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Yan P, Yu X, Chen Z, Lan L, Kang J, Zhao B, Liu D. Assessing the consistency of FIB-4, APRI, and GPR in evaluating significant liver fibrosis and cirrhosis in COVID-19 patients with concurrent liver diseases. BMC Gastroenterol 2025; 25:191. [PMID: 40114058 PMCID: PMC11927168 DOI: 10.1186/s12876-025-03770-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 03/07/2025] [Indexed: 03/22/2025] Open
Abstract
OBJECTIVE This study investigated the consistency of the FIB-4, APRI, and GPR indices in assessing significant liver fibrosis and cirrhosis in patients with Coronavirus Disease 2019(COVID-19) who also suffer from various liver diseases, providing references for the clinical selection and application for non-invasive assessment methods. METHODS The study evaluated 744 COVID-19 patients with coexisting liver diseases: 508 cases with non-alcoholic fatty liver disease (NAFLD), 158 cases with chronic hepatitis B (CHB), and 78 cases with a combination of both ailments. FIB-4, APRI, and GPR were employed to assess significant liver fibrosis and cirrhosis. Concordance among the methods was determined using Kappa analysis, and receiver operating characteristic (ROC) curves helped identify the optimal cutoff values for each index. RESULTS For COVID-19 patients with NAFLD, Kappa values for significant liver fibrosis were 0.81, 0.90, 0.80, and 0.79, and for cirrhosis, they were 0.88, 0.97,0.88, and 0.88, respectively (all p < 0.05). Among those with CHB, Kappa values were 0.81, 0.81, 0.83, and 0.75 for fibrosis, and0.87, 0.91, 0.88, and 0.92 for cirrhosis (all p < 0.05). In patients with coexisting liver diseases, the values were 0.87, 0.86, 0.86, and 0.78 for fibrosis, and 0.67, 0.69, 0.54, and 0.81for cirrhosis (all p < 0.05). Linear trend analysis revealed significant relationships between FIB-4 values, APRI values, GPR values, and the severity of COVID-19 (χ2 trend: 15.205,35.114, and 13.973, respectively, all p < 0.001), between FIB-4 values and APRI values and the coronavirus negative conversion time (all p < 0.05) in COVID-19 with NAFLD, and between FIB-4 values and GPR values and the coronavirus negative conversion time in patients with COVID-19 with CHB(all p < 0.05). CONCLUSION Using the current cutoff values, the non-invasive assessments demonstrated almost perfect consistency in evaluating significant liver fibrosis and cirrhosis in COVID-19 patients with liver diseases, though FIB-4 and GPR showed moderate consistency in cirrhosis evaluation in patients with coexisting liver conditions. Moreover, it also indicated that increased liver fibrosis correlates with more severe COVID-19 and prolonged coronavirus negative conversion time.
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Affiliation(s)
- Pan Yan
- School of Public Health, Chengdu Medical College, Chengdu, Sichuan Province, 610500, China
| | - Xiaoping Yu
- School of Preclinical Medicine, Chengdu University, Chengdu, Sichuan Province, 610106, China
| | - Zhu Chen
- Department of Drug Clinical Trial Center, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China
| | - Lijuan Lan
- The First Ward of Internal Medicine, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China
| | - Jun Kang
- The First Ward of Internal Medicine, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China
| | - Bennan Zhao
- The First Ward of Internal Medicine, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China
| | - Dafeng Liu
- The First Ward of Internal Medicine, Public Health Clinical Centre of Chengdu, Chengdu, Sichuan Province, 610060, China.
- , No.377 Jingming Road, Jinjiang District, Chengdu City, Sichuan Province Chengdu, 610060, China.
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Murakami T, Yamazaki Y, Tateyama Y, Kanayama Y, Uehara D, Suga T, Tojima H, Sato K, Kakizaki S, Uraoka T. Association Between Liver Injury and Pneumonia in Patients Hospitalized with COVID-19, -With a Focus on Pregnant Women. KANZO 2025; 66:71-77. [DOI: 10.2957/kanzo.66.71] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Affiliation(s)
- Tatsuma Murakami
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - Yuichi Yamazaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - Yumeo Tateyama
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - Yuki Kanayama
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - Daisuke Uehara
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - Takayoshi Suga
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - Hiroki Tojima
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - Ken Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
- Department of Healthcare Informatics, Takasaki University of Health and Welfare
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
- Department of Clinical Research, NHO Takasaki General Medical Center
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
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Krasnenkova SF, Zayratyants OV, Midiber KY, Mikhaleva LM. [Liver pathology in COVID-19]. Arkh Patol 2025; 87:53-59. [PMID: 39943730 DOI: 10.17116/patol20258701153] [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] [Indexed: 05/09/2025]
Abstract
The literature review presents an analysis of the pathogenesis and pathological anatomy of liver damage in COVID-19. Liver damage with the steatosis, vascular disorders, mild portal and lobular inflammatory infiltration, cholestasis and clinically - liver failure is observed in majority of the patients with COVID-19. Chronic liver diseases with infection SARS-CoV-2 tend to decompensate, which significantly worsens the prognosis of the disease. Pathogenesis of liver damage in COVID19 is unclear. There was no convincing evidence for the hypothesis of cytotoxicity for hepatocytes or cholangiocytes by SARS-CoV-2. Similar liver morphological changes described by different authors suggest their nonspecific nature and multifactorial pathogenesis related to hypoxia, cytokin storm, systemic inflammatory response syndrome, sepsis and shock, Covid-associated angio- and coagulopathy, as well as drug-induced hepatotoxicity. Further research is needed to clarify the pathogenesis and pathological anatomy of the liver pathology in COVID-19.
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Affiliation(s)
- S F Krasnenkova
- Russian University of Medicine, Moscow, Russia
- Research Institute of Organization of Medicine and Medicine Management, Moscow, Russia
| | - O V Zayratyants
- Russian University of Medicine, Moscow, Russia
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, Moscow, Russia
| | - K Yu Midiber
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, Moscow, Russia
- Peoples' Friendship University of Russia named after Patrice Lumumba, Moscow, Russia
| | - L M Mikhaleva
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, Moscow, Russia
- Russian Medical Academy of Continuous Professional Education, Moscow, Russia
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Cao X, Xie YL, Yi JY, Liu ZL, Han M, Duan JH, Gao Q, Mu H, Zhou CL. Altered Liver Enzyme Markers in Patients with Asymptomatic, and Mild Omicron Infection: A Retrospective Study. J Inflamm Res 2024; 17:6875-6885. [PMID: 39372583 PMCID: PMC11451451 DOI: 10.2147/jir.s478812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 09/27/2024] [Indexed: 10/08/2024] Open
Abstract
Purpose The emergence of the SARS-CoV-2 Omicron variant has posed a significant global public health challenge. Elucidating the laboratory profiles of individuals infected with this variant is crucial for assessing organ damage. This study aimed to investigate the variations in liver function tests and their correlation with demographic characteristics and inflammatory markers in patients with early Omicron variant infections. Patients and Methods A retrospective cohort study was conducted on 1133 mild or asymptomatic COVID-19 cases at Tianjin First Central Hospital. Data on age, gender, body mass index (BMI), and serum markers were collected and analyzed. Statistical analyses were performed using SPSS software, version 24.0. Results Abnormal liver function parameters, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin (TBIL), were observed in 314 (27.71%) patients. "Hepatocellular type" was identified in 56 (4.94%) patients, "cholestatic type" in 185 (16.33%) patients, and "mixed type" in 73 (6.44%) patients. In the mixed group, we observed a pronounced elevation in the levels of ALT, AST, and GGT. Moreover, the hepatocellular group exhibited a statistically significant increase in AST and ALT concentrations relative to both the normal and cholestatic groups. Notably, the cholestatic group demonstrated a substantial increment in ALP levels. Males had a significantly higher prevalence of "abnormal liver enzyme markers" compared to females. Patients with "abnormal liver enzyme markers" exhibited significantly decreased immunoglobulin G (IgG) levels and elevated levels of inflammatory markers, including procalcitonin (PCT), interleukin-6 (IL6), as well as C-reactive protein (CRP) compared to normal group. Logistic regression analysis revealed that male gender and PCT levels were significantly associated with the risk of abnormal liver enzyme markers. Patients in hepatocellular group were likely accompanied with high CRP levels, whereas those in the cholestatic type were associated with high IL6 levels. Conclusion Early Omicron infection might cause liver stress response. Elevated liver enzyme marker levels were correlated with age, gender, inflammatory factors, and IgG.
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Affiliation(s)
- Xi Cao
- Department of Clinical Laboratory, Tianjin First Central Hospital, Tianjin, People’s Republic of China
| | - Yong-Li Xie
- Department of Clinical Laboratory, Tianjin Stomatological Hospital, School of Medicine, Nankai University, Tianjin, People’s Republic of China
- Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Tianjin, People’s Republic of China
| | - Jian-Ying Yi
- Department of Clinical Laboratory, Tianjin First Central Hospital, Tianjin, People’s Republic of China
| | - Zhi-Li Liu
- Department of Clinical Laboratory, the Third Central Hospital, Tianjin, People’s Republic of China
| | - Meng Han
- Department of Clinical Laboratory, Tianjin First Central Hospital, Tianjin, People’s Republic of China
| | - Ji-hui Duan
- Department of Clinical Laboratory, Tianjin First Central Hospital, Tianjin, People’s Republic of China
| | - Qiang Gao
- Department of Clinical Laboratory, Tianjin First Central Hospital, Tianjin, People’s Republic of China
| | - Hong Mu
- Department of Clinical Laboratory, Tianjin First Central Hospital, Tianjin, People’s Republic of China
| | - Chun-lei Zhou
- Department of Clinical Laboratory, Tianjin First Central Hospital, Tianjin, People’s Republic of China
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Żmudka K, Jaroszewicz J, Zarębska-Michaluk D, Rogalska M, Czupryna P, Rorat M, Kozielewicz D, Maciukajć J, Kiciak S, Krępa M, Dutkiewicz E, Stojko M, Spychał A, Ciechanowski P, Bolewska B, Podlasin R, Flisiak R. Association between Liver Damage and Disease Progression Markers with Mortality Risk and Mechanical Ventilation in Hospitalized COVID-19 Patients: A Nationwide Retrospective SARSTer Study. Viruses 2024; 16:1530. [PMID: 39459864 PMCID: PMC11512261 DOI: 10.3390/v16101530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/13/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024] Open
Abstract
(1) Background: Liver damage is an important component of acute COVID-19, and the advancement of preexisting liver disease is associated with a worse prognosis; (2) Methods: A nationwide retrospective study including 7444 patients aimed to evaluate levels of selected markers of liver damage and disease advancement and their association with mortality and mechanical ventilation (MV); (3) Results: Elevation of the following markers in multivariate models were associated with increased odds of mortality: Alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH), fibrosis-4 score (FIB-4), AST-to-platelet ratio index (APRI), and decreased levels of platelet count (PLT). Elevated levels of AST, LDH, APRI, FIB-4, and the AST/ALT ratio and decreased levels of PLT were associated with increased odds of MV in multivariate models. The best predictive accuracy against mortality was achieved with FIB-4 with AUC = 0.733 (95% CI, 0.718-0.749) at the optimal cut-off point of 2.764, while against MV was achieved with LDH with AUC = 0.753 (95% CI, 0.727-0.778) at the optimal cut-off point of 449.5 IU/L. (4) Conclusions: Our study confirms that the advancement of liver damage contributes to a worse prognosis in COVID-19 patients. Markers for liver damage and the advancement of liver disease can provide predictive value in clinical practice among COVID-19 patients.
