Recapitulation of SARS-CoV-2 infection and cholangiocyte damage with human liver ductal organoids

Zhao, Bing; Ni, Chao; Gao, Ran; Wang, Yuyan; Yang, Li; Wei, Jinsong; Lv, Ting; Liang, Jianqing; Zhang, Qisheng; Xü, Wei; Xie, Youhua; Wang, Xiaoyue; Yuan, Zhenghong; Liang, Junbo; Zhang, Rong; Lin, Xinhua

doi:10.1007/s13238-020-00718-6

Cited by 339 publications

(378 citation statements)

References 16 publications

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“…4,8,9 Viral cytopathic effect is exerted on both liver cells and cholangiocytes; indeed, SARS-CoV-2 binds the angiotensin-converting enzyme 2 (ACE2) receptor to enter the cells, 10 which is mainly expressed on cholangiocytes, vascular endothelium and smooth muscle cells. 11,12 Therefore, both vascular and cholangiocellular damage may represent the reasons for the increase in transaminases and cholestasis parameters in infected patients. However, we demonstrated that liver test tend to normalise regardless of the positive or negative result of the final nasopharyngeal swabs.…”

Section: Discussionmentioning

confidence: 99%

Liver involvement is not associated with mortality: results from a large cohort of SARS‐CoV‐2‐positive patients

Ponziani

Zompo

Nesci

et al. 2020

Aliment Pharmacol Ther

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Summary Background Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection is frequently associated with liver test abnormalities. Aims To describe the evolution of liver involvement during SARS‐CoV‐2 infection and its effect on clinical course and mortality. Methods Data of 515 SARS‐CoV‐2‐positive patients were collected at baseline and during follow‐up, last evaluation or death. Stratification based on need for hospitalisation, severe disease and admission to intensive care unit (ICU) was performed. The association between liver test abnormalities (baseline and peak values) and ICU admission or death was also explored. Results Liver test abnormalities were found in 161 (31.3%) patients. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) were increased in 20.4%, 19% and 13.6% of patients, respectively. Baseline liver test abnormalities were associated with increased risk of ICU admission (OR 2.19 [95% CI 1.24‐3.89], P = 0.007) but not with mortality (OR 0.84 [95% CI 0.49‐1.41], P = 0.51). Alkaline phosphatase (ALP) peak values were correlated with risk of death (OR 1.007 [95% CI 1.002‐1.01], P = 0.005) along with age, multiple comorbidities, acute respiratory distress syndrome, ICU admission and C‐reactive protein. Alterations of liver tests worsened within 15 days of hospitalisation; however, in patients with the longest median follow‐up, the prevalence of liver test alterations decreased over time, returning to around baseline levels. Conclusions In SARS‐CoV‐2‐positive patients without pre‐existing severe chronic liver disease, baseline liver test abnormalities are associated with the risk of ICU admission and tend to normalise over time. The ALP peak value may be predictive of a worse prognosis.

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Section: Discussionmentioning

confidence: 99%

Liver involvement is not associated with mortality: results from a large cohort of SARS‐CoV‐2‐positive patients

Ponziani

Zompo

Nesci

et al. 2020

Aliment Pharmacol Ther

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“…45 More importantly, the infection of cholangiocytes by SARS-CoV-2 altered their bile acid (BA) transporting function reducing the expression of the apical sodium-dependent BA transporter and the cystic fibrosis transmembrane regulator. 45,46 Viral load in these organoids decreased after 48 hours and was associated with a high expression of genes related to apoptosis, suggesting that SARS-CoV-2 infection induces cholangiocyte death. 46 Cholestasis has been recently reported in 7 out of 11 Fig.…”

Section: Direct Cytopathic Effects Of Sars-cov-2 On Parenchymal Cellsmentioning

confidence: 99%

“…45,46 Viral load in these organoids decreased after 48 hours and was associated with a high expression of genes related to apoptosis, suggesting that SARS-CoV-2 infection induces cholangiocyte death. 46 Cholestasis has been recently reported in 7 out of 11 Fig. 1 Liver injury in COVID-19.…”

