical virome research, whole-genome/transcriptome amplification is required when starting material is limited. An improved method, named "template-dependent multiple displacement amplification" (tdMDA), has recently been developed in our lab (Wang et al. in BioTechniques 63:21-25. https://doi.org/10.2144/000114566, 2017). In combination with Illumina sequencing and bioinformatics pipelines, its application in virome sequencing was explored using a serum sample from a patient with chronic hepatitis C virus (HCV) infection. In comparison to an amplification-free procedure, virome sequencing via tdMDA showed a 9.47-fold enrichment for HCV-mapped reads and, accordingly, an increase in HCV genome coverage from 28.5% to 70.1%. Eight serum samples from acute patients liver failure (ALF) with or without known etiology were then used for virome sequencing with an average depth at 94,913x. Both similarity-based (mapping, NCBI BLASTn, BLASTp, and profile hidden Markov model analysis) and similarity-independent methods (machine-learning algorithms) identified viruses from multiple families, including Herpesviridae, Picornaviridae, Myoviridae, and Anelloviridae. However, their commensal nature and cross-detection ruled out an etiological interpretation. Together with a lack of detection of novel viruses in a comprehensive analysis at a resolution of single reads, these data indicate that viral agents might be rare in ALF cases with indeterminate etiology.
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Affiliation(s)
- Yi Ren
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
- Wuhan Pulmonary Hospital, Wuhan, 430030, Hubei, China
| | - Yanjuan Xu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
| | - William M Lee
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Adrian M Di Bisceglie
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
- Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
| | - Xiaofeng Fan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
- Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
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35
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Li Q, Yang H, Wang W, Li N, Zou X, Li Y, Fan G, Zhang Y, Kuang T. Brassica rapa Polysaccharides Ameliorate CCl 4 -Induced Acute Liver Injury in Mice through Inhibiting Inflammatory Apoptotic Response and Oxidative Stress. Chem Biodivers 2019; 17:e1900534. [PMID: 31730730 DOI: 10.1002/cbdv.201900534] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 11/14/2019] [Indexed: 12/18/2022]
Abstract
Brassica rapa L., also called NIUMA, is used empirically in Tibetan medicine for its antioxidant, anti-inflammatory and antiradiation activities. This study explored the hepatoprotective effects of B. rapa polysaccharides (BRPs) on acute liver injury induced by carbon tetrachloride (CCl4 ) in mice and the underlying mechanisms. Mice were treated with CCl4 after the oral administration of BRPs (55, 110 and 220 mg/kg) or bifendate (100 mg/kg) for 7 days. Blood and liver samples of mice were collected for analysis after 24 h. The ALP, ALT and AST levels and the biological activities of SOD, MDA and GSH-Px were measured. Histopathological changes in the liver were determined through hematoxylin and eosin staining. Moreover, TNF-α, IL-1β and IL-6 expression levels were detected by commercial reagent kits. Finally, Western blot analysis was used to check the relative expression levels of caspase-3, p-JAK2 and p-STAT3. The BRP pre-treatment significantly decreased the enzymatic activities of ALT, ALP and AST in the serum, markedly increased the activities of SOD and GSH-Px in the liver and reduced the MDA concentration in the liver. BRPs alleviated hepatocyte injury and markedly inhibited the expression of TNF-α, IL-1β and IL-6, also downregulating the CCl4 -induced hepatic tissue expression of caspase-3. Furthermore, BRPs inhibited the JAK2/STAT3 signaling pathway in a dose-dependent manner in the liver. This study demonstrated that BRPs exert hepatoprotective effect against the CCl4 -induced liver injury via modulating the apoptotic and inflammatory responses and downregulating the JAK2/STAT3 signaling pathway. Therefore, B. rapa could be considered a hepatoprotective medicine.