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Affiliation(s)
- Karol Żmudka
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, 40-635 Katowice, Poland (M.S.); (A.S.)
| | - Jerzy Jaroszewicz
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, 40-635 Katowice, Poland (M.S.); (A.S.)
| | - Dorota Zarębska-Michaluk
- Department of Infectious Diseases and Allergology, Jan Kochanowski University, 25-317 Kielce, Poland
| | - Magdalena Rogalska
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, 15-540 Bialystok, Poland; (M.R.); (R.F.)
| | - Piotr Czupryna
- Department of Infectious Diseases and Neuroinfections, Medical University of Bialystok, 15-540 Bialystok, Poland
| | - Marta Rorat
- Department of Social Sciences and Infectious Diseases, Medical Faculty, Wroclaw University of Science and Technology, 50-470 Wroclaw, Poland
| | - Dorota Kozielewicz
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 85-030 Bydgoszcz, Poland
| | - Jadwiga Maciukajć
- Department of Infectious Diseases, District Healthcare Center, 27-200 Starachowice, Poland
| | - Sławomir Kiciak
- Independent Voivodeship Hospital “Jana Bożego” in Lublin, 20-400 Lublin, Poland
| | | | - Ewa Dutkiewicz
- Department of Pediatrics and Infectious Diseases, Regional Hospital in Szczecin, 71-252 Szczecin, Poland
| | - Michał Stojko
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, 40-635 Katowice, Poland (M.S.); (A.S.)
| | - Aleksandra Spychał
- Department of Infectious Diseases and Hepatology, Medical University of Silesia, 40-635 Katowice, Poland (M.S.); (A.S.)
| | - Przemysław Ciechanowski
- Department of Pediatrics and Infectious Diseases, Regional Hospital in Szczecin, 71-252 Szczecin, Poland
| | - Beata Bolewska
- Department of Infectious Diseases, Poznań University of Medical Sciences, 61-285 Poznan, Poland
| | - Regina Podlasin
- IV-th Department, Hospital for Infectious Diseases, 01-201 Warsaw, Poland;
- Department of Infectious Diseases, Collegium Medicum, Cardinal Stefan Wyszynski University in Warsaw, 01-815 Warsaw, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Bialystok, 15-540 Bialystok, Poland; (M.R.); (R.F.)
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Kamiya Y, Shinoda M, Ishii N, Yamamoto S, Sekine T, Morikawa M, Ota S, Toyama‐Kousaka M, Takahashi H, Takei H, Shinkai M. Comparison of liver fibrosis scores and fatty liver on computed tomography as risk factors for severity of COVID-19. JGH Open 2024; 8:e70004. [PMID: 39130093 PMCID: PMC11310555 DOI: 10.1002/jgh3.70004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 06/20/2024] [Accepted: 07/09/2024] [Indexed: 08/13/2024]
Abstract
Background and Aim Increased liver fibrosis scores (LFS), such as fibrosis-4 index (FIB-4) or non-alcoholic fatty liver disease fibrosis score (NFS), and fatty liver are known risk factors for severe coronavirus disease 2019 (COVID-19). The purpose of this study was to identify the best scores, which predict the prognosis of COVID-19. Methods Participants comprised consecutive Japanese COVID-19 patients admitted to our hospital between February 14, 2020, and April 14, 2021. Multivariate logistic regression analysis was performed to evaluate the relationships between LFS (FIB-4, NFS, aspartate aminotransferase-to-platelet ratio index [APRI], BARD score, and hepatic steatosis index [HSI]) or fatty liver on computed tomography (CT), and severity of COVID-19. Results Of the 415 patients (mean age, 59 years), 177 patients (42.7%) needed oxygen therapy, 90 patients (21.7%) worsened to severe COVID-19, and 45 patients (10.8%) died during admission. Multivariate logistic regression analysis showed that increased FIB-4 and NFS were risk factors for death, severe COVID-19, and oxygen demand; that increased BARD was a risk factor for severe COVID-19 and oxygen demand; and that increased APRI and HSI were not risk factors for any status of COVID-19. Furthermore, increased NFS or BARD and fatty liver were independent risk factors for severe COVID-19 and oxygen demand. Conclusions This study showed that FIB-4 and NFS were the best liver fibrosis scores that predicted worse prognosis for COVID-19, and that increased NFS or BARD and fatty liver evident on CT represented independent risk factors for severe COVID-19 and oxygen demand.
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Affiliation(s)
- Yuji Kamiya
- Department of Endocrinology and MetabolismTokyo Shinagawa HospitalTokyoJapan
| | - Masahiro Shinoda
- Department of Respiratory MedicineTokyo Shinagawa HospitalTokyoJapan
| | - Naoki Ishii
- Department of GastroenterologyTokyo Shinagawa HospitalTokyoJapan
| | - Saki Yamamoto
- Department of Endocrinology and MetabolismTokyo Shinagawa HospitalTokyoJapan
| | - Tetsuo Sekine
- Department of Endocrinology and MetabolismTokyo Shinagawa HospitalTokyoJapan
| | - Miwa Morikawa
- Department of Respiratory MedicineTokyo Shinagawa HospitalTokyoJapan
| | - Shinichiro Ota
- Department of Respiratory MedicineTokyo Shinagawa HospitalTokyoJapan
| | | | | | - Hiroaki Takei
- Department of Respiratory MedicineTokyo Shinagawa HospitalTokyoJapan
| | - Masaharu Shinkai
- Department of Respiratory MedicineTokyo Shinagawa HospitalTokyoJapan
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Matsuda H, Nosaka T, Hiramatsu K, Takahashi K, Naito T, Ofuji K, Ohtani M, Imamura Y, Iwasaki H, Nakamoto Y. Analysis of peripheral immune markers to predict liver injury during COVID-19. Clin J Gastroenterol 2024; 17:797-798. [PMID: 38839648 DOI: 10.1007/s12328-024-01995-y] [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: 04/30/2024] [Accepted: 05/30/2024] [Indexed: 06/07/2024]
Affiliation(s)
- Hidetaka Matsuda
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Takuto Nosaka
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Katsushi Hiramatsu
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Kazuto Takahashi
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Tatsushi Naito
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Kazuya Ofuji
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Masahiro Ohtani
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Yoshiaki Imamura
- Division of Diagnostic Pathology/Surgical Pathology, University of Fukui Hospital, Fukui, Japan
| | - Hiromichi Iwasaki
- Division of Infection Control and Prevention, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.
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8
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Tazarghi A, Bazoq S, Taziki Balajelini MH, Ebrahimi M, Hosseini SM, Razavi Nikoo H. Liver injury in COVID-19: an insight into pathobiology and roles of risk factors. Virol J 2024; 21:65. [PMID: 38491495 PMCID: PMC10943793 DOI: 10.1186/s12985-024-02332-y] [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: 08/24/2023] [Accepted: 02/27/2024] [Indexed: 03/18/2024] Open
Abstract
COVID-19 is a complex disease that can lead to fatal respiratory failure with extrapulmonary complications, either as a direct result of viral invasion in multiple organs or secondary to oxygen supply shortage. Liver is susceptible to many viral pathogens, and due to its versatile functions in the body, it is of great interest to determine how hepatocytes may interact with SARS-CoV-2 in COVID-19 patients. Liver injury is a major cause of death, and SARS-CoV-2 is suspected to contribute significantly to hepatopathy. Owing to the lack of knowledge in this field, further research is required to address these ambiguities. Therefore, we aimed to provide a comprehensive insight into host-virus interactions, underlying mechanisms, and associated risk factors by collecting results from epidemiological analyses and relevant laboratory experiments. Backed by an avalanche of recent studies, our findings support that liver injury is a sequela of severe COVID-19, and certain pre-existing liver conditions can also intensify the morbidity of SARS-CoV-2 infection in synergy. Notably, age, sex, lifestyle, dietary habits, coinfection, and particular drug regimens play a decisive role in the final outcome and prognosis as well. Taken together, our goal was to unravel these complexities concerning the development of novel diagnostic, prophylactic, and therapeutic approaches with a focus on prioritizing high-risk groups.
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Affiliation(s)
- Abbas Tazarghi
- Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sahar Bazoq
- Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mohammad Hosein Taziki Balajelini
- Department of Otorhinolaryngology, Neuroscience Research Center, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mohsen Ebrahimi
- Neonatal and Children's Health Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Seyed Mehran Hosseini
- Department of Physiology, School of Medicine, Neuroscience Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
| | - Hadi Razavi Nikoo
- Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
- Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
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9
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Righi FA, Vander Heide RS, Graham RP, Aubry MC, Trejo-Lopez JA, Bois MC, Roden AC, Reichard R, Maleszewski JJ, Alexander MP, Quinton RA, Jenkins SM, Hartley CP, Hagen CE. A case-control autopsy series of liver pathology associated with novel coronavirus disease (COVID-19). Ann Diagn Pathol 2024; 68:152240. [PMID: 37995413 DOI: 10.1016/j.anndiagpath.2023.152240] [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: 10/19/2023] [Revised: 11/16/2023] [Accepted: 11/17/2023] [Indexed: 11/25/2023]
Abstract
BACKGROUND Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 2019 (COVID-19) is most well-known for causing pulmonary injury, a significant proportion of patients experience hepatic dysfunction. The mechanism by which SARS-CoV2 causes liver injury is not fully understood. The goal of this study was to describe the hepatic pathology in a large cohort of deceased patients with COVID-19 as compared to a control group of deceased patients without COVID-19. METHODS Consented autopsy cases at two institutions were searched for documentation of COVID-19 as a contributing cause of death. A group of consecutive consented autopsy cases during the same period, negative for SARS-CoV-2 infection, was used as a control group. The autopsy report and electronic medical records were reviewed for relevant clinicopathologic information. H&E-stained liver sections from both groups were examined for pertinent histologic features. Select cases underwent immunohistochemical staining for CD 68 and ACE2 and droplet digital polymerase chain reaction (ddPCR) assay for evaluation of SARS-CoV2 RNA. RESULTS 48 COVID-19 positive patients (median age 73, M:F 3:1) and 40 COVID-19 negative control patients (median age 67.5, M:F 1.4:1) were included in the study. The COVID-19 positive group was significantly older and had a lower rate of alcoholism and malignancy, but there was no difference in other comorbidities. The COVID-19 positive group was more likely to have received steroids (75.6 % vs. 36.1 %, p < 0.001). Hepatic vascular changes were seen in a minority (10.6 %) of COVID-19 positive cases. When all patients were included, there were no significant histopathologic differences between groups, but when patients with chronic alcoholism were excluded, the COVID-19 positive group was significantly more likely to have steatosis (80.9 % vs. 50.0 %, p = 0.004) and lobular inflammation (45.7 % vs. 20.7 %, p = 0.03). Testing for viral RNA by ddPCR identified 2 of the 18 (11.1 %) COVID-19 positive cases to have SARS-CoV-2 RNA detected within the liver FFPE tissue. CONCLUSIONS The most significant findings in the liver of COVID-19 positive patients were mild lobular inflammation and steatosis. The high rate of steroid therapy in this population may be a possible source of steatosis. Hepatic vascular alterations were only identified in a minority of patients and did not appear to play a predominant role in COVID-19 mediated hepatic injury. Low incidence of SARS-CoV-2 RNA positivity in liver tissue in our cohort suggests hepatic injury in the setting of COVID-19 may be secondary in nature.