Section: Direct Cytopathic Effects Of Sars-cov-2 On Parenchymal Cellsmentioning

confidence: 99%

Direct or Collateral Liver Damage in SARS-CoV-2–Infected Patients

et al. 2020

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Liver injury can result from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with more than one-third of COVID-19 patients exhibiting elevated liver enzymes. Microvesicular steatosis, inflammation, vascular congestion, and thrombosis in the liver have been described in autopsy samples from COVID-19 patients. Several factors, including direct cytopathic effect of the virus, immune-mediated collateral damage, or an exacerbation of preexisting liver disease may contribute to liver pathology in COVID-19. Due to its immunological functions, the liver is an organ likely to participate in the viral response against SARS-CoV-2 and this may predispose it to injury. A better understanding of the mechanism contributing to liver injury is needed to develop and implement early measures to prevent serious liver damage in patients suffering from COVID-19. This review summarizes current reports of SARS-CoV-2 with an emphasis on how direct infection and subsequent severe inflammatory response may contribute to liver injury in patients with and without preexisting liver disease.

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“…Fan et al and Lin et al revealed that SARS-CoV-2 could directly bind to ACE2-positive cholangiocytes and damage bile duct tissue, suggesting a possible mechanism for SARS-CoV-2-induced liver injury (5,6). A more recent study found that SARS-CoV-2 entry receptor ACE2 and the entry associated protease TMPRSS2 are expressed in TROP2 + liver progenitor cells highlighting another potential cause of liver damage (24).…”

Section: Discussionmentioning

confidence: 99%

“…Several recent studies have shown that more than 50% of patients with COVID-19 develop liver abnormalities, of whom 20% have liver injury (1)(2)(3)(4). Two reports showed that SARS-CoV-2 might bind to cholangiocytes that are angiotensin-converting enzyme 2 (ACE2) positive and directly disrupt the barrier and bile acid transporting functions of these cells, which could further contribute to liver injury (5,6). Furthermore, a pathological study based on patients who had died from severe COVID-19 showed that their liver tissue had moderate microvesicular steatosis and mild lobular and portal activity indicating that SARS-CoV-2 might cause liver injury (7).…”

Section: Introductionmentioning

confidence: 99%

Implications of Liver Injury in Risk-Stratification and Management of Patients with COVID-19

Shao

Liang

et al. 2020

Preprint

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BackgroundInfection with SARS-CoV-2 has been associated with liver dysfunction, aggravation of liver burden, and liver injury. This study aimed to assess the effects of liver injuries on the clinical outcomes of patients with COVID-19.MethodsA total of 1,564 patients with severe or critical COVID-19 from Huoshenshan Hospital, Wuhan, were enrolled. Chronic liver disease (CLD) was confirmed by consensus diagnostic criteria. Laboratory test results were compared between different groups. scRNA-seq data and bulk gene expression profiles were used to identify cell types associated with liver injury.ResultsA total of 10.98% of patients with severe or critical COVID-19 developed liver injury after admission that was associated with significantly higher rates of mortality (21.74%, p<0.001) and intensive care unit admission (26.71%, p<0.001). A pre-existing CLD was not associated with a higher risk. However, fatty liver disease and cirrhosis were associated with higher risks, supported by evidences from single cell and bulk transcriptome analysis that showed more TMPRSS2+ cells in these tissues. By generating a model, we were able to predict the risk and severity of liver injury during hospitalization.ConclusionWe demonstrate that liver injury occurring during therapy in patients with COVID-19 is significantly associated with the severity of disease and mortality, but the presence of CLD is not associated. We provide a risk-score model that can predict whether patients with COVID-19 will develop liver injury or proceed to higher risk stages during subsequent hospitalizations. These findings may prove beneficial for the clinical management of patients infected with SARS-CoV-2.

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Recapitulation of SARS-CoV-2 infection and cholangiocyte damage with human liver ductal organoids

Cited by 339 publications

References 16 publications

Liver involvement is not associated with mortality: results from a large cohort of SARS‐CoV‐2‐positive patients

Liver involvement is not associated with mortality: results from a large cohort of SARS‐CoV‐2‐positive patients

Direct or Collateral Liver Damage in SARS-CoV-2–Infected Patients

Implications of Liver Injury in Risk-Stratification and Management of Patients with COVID-19

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