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Affiliation(s)
- Qiuyue Li
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, P. R. China
| | - Hailing Yang
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, P. R. China
| | - Wenxiang Wang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, P. R. China
| | - Ning Li
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, P. R. China
| | - Xuemei Zou
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, P. R. China
| | - Yangxin Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, P. R. China
| | - Gang Fan
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, P. R. China
| | - Yi Zhang
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, P. R. China.,School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, P. R. China
| | - Tingting Kuang
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, P. R. China
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36
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Kwong S, Meyerson C, Zheng W, Kassardjian A, Stanzione N, Zhang K, Wang HL. Acute hepatitis and acute liver failure: Pathologic diagnosis and differential diagnosis. Semin Diagn Pathol 2019; 36:404-414. [PMID: 31405537 DOI: 10.1053/j.semdp.2019.07.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Acute hepatitis and acute liver failure are severe medical conditions that require early clinical intervention. Histopathologic findings on a liver biopsy or a liver explant may help identify the underlying etiology or provide an important direction for further clinical, laboratory and radiographical investigation. This review is divided into two main portions. The first portion concentrates on various etiologies and discusses unique histologic features that can be associated with specific etiologies. The second portion describes the general morphologic features based on which the diagnosis of acute hepatitis and acute liver failure are made. Histopathologic distinction between collapse and cirrhosis and limitations of histopathologic assessment for underlying etiologies are addressed in this portion. Another focus of this review is non-necrotic acute liver failure, which typically features diffuse microvesicular steatosis secondary to various etiologies causing mitochondrial dysfunction. Molecular testing serves an increasingly important role in the diagnosis and management of this group of disorders.
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Affiliation(s)
- Stanley Kwong
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095, United States.
| | - Cherise Meyerson
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095, United States
| | - Wei Zheng
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095, United States
| | - Ari Kassardjian
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095, United States
| | - Nicholas Stanzione
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095, United States
| | - Kuixing Zhang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095, United States
| | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095, United States.
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Khambu B, Yan S, Huda N, Yin XM. Role of High-Mobility Group Box-1 in Liver Pathogenesis. Int J Mol Sci 2019; 20:ijms20215314. [PMID: 31731454 PMCID: PMC6862281 DOI: 10.3390/ijms20215314] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 10/16/2019] [Accepted: 10/23/2019] [Indexed: 12/21/2022] Open
Abstract
High-mobility group box 1 (HMGB1) is a highly abundant DNA-binding protein that can relocate to the cytosol or undergo extracellular release during cellular stress or death. HMGB1 has a functional versatility depending on its cellular location. While intracellular HMGB1 is important for DNA structure maintenance, gene expression, and autophagy induction, extracellular HMGB1 acts as a damage-associated molecular pattern (DAMP) molecule to alert the host of damage by triggering immune responses. The biological function of HMGB1 is mediated by multiple receptors, including the receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs), which are expressed in different hepatic cells. Activation of HMGB1 and downstream signaling pathways are contributing factors in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and drug-induced liver injury (DILI), each of which involves sterile inflammation, liver fibrosis, ductular reaction, and hepatic tumorigenesis. In this review, we will discuss the critical role of HMGB1 in these pathogenic contexts and propose HMGB1 as a bona fide and targetable DAMP in the setting of common liver diseases.
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Affiliation(s)
- Bilon Khambu
- Correspondence: ; Tel.: +1-317-274-1789; Fax: +1-317-491-6639
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38
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Çalışkan AR, Harputluoğlu M. Acute liver failure in adults. TURKISH JOURNAL OF GASTROENTEROLOGY 2019; 30:938-939. [PMID: 31625941 DOI: 10.5152/tjg.2019.260919] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- Ali Rıza Çalışkan
- Department of Gastroenterology, İnönü University Turgut Özal Medical Center, Malatya, Turkey
| | - Murat Harputluoğlu