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Affiliation(s)
- Fabiola A Righi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Richard S Vander Heide
- Department of Pathology, Louisiana State University Health Sciences Center, New Orleans, LA, United States of America
| | - Rondell P Graham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Marie Christine Aubry
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Jorge A Trejo-Lopez
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Melanie C Bois
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Anja C Roden
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Ross Reichard
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Joseph J Maleszewski
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Mariam P Alexander
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Reade A Quinton
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Sarah M Jenkins
- Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, United States of America
| | - Christopher P Hartley
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
| | - Catherine E Hagen
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America.
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10
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Daba TM, Mokonon M, Niguse E, Getahun M. The Potential Mechanisms Behind Adverse Effect of Coronavirus Disease-19 on Heart and Liver Damage: A Review. Ethiop J Health Sci 2024; 34:85-100. [PMID: 38957334 PMCID: PMC11217793 DOI: 10.4314/ejhs.v34i1.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Accepted: 12/02/2023] [Indexed: 07/04/2024] Open
Abstract
Background Coronaviruses (CoVs) belong to the RNA viruses family. The viruses in this family are known to cause mild respiratory disease in humans. The origin of the novel SARS-COV2 virus that caused the coronavirus-19 disease (COVID-19) is the Wuhan city in China from where it disseminated to cause a global pandemic. Although lungs are the predominant target organ for Coronavirus Disease-19 (COVID-19), since its outbreak, the disease is known to affect heart, blood vessels, kidney, intestine, liver and brain. This review aimed to summarize the catastrophic impacts of Coronavirus disease-19 on heart and liver along with its mechanisms of pathogenesis. Methods The information used in this review was obtained from relevant articles published on PubMed, Google Scholar, Google, WHO website, CDC and other sources. Key searching statements and phrases related to COVID-19 were used to retrieve information. Original research articles, review papers, research letters and case reports were used as a source of information. Results Besides causing severe lung injury, COVID-19 has also been reported to affect and cause dysfunction of many other organs. COVID-19 infection can affect people by downregulating membrane-bound active angiotensin-converting enzyme (ACE). People who have deficient ACE2 expression are more vulnerable to COVID-19 infection. The patients' pre-existing co-morbidities are major risk factors that predispose individuals to severe COVID-19. Conclusion The disease severity and its broad spectrum phenotype is a result of combined direct and indirect pathogenic factors. Therefore, protocols that harmonize many therapeutic preferences should be the best alternatives to de-escalate the disease and obviate deaths caused as a result of multiple organ damage and dysfunction induced by the disease.
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Affiliation(s)
- Tolessa Muleta Daba
- Deparment of Biochemistry, Molecular Biology and Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Huye Campus, Rwanda
- Institute of Pharmaceutical Science, Adama Science and Technology University, Adama, Ethiopia
| | - Mulatu Mokonon
- Department of Biology, School of Applied Natural Sciences, Adama Science and Technology University, Adama, Ethiopia
| | - Elsa Niguse
- Department of Biology, School of Applied Natural Sciences, Adama Science and Technology University, Adama, Ethiopia
| | - Meron Getahun
- Department of Biology, School of Applied Natural Sciences, Adama Science and Technology University, Adama, Ethiopia
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11
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Georgieva E, Ananiev J, Yovchev Y, Arabadzhiev G, Abrashev H, Abrasheva D, Atanasov V, Kostandieva R, Mitev M, Petkova-Parlapanska K, Karamalakova Y, Koleva-Korkelia I, Tsoneva V, Nikolova G. COVID-19 Complications: Oxidative Stress, Inflammation, and Mitochondrial and Endothelial Dysfunction. Int J Mol Sci 2023; 24:14876. [PMID: 37834324 PMCID: PMC10573237 DOI: 10.3390/ijms241914876] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 09/28/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
SARS-CoV-2 infection, discovered and isolated in Wuhan City, Hubei Province, China, causes acute atypical respiratory symptoms and has led to profound changes in our lives. COVID-19 is characterized by a wide range of complications, which include pulmonary embolism, thromboembolism and arterial clot formation, arrhythmias, cardiomyopathy, multiorgan failure, and more. The disease has caused a worldwide pandemic, and despite various measures such as social distancing, various preventive strategies, and therapeutic approaches, and the creation of vaccines, the novel coronavirus infection (COVID-19) still hides many mysteries for the scientific community. Oxidative stress has been suggested to play an essential role in the pathogenesis of COVID-19, and determining free radical levels in patients with coronavirus infection may provide an insight into disease severity. The generation of abnormal levels of oxidants under a COVID-19-induced cytokine storm causes the irreversible oxidation of a wide range of macromolecules and subsequent damage to cells, tissues, and organs. Clinical studies have shown that oxidative stress initiates endothelial damage, which increases the risk of complications in COVID-19 and post-COVID-19 or long-COVID-19 cases. This review describes the role of oxidative stress and free radicals in the mediation of COVID-19-induced mitochondrial and endothelial dysfunction.
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Affiliation(s)
- Ekaterina Georgieva
- Department of General and Clinical Pathology, Forensic Medicine, Deontology and Dermatovenerology, Medical Faculty, Trakia University, 11 Armeiska Str., 6000 Stara Zagora, Bulgaria;
| | - Julian Ananiev
- Department of General and Clinical Pathology, Forensic Medicine, Deontology and Dermatovenerology, Medical Faculty, Trakia University, 11 Armeiska Str., 6000 Stara Zagora, Bulgaria;
| | - Yovcho Yovchev
- Department of Surgery and Anesthesiology, University Hospital “Prof. Dr. St. Kirkovich”, 6000 Stara Zagora, Bulgaria; (Y.Y.); (G.A.)
| | - Georgi Arabadzhiev
- Department of Surgery and Anesthesiology, University Hospital “Prof. Dr. St. Kirkovich”, 6000 Stara Zagora, Bulgaria; (Y.Y.); (G.A.)
| | - Hristo Abrashev
- Department of Vascular Surgery, Medical Faculty, Trakia University, 11 Armeiska Str., 6000 Stara Zagora, Bulgaria;
| | - Despina Abrasheva
- II Department of Internal Medicine Therapy: Cardiology, Rheumatology, Hematology and Gastroenterology, Medical Faculty, Trakia University, 6000 Stara Zagora, Bulgaria;
| | - Vasil Atanasov
- Forensic Toxicology Laboratory, Military Medical Academy, 3 G. Sofiiski, 1606 Sofia, Bulgaria; (V.A.); (R.K.)
| | - Rositsa Kostandieva
- Forensic Toxicology Laboratory, Military Medical Academy, 3 G. Sofiiski, 1606 Sofia, Bulgaria; (V.A.); (R.K.)
| | - Mitko Mitev
- Department of Diagnostic Imaging, University Hospital “Prof. Dr. St. Kirkovich”, 6000 Stara Zagora, Bulgaria;
| | - Kamelia Petkova-Parlapanska
- Department of Medical Chemistry and Biochemistry, Medical Faculty, Trakia University, 11 Armeiska Str., 6000 Stara Zagora, Bulgaria; (K.P.-P.); (Y.K.)
| | - Yanka Karamalakova
- Department of Medical Chemistry and Biochemistry, Medical Faculty, Trakia University, 11 Armeiska Str., 6000 Stara Zagora, Bulgaria; (K.P.-P.); (Y.K.)
| | - Iliana Koleva-Korkelia
- Department of Obstetrics and Gynaecology Clinic, University Hospital “Prof. St. Kirkovich”, 6000 Stara Zagora, Bulgaria;
| | - Vanya Tsoneva
- Department of Propaedeutics of Internal Medicine and Clinical Laboratory, Medical Faculty, Trakia University, 11 Armeiska Str., 6000 Stara Zagora, Bulgaria;
| | - Galina Nikolova
- Department of Medical Chemistry and Biochemistry, Medical Faculty, Trakia University, 11 Armeiska Str., 6000 Stara Zagora, Bulgaria; (K.P.-P.); (Y.K.)
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12
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Lim JK, Njei B. Clinical and Histopathological Discoveries in Patients with Hepatic Injury and Cholangiopathy Who Have Died of COVID-19: Insights and Opportunities for Intervention. Hepat Med 2023; 15:151-164. [PMID: 37814605 PMCID: PMC10560482 DOI: 10.2147/hmer.s385133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 09/28/2023] [Indexed: 10/11/2023] Open
Abstract
The COVID-19 pandemic has had a profound impact on global health, necessitating a comprehensive understanding of its diverse manifestations. Cholangiopathy, a condition characterized by biliary dysfunction, has emerged as a significant complication in COVID-19 patients. In this review, we report the epidemiology of COVID-19, describe the hepatotropism of SARS-CoV-2, and present the histopathology of acute liver injury (ALI) in COVID-19. Additionally, we explore the relationship between pre-existing chronic liver disease and COVID-19, shedding light on the increased susceptibility of these individuals to develop cholangiopathy. Through an in-depth analysis of cholangiopathy in COVID-19 patients, we elucidate its clinical manifestations, diagnostic criteria, and underlying pathogenesis involving inflammation, immune dysregulation, and vascular changes. Furthermore, we provide a summary of studies investigating post-COVID-19 cholangiopathy, highlighting the long-term effects and potential management strategies for this condition, and discussing opportunities for intervention, including therapeutic targets, diagnostic advancements, supportive care, and future research needs.
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Affiliation(s)
- Joseph K Lim
- Yale Liver Center and Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Basile Njei
- Yale Liver Center and Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
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13
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Aghamohamadi N, Shahba F, Zarezadeh Mehrabadi A, Khorramdelazad H, Karimi M, Falak R, Emameh RZ. Age-dependent immune responses in COVID-19-mediated liver injury: focus on cytokines. Front Endocrinol (Lausanne) 2023; 14:1139692. [PMID: 37654571 PMCID: PMC10465349 DOI: 10.3389/fendo.2023.1139692] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 07/21/2023] [Indexed: 09/02/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is potentially pathogenic and causes severe symptoms; in addition to respiratory syndromes, patients might experience other severe conditions such as digestive complications and liver complications injury. The abnormality in the liver is manifested by hepatobiliary dysfunction and enzymatic elevation, which is associated with morbidity and mortality. The direct cytopathic effect, immune dysfunction, cytokine storm, and adverse effects of therapeutic regimens have a crucial role in the severity of liver injury. According to aging and immune system alterations, cytokine patterns may also change in the elderly. Moreover, hyperproduction of cytokines in the inflammatory response to SARS-CoV-2 can lead to multi-organ dysfunction. The mortality rate in elderly patients, particularly those with other comorbidities, is also higher than in adults. Although the pathogenic effect of SARS-CoV-2 on the liver has been widely studied, the impact of age and immune-mediated responses at different ages remain unclear. This review discusses the association between immune system responses in coronavirus disease 2019 (COVID-19) patients of different ages and liver injury, focusing on cytokine alterations.
