Reply to: “Liver tests abnormalities in COVID-19: trick or treat?”
Authors: Qingxian Cai, Lin Xu, Jun Chen
Journal: Journal of Hepatology (2020)

COVID-19: Abnormal liver function testsJournal of HepatologyVol. 73Issue 3PreviewRecent data on the coronavirus disease 2019 (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has begun to shine light on the impact of the disease on the liver. But no studies to date have systematically described liver test abnormalities in patients with COVID-19. We evaluated the clinical characteristics of COVID-19 in patients with abnormal liver test results. Full-Text PDF Liver tests abnormalities in COVID-19: trick or treat?Journal of HepatologyVol. 73Issue 5PreviewWe read with interest the recent study by Cai et al.,1 which describes the role of liver function tests (LFTs) in a population of hospitalized patients with COVID-19. The authors' finding of a 41% prevalence of at least 1 elevated LFT in patients at admission appears to be higher than those previously reported in other cohorts of patients from Asia (25–30%).2,3 Similarly, when analyzing a consecutive cohort of 292 patients with RT-PCR-confirmed COVID-19 admitted to our center until 30 March 2020, we also noticed that the prevalence of elevated LFTs was lower in our cohort. Full-Text PDF We thank the Humanitas COVID-19 Task Force for their interest in our manuscript and for their thoughtful comments. In their letter, Vespa et al., pointed out that our finding of a 41% prevalence of elevated liver function tests (LFTs) at admission appears to be higher than rates reported throughout Asia and particularly, the rates reported in their cohort. We reviewed and summarized the articles mentioned in their letter (Table 1).1Cai Q. Huang D. Yu H. Zhu Z. Xia Z. Su Y. et al.COVID-19: abnormal liver function tests.J Hepatol. 2020; 73: 566-574Abstract Full Text Full Text PDF PubMed Scopus (680) Google Scholar, 2Aghemo A. Piovani D. Parigi T.L. Brunetta E. Pugliese N. Vespa E. et al.Covid-19 digestive system involvement and clinical outcomes in a large academic hospital in Milan, Italy.Clin Gastroenterol Hepatol. 2020; 18: 2366-2368.e3Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 3Fan Z. Chen L. Li J. Chen X. Yang J. Tian C. et al.Clinical features of COVID-19-related liver functional abnormality.Clin Gastroenterol Hepatol. 2020; 18: 1561-1566Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar, 4Zhang Y. Zheng L. Liu L. Zhao M. Xiao J. Zhao Q. Liver impairment in COVID-19 patients: a retrospective analysis of 115 cases from a single center in Wuhan city, China.Liver Int. 2020; ([published online ahead of print, 2020 Apr 2])https://doi.org/10.1111/liv.14455Crossref Scopus (339) Google Scholar, 5Chen N. Zhou M. Dong X. Qu J. Gong F. Han Y. et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.Lancet. 2020; 395: 507-513Abstract Full Text Full Text PDF PubMed Scopus (14343) Google Scholar, 6Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; 382: 1708-1720Crossref PubMed Scopus (20258) Google Scholar We found that the prevalence of elevated LFTs at admission in our study was significantly lower than that reported by Vespa et al.[2]Aghemo A. Piovani D. Parigi T.L. Brunetta E. Pugliese N. Vespa E. et al.Covid-19 digestive system involvement and clinical outcomes in a large academic hospital in Milan, Italy.Clin Gastroenterol Hepatol. 2020; 18: 2366-2368.e3Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar: alanine aminotransferase (ALT, 54/417 vs. 78/292, p <0.001), gamma-glutamyltransferase (GGT, 68/417 vs. 106/292, p <0.001) or alkaline phosphatase (ALP, 20/417 vs. 28/292, p = 0.012) and higher for total bilirubin (TBIL, 97/417 vs. 31/292, p <0.001), but comparable with other patient series from Asia.3Fan Z. Chen L. Li J. Chen X. Yang J. Tian C. et al.Clinical features of COVID-19-related liver functional abnormality.Clin Gastroenterol Hepatol. 