- Department of Gastroenterology, İnönü University Turgut Özal Medical Center, Malatya, Turkey
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39
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Wang AW, Wang YJ, Zahm AM, Morgan AR, Wangensteen KJ, Kaestner KH. The Dynamic Chromatin Architecture of the Regenerating Liver. Cell Mol Gastroenterol Hepatol 2019; 9:121-143. [PMID: 31629814 PMCID: PMC6909351 DOI: 10.1016/j.jcmgh.2019.09.006] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 09/19/2019] [Accepted: 09/23/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The adult liver is the main detoxification organ and routinely is exposed to environmental insults but retains the ability to restore its mass and function upon tissue damage. However, extensive injury can lead to liver failure, and chronic injury causes fibrosis, cirrhosis, and hepatocellular carcinoma. Currently, the transcriptional regulation of organ repair in the adult liver is incompletely understood. METHODS We isolated nuclei from quiescent as well as repopulating hepatocytes in a mouse model of hereditary tyrosinemia, which recapitulates the injury and repopulation seen in toxic liver injury in human beings. We then performed the assay for transposase accessible chromatin with high-throughput sequencing specifically in repopulating hepatocytes to identify differentially accessible chromatin regions and nucleosome positioning. In addition, we used motif analysis to predict differential transcription factor occupancy and validated the in silico results with chromatin immunoprecipitation followed by sequencing for hepatocyte nuclear factor 4α (HNF4α) and CCCTC-binding factor (CTCF). RESULTS Chromatin accessibility in repopulating hepatocytes was increased in the regulatory regions of genes promoting proliferation and decreased in the regulatory regions of genes involved in metabolism. The epigenetic changes at promoters and liver enhancers correspond with the regulation of gene expression, with enhancers of many liver function genes showing a less accessible state during the regenerative process. Moreover, increased CTCF occupancy at promoters and decreased HNF4α binding at enhancers implicate these factors as key drivers of the transcriptomic changes in replicating hepatocytes that enable liver repopulation. CONCLUSIONS Our analysis of hepatocyte-specific epigenomic changes during liver repopulation identified CTCF and HNF4α as key regulators of hepatocyte proliferation and regulation of metabolic programs. Thus, liver repopulation in the setting of toxic injury makes use of both general transcription factors (CTCF) for promoter activation, and reduced binding by a hepatocyte-enriched factor (HNF4α) to temporarily limit enhancer activity. All sequencing data in this study were deposited to the Gene Expression Omnibus database and can be downloaded with accession number GSE109466.
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Affiliation(s)
- Amber W Wang
- Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Yue J Wang
- Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida
| | - Adam M Zahm
- Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ashleigh R Morgan
- Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kirk J Wangensteen
- Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Klaus H Kaestner
- Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania.
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40
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Wang AW, Zahm AM, Wangensteen KJ. Cell Type-specific Gene Expression Profiling in the Mouse Liver. J Vis Exp 2019:10.3791/60242. [PMID: 31609340 PMCID: PMC7507956 DOI: 10.3791/60242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Liver repopulation after injury is a crucial feature of mammals which prevents immediate organ failure and death after exposure of environmental toxins. A deeper understanding of the changes in gene expression that occur during repopulation could help identify therapeutic targets to promote the restoration of liver function in the setting of injuries. Nonetheless, methods to isolate specifically the repopulating hepatocytes are inhibited by a lack of cell markers, limited cell numbers, and the fragility of these cells. The development of translating ribosome affinity purification (TRAP) technology in conjunction with the Fah-/- mouse model to recapitulate repopulation in the setting of liver injury allows gene expression profiling of the repopulating hepatocytes. With TRAP, cell type-specific translating mRNA is rapidly and efficiently isolated. We developed a method that utilizes TRAP with affinity-based isolation of translating mRNA from hepatocytes that selectively express the green fluorescent protein (GFP)-tagged ribosomal protein (RP), GFP:RPL10A. TRAP circumvents the long time period required for fluorescence-activated cell sorting that could change the gene expression profile. Furthermore, since only the repopulating hepatocytes express the GFP:RPL10A fusion protein, the isolated mRNA is devoid of contamination from the surrounding injured hepatocytes and other cell types in the liver. The affinity-purified mRNA is of high quality and allows downstream PCR- or high-throughput sequencing-based analysis of gene expression.