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Affiliation(s)
- Nazanin Aghamohamadi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Faezeh Shahba
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Zarezadeh Mehrabadi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Milad Karimi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Falak
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Reza Zolfaghari Emameh
- Department of Energy and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
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14
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Mangoni AA, Zinellu A. An Updated Systematic Review and Meta-Analysis of the Association between the De Ritis Ratio and Disease Severity and Mortality in Patients with COVID-19. Life (Basel) 2023; 13:1324. [PMID: 37374107 DOI: 10.3390/life13061324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 06/01/2023] [Indexed: 06/29/2023] Open
Abstract
Patients with Coronavirus disease 2019 (COVID-19) often have elevations in markers of liver injury, particularly serum aspartate transaminase (AST) and alanine transaminase (ALT). Such alterations may affect the AST/ALT ratio (De Ritis ratio) and, potentially, clinical outcomes. We conducted an updated systematic review and meta-analysis of the association between the De Ritis ratio and COVID-19 severity and mortality in hospitalized patients. PubMed, Web of Science, and Scopus were searched between 1 December 2019 and 15 February 2023. The Joanna Briggs Institute Critical Appraisal Checklist and the Grading of Recommendations, Assessment, Development, and Evaluation were used to assess the risk of bias and the certainty of the evidence, respectively. Twenty-four studies were identified. The De Ritis ratio on admission was significantly higher in patients with severe disease and non-survivors vs. patients with non-severe disease and survivors (15 studies, weighted mean difference = 0.36, 95% CI 0.24 to 0.49, p < 0.001). The De Ritis ratio was also associated with severe disease and/or mortality using odds ratios (1.83, 95% CI 1.40 to 2.39, p ˂ 0.001; nine studies). Similar results were observed using hazard ratios (2.36, 95% CI 1.17 to 4.79, p = 0.017; five studies). In six studies, the pooled area under the receiver operating characteristic curve was 0.677 (95% CI 0.612 to 0.743). In our systematic review and meta-analysis, higher De Ritis ratios were significantly associated with severe disease and mortality in COVID-19 patients. Therefore, the De Ritis ratio can be useful for early risk stratification and management in this patient group (PROSPERO registration number: CRD42023406916).
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Affiliation(s)
- Arduino A Mangoni
- Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Bedford Park, SA 5042, Australia
- Department of Clinical Pharmacology, Flinders Medical Centre, Southern Adelaide Local Health Network, Bedford Park, SA 5042, Australia
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy
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15
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Akkiz H. Unraveling the Molecular and Cellular Pathogenesis of COVID-19-Associated Liver Injury. Viruses 2023; 15:1287. [PMID: 37376587 PMCID: PMC10304875 DOI: 10.3390/v15061287] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 06/29/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) continues to cause substantial morbidity and mortality. Most infections are mild; however, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm, and acute respiratory distress syndrome. Patients with chronic liver disease have been frequently affected, experiencing high morbidity and mortality. In addition, elevated liver enzymes may be a risk factor for disease progression, even in the absence of underlying liver disease. While the respiratory tract is a primary target of SARS-CoV-2, it has become evident that COVID-19 is a multisystemic infectious disease. The hepatobiliary system might be influenced during COVID-19 infection, ranging from a mild elevation of aminotransferases to the development of autoimmune hepatitis and secondary sclerosing cholangitis. Furthermore, the virus can promote existing chronic liver diseases to liver failure and activate the autoimmune liver disease. Whether the direct cytopathic effects of the virus, host reaction, hypoxia, drugs, vaccination, or all these risk factors cause liver injury has not been clarified to a large extent in COVID-19. This review article discussed the molecular and cellular mechanisms involved in the pathogenesis of SARS-CoV-2 virus-associated liver injury and highlighted the emerging role of liver sinusoidal epithelial cells (LSECs) in virus-related liver damage.
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Affiliation(s)
- Hikmet Akkiz
- Department of Gastroenterology and Hepatology, Medical Faculty, Bahçeşehir University, Istanbul 34349, Turkey
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16
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Seyoum F. Mechanisms of severe acute respiratory syndrome coronavirus-2 induced liver damage and alteration of some liver biomarkers: A review. Medicine (Baltimore) 2023; 102:e33517. [PMID: 37171303 PMCID: PMC10174413 DOI: 10.1097/md.0000000000033517] [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: 03/01/2023] [Revised: 03/22/2023] [Accepted: 03/22/2023] [Indexed: 05/13/2023] Open
Abstract
The most serious problem for people suffering from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is liver damage. The liver is a frequently affected organ due to the metabolizing and detoxifying functions of several endogenous and exogenous molecules. In COVID-19-affected individuals, even moderate loss of hepatic function could dramatically affect the therapeutic efficacy of antiviral drugs metabolized in the liver. The clear mechanism of hepatocellular damage from SARS-CoV-2 infection is not fully understood. The main objective of this review is to identify potential mechanisms of SARS-2 induced liver damage, treatment outcomes in SARS-CoV-2-infected patients, and future direction. Electronic databases including Web of Science, Google Scholar, MEDLINE, Scopus, and Cochrane library were used to systematically search without limitation of publication date and status. Observational, retrospective cohort, prospective case-control, cohort studies, cross-sectional studies, or clinical trials were included. Liver damage in coronavirus patients is characterized by histopathological changes and abnormal elevation of some liver function tests. These abnormalities include elevation of Alanine aminotransferase, Aspartate aminotransferase, Gamma-glutamyl transferase, Alkaline phosphatase, and Serum bilirubin levels. Histopathological changes of the liver might consist of complete or partial thrombosis of the portal and sinusoidal vessels, portal tract fibrosis, and focally markedly enlarged and fibrotic hepatocytes. Understanding the fundamental molecular and immunological processes of COVID-19-related liver injury is essential for the selection of appropriate drugs and the logical development of successful treatment.
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Affiliation(s)
- Fikadu Seyoum
- Department of Medical Biochemistry, College of Medicine and Health Sciences, Ambo University, Addis Ababa, Ethiopia
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17
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Matsuda H, Nosaka T, Hiramatsu K, Takahashi K, Naito T, Ofuji K, Ohtani M, Imamura Y, Iwasaki H, Nakamoto Y. Histology and cytokine levels in hepatic injury accompanying a case of non-severe COVID-19. Clin J Gastroenterol 2023; 16:270-278. [PMID: 36690911 PMCID: PMC9870769 DOI: 10.1007/s12328-023-01755-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 01/03/2023] [Indexed: 01/25/2023]
Abstract
The pathogenesis of liver dysfunction that complicates coronavirus disease 2019 (COVID-19) remains unclear, especially in mild to moderate severity cases. In this case, a novel coronavirus infection was detected by polymerase chain reaction (PCR) in a 76-year-old woman hospitalized after presenting with fever. No other abnormal physical findings were observed, and oxygen administration was not required. Chest computed tomography (CT) showed a ground-glass-like and an infiltrative shadow in the right lung, and moderate COVID-19 was diagnosed. Initially, the fever resolved, and PCR turned negative; however, the fever reappeared on hospitalization day 14, and CT showed pneumonia exacerbation accompanied by new onset of fatty liver. Biochemical testing revealed marked liver dysfunction, accompanied by elevated serum interleukin (IL)-6, IL-10, and tumor necrosis factor-α levels. Physical findings and all laboratory parameters improved after conservative treatment, and she was discharged on day 22. A liver biopsy performed 44 days post-discharge showed T-cell-dominant inflammatory cell infiltration, mainly in the portal region. Some hepatocytes showed fatty degeneration.We report a case of moderate COVID-19 in which histological hepatitis persisted after a substantial period had passed since the initial infection had cleared and associated transaminase elevations had resolved, with a comparison of serum cytokine dynamics.
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Affiliation(s)
- Hidetaka Matsuda
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-Cho, Yoshida-Gun, Fukui, 910-1193, Japan
| | - Takuto Nosaka
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-Cho, Yoshida-Gun, Fukui, 910-1193, Japan
| | - Katsushi Hiramatsu
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-Cho, Yoshida-Gun, Fukui, 910-1193, Japan
| | - Kazuto Takahashi
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-Cho, Yoshida-Gun, Fukui, 910-1193, Japan
| | - Tatsushi Naito
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-Cho, Yoshida-Gun, Fukui, 910-1193, Japan
| | - Kazuya Ofuji
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-Cho, Yoshida-Gun, Fukui, 910-1193, Japan
| | - Masahiro Ohtani
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-Cho, Yoshida-Gun, Fukui, 910-1193, Japan
| | - Yoshiaki Imamura
- Division of Diagnostic Pathology/Surgical Pathology, University of Fukui Hospital, Fukui, Japan
| | - Hiromichi Iwasaki
- Division of Infection Control and Prevention, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-Cho, Yoshida-Gun, Fukui, 910-1193, Japan.
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18
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Miranda C, Garlatti E, Da Porto A, Rinaldo E, Grazioli S, Zanette G, Tonizzo M. Liver injury in COVID-19 patients with non-alcoholic fatty liver disease: an update. Arch Med Sci Atheroscler Dis 2023; 8:e1-e10. [PMID: 37153375 PMCID: PMC10161789 DOI: 10.5114/amsad/160950] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Accepted: 02/06/2023] [Indexed: 05/09/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has revolutionized the priorities of the medical society worldwide. Although most patients infected with SARS-CoV-2 exhibit respiratory symptoms, other organs may also be involved, including the liver, often resulting in liver injury. Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and its prevalence is expected to increase together with the epidemics of type 2 diabetes and obesity. Data about liver injury during COVID-19 are numerous, while overviews of this infection in patients with NAFLD, both in terms of respiratory and liver, are emerging. In this review, we summarise the current research focusing on COVID-19 in NAFLD patients and discuss the association between liver injury in COVID-19 subjects and non-alcoholic fatty liver disease.
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Affiliation(s)
- Cesare Miranda
- Clinic of Endocrinology and Metabolism Diseases, Pordenone Hospital, Pordenone, Italy
| | - Elena Garlatti
- Internal Medicine, Santa Maria degli Angeli Hospital, Pordenone, Italy
| | - Andrea Da Porto
- Department of Medicine, Clinica Medica, University of Udine, Udine, Italy
| | - Elena Rinaldo
- Clinic of Endocrinology and Metabolism Diseases, Pordenone Hospital, Pordenone, Italy
| | - Silvia Grazioli
- Internal Medicine, Santa Maria degli Angeli Hospital, Pordenone, Italy
| | - Giorgio Zanette
- Clinic of Endocrinology and Metabolism Diseases, Pordenone Hospital, Pordenone, Italy
| | - Maurizio Tonizzo
- Internal Medicine, Santa Maria degli Angeli Hospital, Pordenone, Italy
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19
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Ali FEM, Abd El-Aziz MK, Ali MM, Ghogar OM, Bakr AG. COVID-19 and hepatic injury: cellular and molecular mechanisms in diverse liver cells. World J Gastroenterol 2023; 29:425-449. [PMID: 36688024 PMCID: PMC9850933 DOI: 10.3748/wjg.v29.i3.425] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/15/2022] [Accepted: 12/23/2022] [Indexed: 01/12/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) represents a global health and economic challenge. Hepatic injuries have been approved to be associated with severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. The viral tropism pattern of SARS-CoV-2 can induce hepatic injuries either by itself or by worsening the conditions of patients with hepatic diseases. Besides, other factors have been reported to play a crucial role in the pathological forms of hepatic injuries induced by SARS-CoV-2, including cytokine storm, hypoxia, endothelial cells, and even some treatments for COVID-19. On the other hand, several groups of people could be at risk of hepatic COVID-19 complications, such as pregnant women and neonates. The present review outlines and discusses the interplay between SARS-CoV-2 infection and hepatic injury, hepatic illness comorbidity, and risk factors. Besides, it is focused on the vaccination process and the role of developed vaccines in preventing hepatic injuries due to SARS-CoV-2 infection.
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Affiliation(s)
- Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt
| | | | - Mahmoud M Ali
- Department of Pharmacology, Al-Azhar University, Assiut 71524, Egypt
| | - Osama M Ghogar
- Department of Biochemistry Faculty of Pharmacy, Badr University in Assiut, Egypt
| | - Adel G Bakr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt
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20
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Khazaaleh S, Alomari M, Sharma S, Kapila N, Zervos XB, Gonzalez AJ. COVID-19 in liver transplant patients: Impact and considerations. World J Transplant 2023; 13:1-9. [PMID: 36687560 PMCID: PMC9850867 DOI: 10.5500/wjt.v13.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 11/04/2022] [Accepted: 12/13/2022] [Indexed: 01/12/2023] Open
Abstract
The coronavirus disease 2019 pandemic has significantly impacted liver tran splantation worldwide, leading to major effects on the transplant process, including the pretransplant, perioperative, and post-transplant periods. It is believed that patients with chronic liver disease, especially those with cirrhosis, have a higher risk of complications from coronavirus disease 2019 infection compared to the general population. However, evaluation of coronavirus disease 2019 effects on liver transplant patients has not uniformly demonstrated worse outcomes. Nonetheless, the pandemic created significant challenges and restrictions on transplant policies and organ allocation.
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Affiliation(s)
- Shrouq Khazaaleh
- Department of Internal Medicine, Cleveland Clinic Fairview Hospital, Cleveland, OH 44126, United States
| | - Mohammad Alomari
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Sanskriti Sharma
- Department of Internal Medicine, WellStar Atlanta Medical Center, Atlanta, GA 30312, United States
| | - Nikhil Kapila
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Xaralambos Bobby Zervos
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Adalberto Jose Gonzalez
- Department of Gastroenterology and Hepatology, Cleveland Clinic Florida, Weston, FL 33331, United States
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21
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Papagiouvanni I, Kotoulas SC, Pataka A, Spyratos DG, Porpodis K, Boutou AK, Papagiouvannis G, Grigoriou I, Vettas C, Goulis I. COVID-19 and liver injury: An ongoing challenge. World J Gastroenterol 2023; 29:257-271. [PMID: 36687117 PMCID: PMC9846934 DOI: 10.3748/wjg.v29.i2.257] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/29/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
The new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in December 2019, in Wuhan, China. The virus was rapidly spread worldwide, causing coronavirus disease 2019 (COVID-19) pandemic. Although COVID-19 is presented, usually, with typical respiratory symptoms (i.e., dyspnea, cough) and fever, extrapulmonary manifestations are also encountered. Liver injury is a common feature in patients with COVID-19 and ranges from mild and temporary elevation of liver enzymes to severe liver injury and, even, acute liver failure. The pathogenesis of liver damage is not clearly defined; multiple mechanisms contribute to liver disorder, including direct cytopathic viral effect, cytokine storm and immune-mediated hepatitis, hypoxic injury, and drug-induced liver toxicity. Patients with underlying chronic liver disease (i.e., cirrhosis, non-alcoholic fatty liver disease, alcohol-related liver disease, hepatocellular carcinoma, etc.) may have greater risk to develop both severe COVID-19 and further liver deterioration, and, as a consequence, certain issues should be considered during disease management. The aim of this review is to present the prevalence, clinical manifestation and pathophysiological mechanisms of liver injury in patients with SARS-CoV-2 infection. Moreover, we overview the association between chronic liver disease and SARS-CoV-2 infection and we briefly discuss the management of liver injury during COVID-19.
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Affiliation(s)
- Ioanna Papagiouvanni
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Thessaloniki, Greece
| | | | - Athanasia Pataka
- Department of Respiratory Medicine, G Papanikolaou Hospital, Resp Failure Unit, Aristotle University of Thessaloniki, Thessaloniki 57001, Greece
| | - Dionisios G Spyratos
- Pulmonary Department, Aristotle University of Thessaloniki, Thessaloniki 57001, Greece
| | - Konstantinos Porpodis
- Pulmonary Department, Aristotle University of Thessaloniki, Thessaloniki 57001, Greece
| | - Afroditi K Boutou
- Pulmonary Department, G Papanikolaou Hospital, Resp Failure Unit, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Georgios Papagiouvannis
- Department of Pharmacy, School of Health Sciences, Frederick University, Nicosia 1036, Cyprus
| | - Ioanna Grigoriou
- Respiratory Failure Clinic, Papanikolaou General Hospital, Thessloniki 57001, Greece
| | - Christos Vettas
- Fourth Department of Internal Medicine, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Ioannis Goulis
- Fourth Department of Internal Medicine, Hippokration General Hospital, Thessaloniki 54642, Greece
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22
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Dietrich CG, Geier A, Merle U. Non-alcoholic fatty liver disease and COVID-19: Harmless companions or disease intensifier? World J Gastroenterol 2023; 29:367-377. [PMID: 36687116 PMCID: PMC9846932 DOI: 10.3748/wjg.v29.i2.367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 11/09/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
The pandemics of coronavirus disease 2019 (COVID-19) and non-alcoholic fatty liver disease (NAFLD) coexist. Elevated liver function tests are frequent in COVID-19 and may influence liver damage in NAFLD, while preexisting liver damage from NAFLD may influence the course of COVID-19. However, the prognostic relevance of this interaction, though, is unclear. Obesity is a risk factor for the presence of NAFLD as well as a severe course of COVID-19. Cohort studies reveal conflicting results regarding the influence of NAFLD presence on COVID-19 illness severity. Striking molecular similarities of cytokine pathways in both diseases, including postacute sequelae of COVID-19, suggest common pathways for chronic low-activity inflammation. This review will summarize existing data regarding the interaction of both diseases and discuss possible mechanisms of the influence of one disease on the other.
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Affiliation(s)
| | - Andreas Geier
- Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg 97080, Germany
| | - Uta Merle
- Department of Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg 69120, Germany
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23
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Brandi N, Spinelli D, Granito A, Tovoli F, Piscaglia F, Golfieri R, Renzulli M. COVID-19: Has the Liver Been Spared? Int J Mol Sci 2023; 24:1091. [PMID: 36674607 PMCID: PMC9866733 DOI: 10.3390/ijms24021091] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 01/09/2023] Open
Abstract
The liver is a secondary and often collateral target of COVID-19 disease but can lead to important consequences. COVID-19 might directly cause a high number of complications in patients with pre-existing chronic liver disease, increasing their risk of hepatic decompensation. Moreover, it also determines indirect consequences in the management of patients with liver disease, especially in those suffering from decompensated cirrhosis and HCC, as well as in the execution of their follow-up and the availability of all therapeutic possibilities. Liver imaging in COVID-19 patients proved to be highly nonspecific, but it can still be useful for identifying the complications that derive from the infection. Moreover, the recent implementation of telemedicine constitutes a possible solution to both the physical distancing and the re-organizational difficulties arising from the pandemic. The present review aims to encompass the currently hypothesized pathophysiological mechanisms of liver injury in patients with COVID-19 mediated by both the direct invasion of the virus and its indirect effects and analyze the consequence of the pandemic in patients with chronic liver disease and liver tumors, with particular regard to the management strategies that have been implemented to face this worldwide emergency and that can be further improved.
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Affiliation(s)
- Nicolò Brandi
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy
| | - Daniele Spinelli
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Rita Golfieri
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy
| | - Matteo Renzulli
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, 40138 Bologna, Italy
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24
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Naeem M, Bano N, Manzoor S, Ahmad A, Munawar N, Razak SIA, Lee TY, Devaraj S, Hazafa A. Pathogenetic Mechanisms of Liver-Associated Injuries, Management, and Current Challenges in COVID-19 Patients. Biomolecules 2023; 13:99. [PMID: 36671484 PMCID: PMC9855873 DOI: 10.3390/biom13010099] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 11/28/2022] [Accepted: 12/10/2022] [Indexed: 01/06/2023] Open
Abstract
The global outbreak of COVID-19 possesses serious challenges and adverse impacts for patients with progression of chronic liver disease and has become a major threat to public health. COVID-19 patients have a high risk of lung injury and multiorgan dysfunction that remains a major challenge to hepatology. COVID-19 patients and those with liver injury exhibit clinical manifestations, including elevation in ALT, AST, GGT, bilirubin, TNF-α, and IL-6 and reduction in the levels of CD4 and CD8. Liver injury in COVID-19 patients is induced through multiple factors, including a direct attack of SARS-CoV-2 on liver hepatocytes, hypoxia reperfusion dysfunction, cytokine release syndrome, drug-induced hepatotoxicity caused by lopinavir and ritonavir, immune-mediated inflammation, renin-angiotensin system, and coagulopathy. Cellular and molecular mechanisms underlying liver dysfunction are not fully understood in severe COVID-19 attacks. High mortality and the development of chronic liver diseases such as cirrhosis, alcoholic liver disease, autoimmune hepatitis, nonalcoholic fatty liver disease, and hepatocellular carcinoma are also associated with patients with liver damage. COVID-19 patients with preexisting or developing liver disease should be managed. They often need hospitalization and medication, especially in conjunction with liver transplants. In the present review, we highlight the attack of SARS-CoV-2 on liver hepatocytes by exploring the cellular and molecular events underlying the pathophysiological mechanisms in COVID-19 patients with liver injury. We also discuss the development of chronic liver diseases during the progression of SARS-CoV-2 replication. Lastly, we explore management principles in COVID-19 patients with liver injury and liver transplantation.
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Affiliation(s)
- Muhammad Naeem
- College of Life Science, Hebei Normal University, Shijiazhuang 050024, China
| | - Naheed Bano
- Department of Fisheries and Aquaculture, Muhammad Nawaz Sharif University of Agriculture, Multan 60000, Pakistan
| | - Saba Manzoor
- Department of Zoology, University of Sialkot, Sialkot 51310, Pakistan
| | - Aftab Ahmad
- Biochemistry/Center for Advanced Studies in Agriculture and Food Security (CAS-AFS), University of Agriculture, Faisalabad 38040, Pakistan
| | - Nayla Munawar
- Department of Chemistry, College of Science, United Arab Emirates University, Al-Ain 15551, United Arab Emirates
| | - Saiful Izwan Abd Razak
- BioInspired Device and Tissue Engineering Research Group (BioInspira), Department of Biomedical Engineering and Health Sciences, Faculty of Electrical Engineering, Universiti Teknologi Malaysia, Johor Bahru 81310, Malaysia
- Sports Innovation & Technology Centre, Institute of Human Centred Engineering, Universiti Teknologi Malaysia, Johor Bahru 81310, Malaysia
| | - Tze Yan Lee
- School of Liberal Arts, Science and Technology (PUScLST) Perdana University, Suite 9.2, 9th Floor, Wisma Chase Perdana, Changkat Semantan Damansara Heights, Kuala Lumpur 50490, Malaysia
| | - Sutha Devaraj
- Faculty of Medicine, AIMST University, Bedong 08100, Malaysia
| | - Abu Hazafa
- Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
- Department of Biochemistry, University of Agriculture Faisalabad, Faisalabad 38040, Pakistan
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25
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Bucurica S, Ionita Radu F, Bucurica A, Socol C, Prodan I, Tudor I, Sirbu CA, Plesa FC, Jinga M. Risk of New-Onset Liver Injuries Due to COVID-19 in Preexisting Hepatic Conditions-Review of the Literature. MEDICINA (KAUNAS, LITHUANIA) 2022; 59:medicina59010062. [PMID: 36676691 PMCID: PMC9864905 DOI: 10.3390/medicina59010062] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/21/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022]
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacted the world and caused the 2019 coronavirus disease (COVID-19) pandemic. The clinical manifestations of the virus can vary from patient to patient, depending on their respective immune system and comorbidities. SARS-CoV-2 can affect patients through two mechanisms: directly by targeting specific receptors or by systemic mechanisms. We reviewed data in the latest literature in order to discuss and determine the risk of new-onset liver injuries due to COVID-19 in preexisting hepatic conditions. The particular expression of angiotensin-converting enzyme 2 (ACE2) receptors is an additional risk factor for patients with liver disease. COVID-19 causes more severe forms in patients with non-alcoholic fatty liver disease (NAFLD), increases the risk of cirrhosis decompensation, and doubles the mortality for these patients. The coinfection SARS-CoV-2-viral hepatitis B or C might have different outcomes depending on the stage of the liver disease. Furthermore, the immunosuppressant treatment administered for COVID-19 might reactivate the hepatic virus. The high affinity of SARS-CoV-2 spike proteins for cholangiocytes results in a particular type of secondary sclerosing cholangitis. The impact of COVID-19 infection on chronic liver disease patients is significant, especially in cirrhosis, influencing the prognosis and outcome of these patients.