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Affiliation(s)
- Amber W Wang
- Department of Genetics, University of Pennsylvania
| | - Adam M Zahm
- Department of Genetics, University of Pennsylvania
| | - Kirk J Wangensteen
- Department of Genetics, University of Pennsylvania; Department of Medicine, University of Pennsylvania;
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41
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Jeong TB, Kim JH, Kim SH, Lee S, Son SW, Lim Y, Cho JY, Hwang DY, Kim KS, Kwak JH, Jung YS. Comparison of toxic responses to acetaminophen challenge in ICR mice originating from different sources. Lab Anim Res 2019; 35:16. [PMID: 32257904 PMCID: PMC7081583 DOI: 10.1186/s42826-019-0017-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 08/22/2019] [Indexed: 01/06/2023] Open
Abstract
Acetaminophen (APAP) is the most common antipyretic analgesic worldwide. However, APAP overdose causes severe liver injury, especially centrilobular necrosis, in humans and experimental animals. At therapeutic dosage, APAP is mainly metabolized by sulfation and glucuronidation, and partly by cytochrome P450-mediated oxidation. However, APAP overdose results in production of excess reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), by cytochromes P450; NAPQI overwhelms the level of glutathione (GSH), which could otherwise detoxify it. NAPQI binds covalently to proteins, leading to cell death. A number of studies aimed at the prevention and treatment of APAP-induced toxicity are underway. Rats are more resistant than mice to APAP hepatotoxicity, and thus mouse models are mainly used. In the present study, we compared the toxic responses induced by APAP overdose in the liver of ICR mice obtained from three different sources and evaluated the usability of the Korl:ICR stock established by the National Institute of Food and Drug Safety Evaluation in Korea. Administration of APAP (300 mg/kg) by intraperitoneal injection into male ICR mice enhanced CYP2E1 protein expression and depleted hepatic GSH level 2 h after treatment accompanied with significantly increased level of hepatic malondialdehyde, a product of lipid peroxidation. Regardless of the source of the mice, hepatotoxicity, as evidenced by activity of serum alanine aminotransferase, increased from 8 h and peaked at 24 h after APAP treatment. In summary, hepatotoxicity was induced after the onset of oxidative stress by overdose of APAP, and the response was the same over time among mice of different origins.
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Affiliation(s)
- Tae Bin Jeong
- 1College of Pharmacy, Pusan National University, Busan, 46241 South Korea
| | - Joung-Hee Kim
- 1College of Pharmacy, Pusan National University, Busan, 46241 South Korea
| | - Sou Hyun Kim
- 1College of Pharmacy, Pusan National University, Busan, 46241 South Korea
| | - Seunghyun Lee
- 1College of Pharmacy, Pusan National University, Busan, 46241 South Korea
| | - Seung Won Son
- 1College of Pharmacy, Pusan National University, Busan, 46241 South Korea
| | - Yong Lim
- 2Department of Clinical Laboratory Science, College of Nursing and Healthcare Science, Dong-Eui University, Busan, South Korea
| | - Joon-Yong Cho
- 3Exercise Biochemistry Laboratory, Korea National Sport University, Seoul, South Korea
| | - Dae Youn Hwang
- 4Department of Biomaterials Science, College of Natural Resources & Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, South Korea
| | - Kil Soo Kim
- 5College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea
| | - Jae-Hwan Kwak
- 6College of Pharmacy, Brain Busan 21 Plus Program, Kyungsung University, Busan, South Korea
| | - Young-Suk Jung
- 1College of Pharmacy, Pusan National University, Busan, 46241 South Korea
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Penrice DD, Kamboj AK, Greenlund LS. 31-Year-Old Woman With Jaundice and Abdominal Pain. Mayo Clin Proc 2019; 94:e105-e109. [PMID: 31400908 DOI: 10.1016/j.mayocp.2019.01.051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 12/21/2018] [Accepted: 01/08/2019] [Indexed: 11/20/2022]
Affiliation(s)
- Daniel D Penrice
- Resident in Internal Medicine, Mayo Clinic School of Graduate Medical Education, Rochester, MN
| | - Amrit K Kamboj
- Resident in Internal Medicine, Mayo Clinic School of Graduate Medical Education, Rochester, MN
| | - Laura S Greenlund
- Advisor to Residents and Consultant in Community Internal Medicine, Mayo Clinic, Rochester, MN.