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Affiliation(s)
- Sandica Bucurica
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Gastroenterology, ‘Dr. Carol Davila’ Central Military Emergency University Hospital, 010242 Bucharest, Romania
| | - Florentina Ionita Radu
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Gastroenterology, ‘Dr. Carol Davila’ Central Military Emergency University Hospital, 010242 Bucharest, Romania
- Correspondence: (F.I.R.); (F.C.P.)
| | - Ana Bucurica
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Calin Socol
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Ioana Prodan
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Gastroenterology, ‘Dr. Carol Davila’ Central Military Emergency University Hospital, 010242 Bucharest, Romania
| | - Ioana Tudor
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Gastroenterology, ‘Dr. Carol Davila’ Central Military Emergency University Hospital, 010242 Bucharest, Romania
| | - Carmen Adella Sirbu
- Department of Neurology, ‘Dr. Carol Davila’ Central Military Emergency University Hospital, 010242 Bucharest, Romania
- Centre for Cognitive Research in Neuropsychiatric Pathology (Neuropsy-Cog), Department of Neurology, Faculty of Medicine, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timișoara, Romania
| | - Florentina Cristina Plesa
- Department of Neurology, ‘Dr. Carol Davila’ Central Military Emergency University Hospital, 010242 Bucharest, Romania
- Department of Preclinical Disciplines, Titu Maiorescu University of Medicine, 031593 Bucharest, Romania
- Correspondence: (F.I.R.); (F.C.P.)
| | - Mariana Jinga
- Department of Gastroenterology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Gastroenterology, ‘Dr. Carol Davila’ Central Military Emergency University Hospital, 010242 Bucharest, Romania
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26
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Jia FJ, Han J. Liver injury in COVID-19: Holds ferritinophagy-mediated ferroptosis accountable. World J Clin Cases 2022; 10:13148-13156. [PMID: 36683648 PMCID: PMC9850986 DOI: 10.12998/wjcc.v10.i36.13148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 11/20/2022] [Accepted: 12/08/2022] [Indexed: 12/26/2022] Open
Abstract
Even in patients without a history of liver disease, liver injury caused by coronavirus disease 2019 (COVID-19) is gradually becoming more common. However, the precise pathophysiological mechanisms behind COVID-19's liver pathogenicity are still not fully understood. We hypothesize that inflammation may become worse by cytokine storms caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Elevated ferritin levels can initiate ferritinophagy mediated by nuclear receptor coactivator 4 (NCOA4), which leads to iron elevation, and ferroptosis. In COVID-19 patients, ferroptosis can be restricted to reduce disease severity and liver damage by targeting NCOA4-mediated ferritinophagy. To confirm the role of ferritinophagy-mediated ferroptosis in SARS-CoV-2 infection, further research is required.
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Affiliation(s)
- Feng-Ju Jia
- School of Nursing, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Jing Han
- School of Nursing, Qingdao University, Qingdao 266071, Shandong Province, China
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27
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Elghannam MT, Hassanien MH, Ameen YA, ELattar GM, ELRay AA, Turky EA, ELTalkawy MD. COVID-19 and liver diseases. EGYPTIAN LIVER JOURNAL 2022; 12:43. [PMID: 35880136 PMCID: PMC9301896 DOI: 10.1186/s43066-022-00202-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 07/06/2022] [Indexed: 12/15/2022] Open
Abstract
Coronavirus causes an outbreak of viral pneumonia that spread throughout the world. Liver injury is becoming more widely recognized as a component of the clinical picture of COVID-19 infection. Hepatitis with serum ALT elevation has been reported in up to half of patients. Patients with CLD were at a higher risk of decompensation with liver failure, hospitalization, and mortality. The percentage of acute liver injury (ALI) varied from 5 to 28%. COVID-19 hinders HCV elimination by 2030. It is recommended to continue treatment of chronic HCV and chronic HBV if already receiving treatment. Consider using antiviral therapy to prevent viral flare-ups in patients with occult or resolved HBV and COVID-19 who are receiving immunosuppressive agents. Patients with AIH do not have an increased risk of adverse outcomes even in high-risk areas. There is an association between MAFLD and disease progression. Patients with any type of cancer are at a higher risk of infection and are more likely to develop more severe clinical outcomes. Most societies advise against immunosuppressant modifications in patients with mild COVID-19, whereas in rare cases such as severe lymphopenia, worsening pneumonia, or bacterial or fungal superinfection, reduction or discontinuation of antiproliferative agents and lymphocyte-depleting therapies has been suggested.
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28
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Hanif FM, Majid Z, Ahmed S, Luck NH, Mubarak M. Hepatic manifestations of coronavirus disease 2019 infection: Clinical and laboratory perspective. World J Virol 2022; 11:453-466. [PMID: 36483109 PMCID: PMC9724207 DOI: 10.5501/wjv.v11.i6.453] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/17/2022] [Accepted: 11/07/2022] [Indexed: 11/23/2022] Open
Abstract
The novel coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has become a global challenge of unprecedented nature since December 2019. Although most patients with COVID-19 exhibit mild clinical manifestations and upper respiratory tract involvement, in approximately 5%-10% of patients, the disease is severe and involves multiple organs, leading to multi-organ dysfunction and failure. The liver and gastrointestinal tract are also frequently involved in COVID-19. In the context of liver involvement in patients with COVID-19, many key aspects need to be addressed in both native and transplanted organs. This review focuses on the clinical presentations and laboratory abnormalities of liver function tests in patients with COVID-19 with no prior liver disease, patients with pre-existing liver diseases and liver transplant recipients. A brief overview of the history of COVID-19 and etiopathogenesis of the liver injury will also be described as a prelude to better understanding the above aspects.
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Affiliation(s)
- Farina M Hanif
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Zain Majid
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Shoaib Ahmed
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Nasir H Luck
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Muhammed Mubarak
- Department of Pathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
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29
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Wang H, Wang X, Li T, Lai D, Zhang YD. Adverse effect signature extraction and prediction for drugs treating COVID-19. Front Genet 2022; 13:1019940. [DOI: 10.3389/fgene.2022.1019940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/13/2022] [Indexed: 11/06/2022] Open
Abstract
Given the considerable cost of drug discovery, drug repurposing is becoming attractive as it can effectively shorten the development timeline and reduce the development cost. However, most existing drug-repurposing methods omitted the heterogeneous health conditions of different COVID-19 patients. In this study, we evaluated the adverse effect (AE) profiles of 106 COVID-19 drugs. We extracted four AE signatures to characterize the AE distribution of 106 COVID-19 drugs by non-negative matrix factorization (NMF). By integrating the information from four distinct databases (AE, bioassay, chemical structure, and gene expression information), we predicted the AE profiles of 91 drugs with inadequate AE feedback. For each of the drug clusters, discriminant genes accounting for mechanisms of different AE signatures were identified by sparse linear discriminant analysis. Our findings can be divided into three parts. First, drugs abundant with AE-signature 1 (for example, remdesivir) should be taken with caution for patients with poor liver, renal, or cardiac functions, where the functional genes accumulate in the RHO GTPases Activate NADPH Oxidases pathway. Second, drugs featuring AE-signature 2 (for example, hydroxychloroquine) are unsuitable for patients with vascular disorders, with relevant genes enriched in signal transduction pathways. Third, drugs characterized by AE signatures 3 and 4 have relatively mild AEs. Our study showed that NMF and network-based frameworks contribute to more precise drug recommendations.
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Abstract
With the spread of coronavirus disease 2019 (COVID-19) worldwide, extrapulmonary lesions, including liver dysfunction, have attracted growing attention. The mechanisms underlying liver dysfunction in COVID-19 remain unclear. The reported prevalence of liver dysfunction varies widely across studies. In addition, its impact on clinical outcomes and its recovery after discharge are still controversial. In this review, pathological and laboratory findings were analyzed to reveal the potential mechanisms of COVID-19-induced liver injury from onset to recovery. Four patterns of liver damage were summarized according to the pathological findings, including hypoxemia and shock changes, vascular thrombosis and vascular damage, bile duct damage, and other histological changes. With a strict definition, the prevalence of liver dysfunction was not as high as reported. Meanwhile, liver dysfunction improved during the process of recovery. Nevertheless, the definite liver dysfunction was significantly associated with severe clinical course, which should not be ignored.
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Affiliation(s)
- Wen-Zheng Yuan
- Department of Gastrointestinal Surgery II, Renmin Hospital, Wuhan University, Wuhan, Hubei Province, China
| | - Tao Fu
- Department of Gastrointestinal Surgery II, Renmin Hospital, Wuhan University, Wuhan, Hubei Province, China
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31
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Huang Z, Zhang H, Fu X, Han L, Zhang H, Zhang L, Zhao J, Xiao D, Li H, Li P. Autophagy-driven neutrophil extracellular traps: The dawn of sepsis. Pathol Res Pract 2022; 234:153896. [PMID: 35462228 DOI: 10.1016/j.prp.2022.153896] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 03/28/2022] [Accepted: 04/11/2022] [Indexed: 12/12/2022]
Abstract
Sepsis is a systemic inflammatory syndrome caused by infection disorders. The core mechanism of sepsis is immune dysfunction. Neutrophils are the most abundant circulating white blood cells, which play a crucial role in mediating the innate immune response. Previous studies have shown that an effective way to treat sepsis is through the regulation of neutrophil functions. Autophagy, a highly conserved degradation process, is responsible for removing denatured proteins or damaged organelles within cells and protecting cells from external stimuli. It is a key homeostasis process that promotes neutrophil function and differentiation. Autophagy has been shown to be closely associated with inflammation and immunity. Neutrophils, the first line of innate immunity, migrate to inflammatory sites upon their activation. Neutrophil-mediated autophagy may participate in the clinical course of sepsis. In this review, we summarized and analyzed the latest research findings on the changes in neutrophil external traps during sepsis, the regulatory role of autophagy in neutrophil, and the potential application of autophagy-driven NETs in sepsis, so as to guide clinical treatment of sepsis.
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Affiliation(s)
- Zhenzhen Huang
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Haodong Zhang
- Department of Hypertension Center, Lanzhou University Second Hospital, Lanzhou, China
| | - Xu Fu
- Key Laboratory of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Li Han
- Key Laboratory of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Haidan Zhang
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Ling Zhang
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Jing Zhao
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Danyang Xiao
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Hongyao Li
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China
| | - Peiwu Li
- Department of Emergency Medicine, Lanzhou University Second Hospital, Lanzhou, China.