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43
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Li G, Zhou Z, Yao L, Xu Y, Wang L, Fan X. Full annotation of serum virome in Chinese blood donors with elevated alanine aminotransferase levels. Transfusion 2019; 59:3177-3185. [PMID: 31393615 DOI: 10.1111/trf.15476] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 07/14/2019] [Accepted: 07/20/2019] [Indexed: 12/30/2022]
Abstract
BACKGROUND A serum alanine aminotransferase (ALT) test is currently demanded for blood donation in China. One of the major reasons to include such a test is possible etiology of known or unknown hepatotropic viruses. However, this hypothesis has never been examined convincingly. STUDY DESIGN AND METHODS The study recruited 90 Chinese blood donors that were divided into three groups based on their ALT values. Serum virome from these donors was explored using a metagenomics approach with enhanced sensitivity resolved at single sequencing reads. RESULTS Anellovirus and pegivirus C (GBV-C) were detected among these donors. None of them were found solely in donors with abnormal liver enzyme. Anellovirus was highly prevalent (93.3%) and the co-infection with multiple genera (alpha, beta, and gammatorquevirus) were more common in the donors with normal ALT values in comparison to those with elevated ALT (single/double/triple Anellovirus genera, 1/3/24 vs. 7/7/14 or 6/7/13, p = 0.009). For unmapped reads that accounted for 15 ± 14.9% of the data, similarity-based (BLASTN, BLASTP, and HMMER3) and similarity-independent (k-mer frequency) analysis identified several circular rep encoding ssDNA (CRESS-DNA) genomes. Direct PCR testing indicated these genomes were likely reagent contaminants. CONCLUSION Viral etiology is not responsible for elevated ALT levels in Chinese blood donors. The ALT test, if not abandoned, should be adjusted for its cutoff in response to donor shortage in China.
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Affiliation(s)
- Gang Li
- Wuhan Blood Center, Wuhan, China
| | | | - Li Yao
- Wuhan Blood Center, Wuhan, China
| | - Yanjuan Xu
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Lan Wang
- Wuhan Blood Center, Wuhan, China
| | - Xiaofeng Fan
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri.,Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, Missouri
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Riebensahm C, Ka D, Sow A, Semmo N, Wandeler G. A closer look at the spectrum of drug-induced liver injury in sub-Saharan Africa. Expert Rev Clin Pharmacol 2019; 12:875-883. [PMID: 31269818 DOI: 10.1080/17512433.2019.1638251] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Introduction: Drug-induced liver injury (DILI) has become the most frequent cause of acute liver failure in high-income countries. However, little is known about the determinants of DILI in sub-Saharan Africa (SSA), where the prescription of antimicrobials and the use of potentially hepatotoxic traditional medicine are common. Areas covered: Based on an extensive literature search, we summarize current data available on the epidemiology and risk factors of DILI in SSA. We discuss the most likely causes of DILI in the region, including antimicrobial therapies and traditional medicine. We also highlight research gaps as well as barriers to diagnosis and management of the condition, and explore ways to address these important challenges. Expert opinion: DILI is underestimated in SSA and several factors challenge its early diagnosis, including lack of information on the causes of DILI in the region, sub-optimal knowledge about the condition among clinicians, and structural difficulties faced by health care systems. In order to better prevent the occurrence of DILI and its complications, it is crucial to enhance awareness among health care providers and patients, adapt drug prescription habits and regulations, and improve current knowledge on the main risk factors for DILI, including host genetic and environmental determinants.