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32
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Zhu Y, Chen X, Liu X. NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond. Front Immunol 2022; 13:838011. [PMID: 35309344 PMCID: PMC8924116 DOI: 10.3389/fimmu.2022.838011] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/08/2022] [Indexed: 12/13/2022] Open
Abstract
Infection with SARS-CoV-2, the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic, causes respiratory problems and multifaceted organ dysfunction. A crucial mechanism of COVID-19 immunopathy is the recruitment and activation of neutrophils at the infection site, which also predicts disease severity and poor outcomes. The release of neutrophil extracellular traps (NETs), occurring during a regulated form of neutrophil cell death known as NETosis, is a key effector function that mediates harmful effects caused by neutrophils. Abundant NETosis and NET generation have been observed in the neutrophils of many COVID-19 patients, leading to unfavorable coagulopathy and immunothrombosis. Moreover, excessive NETosis and NET generation are now more widely recognized as mediators of additional pathophysiological abnormalities following SARS-CoV-2 infection. In this minireview, we introduce subtypes of NET-producing neutrophils (e.g., low-density granulocytes) and explain the biological importance of NETs and the protein cargos of NETs in COVID-19. In addition, we discuss the mechanisms by which SARS-CoV-2 causes NETosis by upregulating viral processes (e.g., viral entry and replication) as well as host pro-NET mechanisms (e.g., proinflammatory mediator release, platelet activation, and autoantibody production). Furthermore, we provide an update of the main findings of NETosis and NETs in immunothrombosis and other COVID-19-related disorders, such as aberrant immunity, neurological disorders, and post COVID-19 syndromes including lung fibrosis, neurological disorder, tumor progression, and deteriorated chronic illness. Finally, we address potential prospective COVID-19 treatment strategies that target dysregulated NETosis and NET formation via inhibition of NETosis and promotion of NET degradation, respectively.
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Affiliation(s)
- Yuanfeng Zhu
- Clinical Medical Research Center, Southwest Hospital, Army Military Medical University, Chongqing, China
| | - Xiaoli Chen
- Clinical Medical Research Center, Southwest Hospital, Army Military Medical University, Chongqing, China
| | - Xin Liu
- Clinical Medical Research Center, Southwest Hospital, Army Military Medical University, Chongqing, China
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Gonçalves Júnior J. COVID-19, liver dysfunction and pathophysiology: A conceptual discussion. World J Gastroenterol 2022; 28:683-688. [PMID: 35317425 PMCID: PMC8900549 DOI: 10.3748/wjg.v28.i6.683] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 08/21/2021] [Accepted: 01/20/2022] [Indexed: 02/06/2023] Open
Abstract
The intra and extracellular pathways of hepatic injury by coronavirus disease 2019 (COVID-19) are still being studied. Understanding them is important to treat this viral disease and other liver and biliary tract disorders. Thus, this paper aims to present three hypotheses about liver injury caused by COVID-19: (1) The interactions between severe acute respiratory syndrome coronavirus 2 spike protein and membrane receptors in the hepatocyte; (2) The dysbiosis and “gut-liver axis” disruption in patients with serious clinical presentations of COVID-19; and (3) The inflammatory response exacerbated through the production of interleukins such as interleukin-6. However, despite these new perspectives, the pathophysiological process of liver injury caused by COVID-19 is still complex and multifactorial. Thus, understanding all these variables is a challenge to science but also the key to propose individualized and effective patient therapies.
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Affiliation(s)
- Jucier Gonçalves Júnior
- Department of Internal Medicine, Division of Rheumatology, São Paulo University, São Paulo 01246-903, State, Brazil
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Patients with COVID-19: in the dark-NETs of neutrophils. Cell Death Differ 2021; 28:3125-3139. [PMID: 34031543 PMCID: PMC8142290 DOI: 10.1038/s41418-021-00805-z] [Citation(s) in RCA: 196] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/07/2021] [Accepted: 05/10/2021] [Indexed: 02/07/2023] Open
Abstract
SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.
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Moreira JLDS, Barbosa SMB, Gonçalves Júnior J. Pathophysiology and molecular mechanisms of liver injury in severe forms of COVID-19: An integrative review. Clin Res Hepatol Gastroenterol 2021; 45:101752. [PMID: 34303828 PMCID: PMC8299216 DOI: 10.1016/j.clinre.2021.101752] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/16/2021] [Accepted: 06/21/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS SARS-CoV-2 has primary pulmonary impairment, but other organs such as the liver can also be affected. This implies a worsening of patient's prognosis and an increase in morbidity and mortality. The metabolic pathways and molecular factors involved in the genesis of this injury are still unknown. Therefore, we aimed to carry out an integrative review about the pathophysiology and possible molecular mechanisms of liver injury by COVID-19. METHODS We carried out an integrative literature review in the following databases: PubMed, Scopus, and Embase from December 2020 to March 2021 using the following descriptors: # 1 "COVID-19" (MeSH) AND / OR # 2 "Liver injury" (MeSH) AND / OR # 3 "Pathophysiology" (MesH). RESULTS The data were extracted and divided into two main themes, for heuristic purposes: "Hepatotropism and SARS-CoV-2", and "Pathophysiological hypotheses for liver injury associated with SARS-CoV-2". CONCLUSIONS The virus seems to promote liver damage through five mechanisms: direct injury, humoral and cellular inflammatory response, hypoxemia caused by a decrease in the effective circulating volume, reinfection through the portal system, and use of drugs in the treatment. The literature also points out that the expression of the angiotensin-converting enzyme II and transmembrane serine protease 2 receptors is expressive in cholangiocyte and is present in hepatocytes, which is a risk factor for the virus to enter these cells. Finally, patients with previous liver disease appear to be more susceptible to liver injury by COVID-19.
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Affiliation(s)
| | | | - Jucier Gonçalves Júnior
- Departament of Internal Medicine - Division of Rheumathology, Universidade de São Paulo (USP), São Paulo, Brazil.
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Trukhan DI, Davydov EL. Liver drug damage: possibilities of polyionic succinate-methioninic complex during the pandemic of new coronavirus infection (COVID-19). MEDITSINSKIY SOVET = MEDICAL COUNCIL 2021:110-121. [DOI: 10.21518/2079-701x-2021-15-110-121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
Abstract
Medicinal liver damage is an important problem not only in the framework of hepatology and gastroenterology, but also for internal medicine in general, which is due to the difficulties of correct and timely diagnosis of this pathology. In the first part of the review, the main mechanisms of liver tissue damage and clinical and formological manifestations of drug-induced liver damage are considered.The pandemic of the new coronavirus infection (COVID-19), spread by the SARS-CoV-2 virus, has become a challenge to health systems around the world. The global clinical experience gained over the past year in the management of patients with a new coronavirus infection makes it possible to highlight a number of relevant clinical aspects, one of which is drug-induced liver damage associated with the treatment of COVID-19. In the second part of the review, the possible mechanisms of influence of COVID-19 on the hepatobiliary system are considered, which include viral cytotoxicity, a secondary effect of immune dysregulation; hypoxia as a result of respiratory failure and subsequent ischemic liver damage; reactivation of already existing liver pathology and drug damage to the liver. It has been established that a large number of drugs used to treat COVID-19 - antiviral agents, antibacterials, non-steroidal anti-inflammatory drugs, steroids and others - have hepatoxic effects and can cause liver damage. In the context of the COVID-19 pandemic, for patients with a new coronavirus infection and drug-induced liver damage, a rational, pathogenetically justified choice of a hepatoprotective drug is of particular importance. In the final part of the review, the possibilities of the polyionic succinate-methionine complex in the treatment of drug-induced liver damage are considered and a clinical example of the drug application in a patient with drug-induced liver damage during treatment with COVID-19 is given.
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Affiliation(s)
| | - E. L. Davydov
- Krasnoyarsk State Medical University named after Professor V.F. Voino-Yasenetsky
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37
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Xu Y, Yang X, Bian H, Xia M. Metabolic dysfunction associated fatty liver disease and coronavirus disease 2019: clinical relationship and current management. Lipids Health Dis 2021; 20:126. [PMID: 34602072 PMCID: PMC8487451 DOI: 10.1186/s12944-021-01564-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/20/2021] [Indexed: 02/07/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). At present, the COVID-19 has been prevalent worldwide for more than a year and caused more than four million deaths. Liver injury was frequently observed in patients with COVID-19. Recently, a new definition of metabolic dysfunction associated fatty liver disease (MAFLD) was proposed by a panel of international experts, and the relationship between MAFLD and COVID-19 has been actively investigated. Several previous studies indicated that the patients with MAFLD had a higher prevalence of COVID-19 and a tendency to develop severe type of respiratory infection, and others indicated that liver injury would be exacerbated in the patients with MAFLD once infected with COVID-19. The mechanism underlying the relationship between MAFLD and COVID-19 infection has not been thoroughly investigated, and recent studies indicated that multifactorial mechanisms, such as altered host angiotensin converting enzyme 2 (ACE2) receptor expression, direct viral attack, disruption of cholangiocyte function, systemic inflammatory reaction, drug-induced liver injury, hepatic ischemic and hypoxic injury, and MAFLD-related glucose and lipid metabolic disorders, might jointly contribute to both of the adverse hepatic and respiratory outcomes. In this review, we discussed the relationship between MAFLD and COVID-19 based on current available literature, and summarized the recommendations for clinical management of MAFLD patients during the pandemic of COVID-19.
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Affiliation(s)
- Yanlan Xu
- Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Department of Geriatrics, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, 201700, China
| | - Xinyu Yang
- Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Hua Bian
- Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Fudan Institute for Metabolic Diseases, Shanghai, 200032, China.
| | - Mingfeng Xia
- Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Fudan Institute for Metabolic Diseases, Shanghai, 200032, China.
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38
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Neutrophil extracellular traps and organ dysfunction in sepsis. Clin Chim Acta 2021; 523:152-162. [PMID: 34537216 DOI: 10.1016/j.cca.2021.09.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/09/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022]
Abstract
Sepsis is a clinical syndrome resulting from infection followed by inflammation and is one of the significant causes of mortality worldwide. The underlying reason is the host's uncontrolled inflammatory response due to an infection led to multiple organ dysfunction/failure. Neutrophils, an innate immune cell, are forerunners to reach the site of infection/inflammation for clearing the infection and resolute the inflammation during sepsis. A relatively new neutrophil effector function, neutrophil extracellular traps (NETs), have been demonstrated to kill the pathogens by releasing DNA decorated with histone and granular proteins. A growing number of pieces of shreds of evidence suggest that unregulated incidence of NETs have a significant influence on the pathogenesis of sepsis-induced multiple organ damage, including arterial hypotension, hypoxemia, coagulopathy, renal, neurological, and hepatic dysfunction. Thus, excessive production and improper resolution of NETs are of significant therapeutic value in combating sepsis-induced multiple organ failure. The purpose of this review is intended to highlight the role of NETs in sepsis-induced organ failure. Furthermore, the current status of therapeutic strategies to intersect the harmful effects of NETs to restore organ functions is discussed.