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Affiliation(s)
- Carlotta Riebensahm
- Division of Hepatology, Bern University Hospital, University of Bern , Bern , Switzerland
| | - Daye Ka
- Division of Hepatology, Bern University Hospital, University of Bern , Bern , Switzerland.,Department of Infectious Diseases, Hôpital Fann , Dakar , Senegal
| | - Abdoul Sow
- Division of Hepatology, Bern University Hospital, University of Bern , Bern , Switzerland.,Division of Gastroenterology and Hepatology, Hôpital Principal , Dakar , Senegal
| | - Nasser Semmo
- Division of Hepatology, Bern University Hospital, University of Bern , Bern , Switzerland
| | - Gilles Wandeler
- Department of Infectious Diseases, Hôpital Fann , Dakar , Senegal.,Department of Infectious Diseases, Bern University Hospital, University of Bern , Bern , Switzerland
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SIRT1 Modulators in Experimentally Induced Liver Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:8765954. [PMID: 31281594 PMCID: PMC6589266 DOI: 10.1155/2019/8765954] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 03/21/2019] [Accepted: 05/15/2019] [Indexed: 12/11/2022]
Abstract
This article is directed at highlighting the involvement of the endogenous stress sensor SIRT1 (silent information regulator T1) as a possible factor involved in hepatoprotection. The selective SIRT1 modulators whether activators (STACs) or inhibitors are being tried experimentally and clinically. We discuss the modulation of SIRT1 on cytoprotection or even cytotoxicity in the liver chemically injured by hepatotoxic agents in rats, to shed light on the crosstalk between SIRT1 and its modulators. A combination of D-galactosamine and lipopolysaccharide (D-GalN/LPS) downregulated SIRT1 expression, while SIRT1 activators, SRT1720, resveratrol, and quercetin, upregulated SIRT1 and alleviated D-GalN/LPS-induced acute hepatotoxicity. Liver injury markers exhibited an inverse relationship with SIRT1 expression. However, under subchronic hepatotoxicity, quercetin decreased the significant increase in SIRT1 expression to lower levels which are still higher than normal ones and mitigated the liver-damaging effects of carbon tetrachloride. Each of these STACs was hepatoprotective and returned the conventional antioxidant enzymes to the baseline. Polyphenols tend to fine-tune SIRT1 expression towards normal in the liver of intoxicated rats in both acute and subchronic studies. Together, all these events give an impression that the cytoprotective effects of SIRT1 are exhibited within a definite range of expression. The catalytic activity of SIRT1 is important in the hepatoprotective effects of polyphenols where SIRT1 inhibitors block and the allosteric SIRT1 activators mimic the hepatoprotective effects of polyphenols. Our findings indicate that the pharmacologic modulation of SIRT1 could represent both an important move in alleviating hepatic insults and a future major step in the treatment of xenobiotic-induced hepatotoxicity.
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Expression of drug metabolizing enzymes and transporters in the cochlea: Implications for drug delivery and ototoxicity. Hear Res 2019; 379:98-102. [PMID: 31121337 DOI: 10.1016/j.heares.2019.05.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 04/24/2019] [Accepted: 05/13/2019] [Indexed: 11/22/2022]
Abstract
Inner ear drug delivery is a major area of research and development, but relatively little is known about basic drug metabolism in the cochlea. Additionally, the use of potentially ototoxic drugs such as NSAIDs, chemotherapeutics and aminoglycosides is common, but little is known about the role of metabolism in ototoxicity of those drugs. To address those issues, we compared expression of major Cytochromes P450 (Cyps), UDP-glucuronosyl-transferases (Ugts), sulfotransferases (Sults), and drug transporters between cochleae and liver, an organ with high expression, in mice using qPCR and enzyme kinetics. Together, the tested drug-metabolizing enzymes (DMEs) and transporters account for metabolism of approximately 70-80% of all medically important drugs in the body. Expression of most Cyps was low in the cochlea compared to liver, but three displayed similar expression levels to the liver, and one (Cyp2c65) had significantly higher levels of expression in the cochlea (1.9 ± 0.06 fold vs. liver). Enzyme kinetics revealed undetectable levels of p450 activity in the cochlea, especially as compared to the liver. Similar results were obtained for expression of Ugts and Sults. Interestingly, expression of most transporters was also low, with one major exception: Mdr1/P-glycoprotein (P-gp), which is generally thought to be highly expressed in liver and poorly expressed in most of the nervous system, was 3-fold greater in cochlea. Importantly, P-gp is known to protect other tissues from toxicity of cancer drugs by acting as an efflux pump. Our data demonstrate overall low levels of expression of DMEs and transporters in the cochlea, and identify a few that may be important to consider when designing and testing drugs for local delivery to the inner ear.
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Then EO, Gayam V, Are VS, Sunkara T, Gaduputi V. Herpes Simplex Virus Hepatitis: A Brief Review of an Oft-overlooked Pathology. Cureus 2019; 11:e4313. [PMID: 31183293 PMCID: PMC6538099 DOI: 10.7759/cureus.4313] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Herpes simplex virus (HSV) is a rarely reported cause of viral hepatitis. Aggressive in nature, most cases of HSV hepatitis rapidly progress to fulminant hepatic failure. Present day, its pathogenesis is yet to be elucidated, but its complications and associated high mortality rate are clear. Clinically, its symptoms mimic those of other causes of acute hepatic failure thus making the diagnosis of HSV hepatitis a precarious task. Although treatment in the form of acyclovir is readily available, most cases have a poor prognosis due to late initiation of therapy. This makes the early identification of HSV essential in improving outcomes and potentially preventing mortality.
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Affiliation(s)
- Eric O Then
- Internal Medicine, St. Barnabas Hospital Health System, Bronx, USA
| | - Vijay Gayam
- Internal Medicine, Interfaith Medical Center, Brooklyn, USA
| | - Vijay S Are
- Internal Medicine, Stormont Vail Health System, Lawrence, USA
| | - Tagore Sunkara
- Internal Medicine, Mercy Medical Center, Des Moines, USA
| | - Vinaya Gaduputi
- Internal Medicine, St. Barnabas Hospital Health System, Bronx, USA
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Clemens MM, McGill MR, Apte U. Mechanisms and biomarkers of liver regeneration after drug-induced liver injury. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2019; 85:241-262. [PMID: 31307589 DOI: 10.1016/bs.apha.2019.03.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver, the major metabolic organ in the body, is known for its remarkable capacity to regenerate. Whereas partial hepatectomy (PHx) is a popular model for the study of liver regeneration, the liver also regenerates after acute injury, but less is known about the mechanisms that drive it. Recent studies have shown that liver regeneration is critical for survival in acute liver failure (ALF), which is usually due to drug-induced liver injury (DILI). It is sometimes assumed that the signaling pathways involved are similar to those that regulate regeneration after PHx, but there are likely to be critical differences. A better understanding of regeneration mechanisms after DILI and hepatotoxicity in general could lead to development of new therapies for ALF patients and new biomarkers to predict patient outcome. Here, we summarize what is known about the mechanisms of liver regeneration and repair after hepatotoxicity. We also review the literature in the emerging field of liver regeneration biomarkers.
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Affiliation(s)
- Melissa M Clemens
- Interdisciplinary Biomedical Sciences Graduate Program, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - 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, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
| | - Udayan Apte
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States
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Slowik V, Borude P, Jaeschke H, Woolbright BL, Lee WM, Apte U. Leukocyte cell derived chemotaxin-2 (Lect2) as a predictor of survival in adult acute liver failure. Transl Gastroenterol Hepatol 2019; 4:17. [PMID: 30976720 DOI: 10.21037/tgh.2019.03.03] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 03/13/2019] [Indexed: 12/19/2022] Open
Abstract
Background One of the major issues in the field of acute liver failure (ALF) is the lack of reliable biomarkers that predict outcome. Many cases present with very limited treatment options and prognostic indicators are invaluable. We tested whether leukocyte cell derived chemotaxin 2 can be used as a prognostic biomarker to predict patient survival either alone or in combination with other routine clinical parameters. Methods Serum samples and associated clinical data from came from two independent sources, the Acute Liver Failure Study Group (ALFSG) registry and the University of Kansas Medical Center. We analyzed a total of 61 cases, each with individual time points collected over a period of 0 to 7 days after hospital admission. Analysis was developed to compare responses in survivors vs. non-survivors. Results The data indicate that survivors had significantly lower serum levels of leukocyte cell derived chemotaxin 2 compared to non-survivors (P=0.03). Further, it was able to predict patient survival when taken together with either international normalized ratio (INR) alone (71% concordance) or INR and bilirubin (76% concordance) or INR and serum albumin (77% concordance). Furthermore, when we analyzed data for each day, serum Lect2 and INR taken together were able to predict survival at day three after hospital admission with 86.3% concordance. Conclusions These studies have revealed test batteries consisting of easily available serum tests that are concordant with survival status of ALF patients early during the clinical course.
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Affiliation(s)
- Voytek Slowik
- Department of Gastroenterology Hepatology and Nutrition, Children's Mercy Kansas City, Kansas City, MO 64108, USA
| | - Prachi Borude
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Benjamin L Woolbright
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - William M Lee
- Department of Internal Medicine and Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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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.
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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
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