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Kim SW, Jeon JH, Moon JS, Kim MK. High Fibrosis-4 Index Is Related with Worse Clinical Outcome in Patients with Coronavirus Disease 2019 and Diabetes Mellitus: A Multicenter Observational Study. Endocrinol Metab (Seoul) 2021; 36:800-809. [PMID: 34418914 PMCID: PMC8419603 DOI: 10.3803/enm.2021.1040] [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: 03/17/2021] [Accepted: 05/31/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Based on recent evidence on the importance of the presence of diabetes mellitus (DM) and fibrosis-4 (FIB-4) index in coronavirus disease 2019 (COVID-19) mortality, we analyzed whether these factors could additively predict such mortality. METHODS This multicenter observational study included 1,019 adult inpatients admitted to university hospitals in Daegu. The demographic and laboratory findings, mortality, prevalence of severe disease, and duration of quarantine were compared between patients with and without DM and/or a high FIB-4 index. The mortality risk and corresponding hazard ratio (HR) were analyzed using the Kaplan-Meier method and Cox proportional hazard models. RESULTS The patients with DM (n=217) exhibited significantly higher FIB-4 index and mortality compared to those without DM. Although DM (HR, 2.66; 95% confidence interval [CI], 1.63 to 4.33) and a high FIB-4 index (HR, 4.20; 95% CI, 2.21 to 7.99) were separately identified as risk factors for COVID-19 mortality, the patients with both DM and high FIB-4 index had a significantly higher mortality (HR, 9.54; 95% CI, 4.11 to 22.15). Higher FIB-4 indices were associated with higher mortality regardless of DM. A high FIB-4 index with DM was more significantly associated with a severe clinical course with mortality (odds ratio, 11.24; 95% CI, 5.90 to 21.41) than a low FIB-4 index without DM, followed by a high FIB-4 index alone and DM alone. The duration of quarantine and hospital stay also tended to be longer in those with both DM and high FIB-4 index. CONCLUSION Both DM and high FIB-4 index are independent and additive risk factors for COVID-19 mortality.
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Affiliation(s)
- Sung-Woo Kim
- Department of Internal Medicine, Daegu Catholic University Hospital, Daegu Catholic University School of Medicine, Daegu, Korea
| | - Jae-Han Jeon
- Department of Internal Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jun Sung Moon
- Department of Internal Medicine, Yeungnam University Hospital, Yeungnam University College of Medicine, Daegu, Korea
- Jun Sung Moon, Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeungnam University Hospital, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea Tel: +82-53-620-3825, Fax: +82-53-654-3486, E-mail:
| | - Mi Kyung Kim
- Department of Internal Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Korea
- Corresponding authors: Mi Kyung Kim, Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, 1035 Dalgubeol-daero, Dalseo-gu, Daegu 42601, Korea, Tel: +82-53-258-7730, Fax: +82-53-258-4990, E-mail:
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Wong GLH, Yip TCF, Wong VWS, Tse YK, Hui DSC, Lee SS, Yeoh EK, Chan HLY, Lui GCY. SARS-CoV-2 Viral Persistence Based on Cycle Threshold Value and Liver Injury in Patients With COVID-19. Open Forum Infect Dis 2021; 8:ofab205. [PMID: 34099979 PMCID: PMC8135402 DOI: 10.1093/ofid/ofab205] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Liver injury in patients with coronavirus disease 2019 (COVID-19) is common and prognostic. Direct viral tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for angiotensin-converting enzyme 2 receptors in hepatocytes may be one of the mechanisms of liver injury. We aimed to determine the role of viral persistence of SARS-CoV-2, based on cycle threshold (Ct) value, in liver injury in COVID-19. METHODS This was a territory-wide retrospective cohort study of all public hospitals in Hong Kong. Laboratory-confirmed COVID-19 was identified. Serial liver biochemistries and Ct values of SARS-CoV-2 RNA were analyzed. RESULTS We identified 7622 COVID-19 patients (mean age, 47 years; 48.2% male) diagnosed from March 24 to January 1, 2021, who had serial liver biochemistries and Ct values. A total of 1363 (17.9%) COVID-19 patients had alanine transferase (ALT)/aspartate aminotransferase (AST) elevations with 2 temporal patterns-early (within first 14 days of symptom onset) and late (>14 days from symptom onset). COVID-19 patients with ALT/AST elevations had a lower Ct value at admission (23 vs 25; P < .001), day 5 (24 vs 26; P < .001), and day 20 (31 vs 32; P < .001) after admission, compared with those without ALT/AST elevations. COVID-19 patients with ALT/AST elevations had a longer duration from first positive to first negative reverse transcription polymerase chain reaction test for SARS-CoV-2 (13 vs 9 days; P < .001). ALT/AST elevation and presence of diabetes were independent risk factors of viral persistence. CONCLUSIONS Liver injury in COVID-19 is linked to a higher SARS-CoV-2 viral load during the early phase of infection, signifying a possible direct viral injury to the liver. Prolonged viral persistence of SARS-CoV-2 is associated with liver injury.
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Affiliation(s)
- Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Medical Data Analytic Centre (MDAC), Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Terry Cheuk-Fung Yip
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Medical Data Analytic Centre (MDAC), Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Medical Data Analytic Centre (MDAC), Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yee-Kit Tse
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Medical Data Analytic Centre (MDAC), Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - David Shu-Cheong Hui
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Medical Data Analytic Centre (MDAC), Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Stanley Ho Centre for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Shui-Shan Lee
- Stanley Ho Centre for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Eng-Kiong Yeoh
- Centre for Health Systems and Policy Research, Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Henry Lik-Yuen Chan
- Medical Data Analytic Centre (MDAC), Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Union Hospital, Hong Kong SAR, China
| | - Grace Chung-Yan Lui
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Medical Data Analytic Centre (MDAC), Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
- Stanley Ho Centre for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
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Deng ML, Chen YJ, Yang ML, Liu YW, Chen H, Tang XQ, Yang XF. COVID-19 combined with liver injury: Current challenges and management. World J Clin Cases 2021; 9:3487-3497. [PMID: 34046449 PMCID: PMC8130088 DOI: 10.12998/wjcc.v9.i15.3487] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/07/2021] [Accepted: 03/29/2021] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) combined with liver injury has become a very prominent clinical problem. Due to the lack of a clear definition of liver injury in patients with COVID-19, the different selection of evaluation parameters and statistical time points, there are the conflicting conclusions about the incidence rate in different studies. The mechanism of COVID-19 combined with liver injury is complicated, including the direct injury of liver cells caused by severe acute respiratory syndrome coronavirus 2 replication and liver injury caused by cytokines, ischemia and hypoxia, and drugs. In addition, underlying diseases, especially chronic liver disease, can aggravate COVID-19 liver injury. In the treatment of COVID-19 combined with liver injury, the primary and basic treatment is to treat the etiology and pathogenesis, followed by support, liver protection, and symptomatic treatment according to the clinical classification and severity of liver injury. This article evaluates the incidence, pathogenesis and prevention and treatment of COVID-19 combined with liver injury, and aims to provide countermeasures for the prevention and treatment of COVID-19 combined with liver injury.
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Affiliation(s)
- Man-Ling Deng
- Department of Gastroenterology, The Affiliated Nanhua Hospital, Hengyang Medical College, University of South China, Hengyang 421002, Hunan Province, China
| | - Yong-Jun Chen
- Department of Neurology, The Affiliated Nanhua Hospital, Hengyang Medical College, University of South China, Hengyang 421002, Hunan Province, China
| | - Mei-Ling Yang
- Department of Oncology, The Affiliated Nanhua Hospital, Hengyang Medical College, University of South China, Hengyang 421002, Hunan Province, China
| | - Yi-Wen Liu
- Department of Gastroenterology, The Affiliated Nanhua Hospital, Hengyang Medical College, University of South China, Hengyang 421002, Hunan Province, China
| | - Hui Chen
- Department of Gastroenterology, The Affiliated Nanhua Hospital, Hengyang Medical College, University of South China, Hengyang 421002, Hunan Province, China
| | - Xiao-Qing Tang
- Institute of Clinical Medicine, The First Affiliated Hospital, Hengyang Medical College, University of South China, Hengyang 421001, Hunan Province, China
| | - Xue-Feng Yang
- Department of Gastroenterology, The Affiliated Nanhua Hospital, Hengyang Medical College, University of South China, Hengyang 421002, Hunan Province, China
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Del Nonno F, Nardacci R, Colombo D, Visco-Comandini U, Cicalini S, Antinori A, Marchioni L, D’Offizi G, Piacentini M, Falasca L. Hepatic Failure in COVID-19: Is Iron Overload the Dangerous Trigger? Cells 2021; 10:cells10051103. [PMID: 34064487 PMCID: PMC8147922 DOI: 10.3390/cells10051103] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/30/2021] [Accepted: 05/03/2021] [Indexed: 02/07/2023] Open
Abstract
Liver injury in COVID-19 patients has progressively emerged, even in those without a history of liver disease, yet the mechanism of liver pathogenicity is still controversial. COVID-19 is frequently associated with increased serum ferritin levels, and hyperferritinemia was shown to correlate with illness severity. The liver is the major site for iron storage, and conditions of iron overload have been established to have a pathogenic role in development of liver diseases. We presented here six patients who developed severe COVID-19, with biochemical evidence of liver failure. Three cases were survived patients, who underwent liver biopsy; the other three were deceased patients, who were autopsied. None of the patients suffered underlying liver pathologies. Histopathological and ultrastructural analyses were performed. The most striking finding we demonstrated in all patients was iron accumulation into hepatocytes, associated with degenerative changes. Abundant ferritin particles were found enclosed in siderosomes, and large aggregates of hemosiderin were found, often in close contact with damaged mitochondria. Iron-caused oxidative stress may be responsible for mitochondria metabolic dysfunction. In agreement with this, association between mitochondria and lipid droplets was also found. Overall, our data suggest that hepatic iron overload could be the pathogenic trigger of liver injury associated to COVID-19.
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Affiliation(s)
- Franca Del Nonno
- Pathology Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, 00149 Rome, Italy; (F.D.N.); (D.C.)
| | - Roberta Nardacci
- Laboratory of Electron Microscopy, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, 00149 Rome, Italy; (R.N.); (M.P.)
| | - Daniele Colombo
- Pathology Unit, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, 00149 Rome, Italy; (F.D.N.); (D.C.)
| | | | - Stefania Cicalini
- HIV/AIDS Department, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, 00149 Rome, Italy; (S.C.); (A.A.)
| | - Andrea Antinori
- HIV/AIDS Department, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, 00149 Rome, Italy; (S.C.); (A.A.)
| | - Luisa Marchioni
- Clinical Department, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, 00149 Rome, Italy;
| | - Gianpiero D’Offizi
- Hepatology Unit “Lazzaoro Spallanzani”-IRCCS, 00149 Rome, Italy; (U.V.-C.); (G.D.)
| | - Mauro Piacentini
- Laboratory of Electron Microscopy, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, 00149 Rome, Italy; (R.N.); (M.P.)
- Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy
| | - Laura Falasca
- Laboratory of Electron Microscopy, National Institute for Infectious Diseases “Lazzaro Spallanzani”-IRCCS, 00149 Rome, Italy; (R.N.); (M.P.)
- Correspondence:
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Sumida Y, Yoneda M. COVID-19-associated liver injury (COVALI): role of hepatologists. J Gastroenterol 2021; 56:786-787. [PMID: 34212231 PMCID: PMC8249182 DOI: 10.1007/s00535-021-01809-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/28/2021] [Indexed: 02/04/2023]
Affiliation(s)
- Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195 Japan
| | - Masashi Yoneda
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi 480-1195 Japan
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44
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Li D, Ding X, Tian D, Xia L. Reply to: "COVID-19-associated liver injury (COVALI): role of hepatologists". J Gastroenterol 2021; 56:788-789. [PMID: 34251568 PMCID: PMC8274257 DOI: 10.1007/s00535-021-01807-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 06/25/2021] [Indexed: 02/04/2023]
Affiliation(s)
- Dongxiao Li
- Department of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, 450004 Henan China ,Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei China
| | - Xiangming Ding
- Department of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, 450004 Henan China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei China
| | - Limin Xia
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 Hubei China
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