2020; 18: 1561-1566Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar, 4Zhang Y. Zheng L. Liu L. Zhao M. Xiao J. Zhao Q. Liver impairment in COVID-19 patients: a retrospective analysis of 115 cases from a single center in Wuhan city, China.Liver Int. 2020; ([published online ahead of print, 2020 Apr 2])https://doi.org/10.1111/liv.14455Crossref Scopus (339) Google Scholar, 5Chen N. Zhou M. Dong X. Qu J. Gong F. Han Y. et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.Lancet. 2020; 395: 507-513Abstract Full Text Full Text PDF PubMed Scopus (14343) Google Scholar, 6Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; 382: 1708-1720Crossref PubMed Scopus (20258) Google Scholar In fact, due to the differences in the cut-off values of elevated LFTs, underlying liver disease, and demographic factors, the prevalence of elevated LFTs in patients with COVID-19 at admission may vary widely. Of note, it has been observed that the prevalence of elevated LFTs would increase in the course of COVID-19, as seen in our study,[2]Aghemo A. Piovani D. Parigi T.L. Brunetta E. Pugliese N. Vespa E. et al.Covid-19 digestive system involvement and clinical outcomes in a large academic hospital in Milan, Italy.Clin Gastroenterol Hepatol. 2020; 18: 2366-2368.e3Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar which found that the time from disease onset to hospitalization significantly influenced the elevated rate of LFTs at admission.Table 1The prevalence of elevated LFTs reported in different cohorts of patients with COVID-19.Sample sizeElevated LFTs (%)Elevated LFTs, cut-off value, %Overall prognosisALTASTTBILGGTALPCai et al.[1]Cai Q. Huang D. Yu H. Zhu Z. Xia Z. Su Y. et al.COVID-19: abnormal liver function tests.J Hepatol. 2020; 73: 566-574Abstract Full Text Full Text PDF PubMed Scopus (680) Google Scholar41741%>40 U/L, 13.0>40 U/L, 18.3>17.1 μmol/L, 23.2>49 U/L, 16.3>135 U/L, 4.891 (21.8%) developed severe disease during hospitalization.Vespa et al.[2]Aghemo A. Piovani D. Parigi T.L. Brunetta E. Pugliese N. Vespa E. et al.Covid-19 digestive system involvement and clinical outcomes in a large academic hospital in Milan, Italy.Clin Gastroenterol Hepatol. 2020; 18: 2366-2368.e3Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar292n/a>50 U/L, 26.7>50 U/L, 18.5>1.2 mg/dl, 10.6>55 U/L, 36.2>150 U/L, 9.627 (9.2%) patients were transferred to ICU, and 56 (19 .2%) died.Fan et al.[3]Fan Z. Chen L. Li J. Chen X. Yang J. Tian C. et al.Clinical features of COVID-19-related liver functional abnormality.Clin Gastroenterol Hepatol. 2020; 18: 1561-1566Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar14737.2%>40 U/L, 18.2>35 U/L, 21.6>20.5 μmol/L, 6.1>45 U/L, 17.6>100 U/L, 4.11 patient died.Zhang et al.[4]Zhang Y. Zheng L. Liu L. Zhao M. Xiao J. Zhao Q. Liver impairment in COVID-19 patients: a retrospective analysis of 115 cases from a single center in Wuhan city, China.Liver Int. 2020; ([published online ahead of print, 2020 Apr 2])https://doi.org/10.1111/liv.14455Crossref Scopus (339) Google Scholar115n/a>50 U/L, 9.6>40 U/L, 14.8>21 μmol/L, 6.1>57, 13.0>120, 5.231 cases (26.96%) were evaluated as severe cases, 7 (6.09%) patients progressed to critical condition and 1 died (0.87%).Chen et al.[5]Chen N. Zhou M. Dong X. Qu J. Gong F. Han Y. et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.Lancet. 2020; 395: 507-513Abstract Full Text Full Text PDF PubMed Scopus (14343) Google Scholar9943.4%>50 U/L, 28.3>40 U/L, 35.4>21 μmol/L, 18.2n.a.n.a.17 (17%) patients developed acute respiratory distress syndrome and 11(11%) patients died.Guan et al.[6]Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; 382: 1708-1720Crossref PubMed Scopus (20258) Google Scholar1099n/a>40 U/L, 21.3>40 U/L, 22.2>17.1 μmol/L, 10.5n.a.n.a.173 (15.7%) developed severe disease during hospitalization.Comparison of categorical variables was done using the χ2 test or the Fisher exact test, if the cell counts were small. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; ICU, intensive care unit; LFT, liver function test; n.a., not available; TBIL, total bilirubin. Open table in a new tab Comparison of categorical variables was done using the χ2 test or the Fisher exact test, if the cell counts were small. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase; ICU, intensive care unit; LFT, liver function test; n.a., not available; TBIL, total bilirubin. Because of the limited medical resources available during the beginning of the pandemic, many hospitals in high pandemic areas may have only received patients with severe disease, which would result in seeing patients with more severe liver injury. In our study, all laboratory-confirmed patients with COVID-19 who were admitted to the only referral hospital in Shenzhen, China from January 11 to February 21, 2020 were included. Elevated LFTs were defined as the following criteria: AST or ALT values >40 IU/L, GGT >49 U/L, ALP >135 U/L, and TBIL >17.1 mol/L. Of the 417 patients in our studies, 21 (5.04%) had underlying liver disease, 123 (32%) were overweight, and 41 (10.7%) were obese at admission. The median time from disease onset to hospitalization was 4 days (IQR 1–5). So far, older age has been acknowledged as one of the most important risk factors for deterioration due to COVID-19.[7]Cai Q.X. Huang D.L. Ou P.C. Yu H. Zhu Z.B. Xia Z. et al.COVID-19 in a designated infectious diseases hospital outside Hubei Province, China.Allergy. 2020; 75: 1742-1752Crossref PubMed Scopus (333) Google Scholar Others at highest risk of severe COVID-19 are people with certain underlying conditions, including hypertension, cardiovascular disease, diabetes, chronic respiratory disease, cancer, renal disease, and obesity.[8]Cai Q. Chen F. Wang T. Luo F. Liu X. Wu Q. et al.Obesity and COVID-19 severity in a designated hospital in Shenzhen, China.Diabetes Care. 2020; 43 ([published online ahead of print, 2020 may 14]): 1392-1398Crossref PubMed Scopus (441) Google Scholar Some studies have also reported that abnormal LFTs were associated with overall prognosis.[3]Fan Z. Chen L. Li J. Chen X. Yang J. Tian C. et al.Clinical features of COVID-19-related liver functional abnormality.Clin Gastroenterol Hepatol. 2020; 18: 1561-1566Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar,[4]Zhang Y. Zheng L. Liu L. Zhao M. Xiao J. Zhao Q. Liver impairment in COVID-19 patients: a retrospective analysis of 115 cases from a single center in Wuhan city, China.Liver Int. 2020; ([published online ahead of print, 2020 Apr 2])https://doi.org/10.1111/liv.14455Crossref Scopus (339) Google Scholar Fan et al., for example, reported that baseline abnormal liver function was associated with prolonged hospital stay.[3]Fan Z. Chen L. Li J. Chen X. Yang J. Tian C. et al.Clinical features of COVID-19-related liver functional abnormality.Clin Gastroenterol Hepatol. 2020; 18: 1561-1566Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar In a recent systematic review, Kunutsor and Laukkanen conducted a meta-analysis of 16 retrospective cohort studies based in China and concluded that elevated levels of liver injury markers, particularly aminotransferases, may be associated with progression to severe disease or death.[9]Kunutsor S.K. Laukkanen J.A. Markers of liver injury and clinical outcomes in COVID-19 patients: a systematic review and meta-analysis.J Infect. 2020; (S0163-4453(20)30325-X)https://doi.org/10.1016/j.jinf.2020.05.045Abstract Full Text Full Text PDF Scopus (27) Google Scholar As seen in Table 1, the cohorts with higher mortality usually had more severe LFT changes. In the study by Vespa et al.,[2]Aghemo A. Piovani D. Parigi T.L. Brunetta E. Pugliese N. Vespa E. et al.Covid-19 digestive system involvement and clinical outcomes in a large academic hospital in Milan, Italy.Clin Gastroenterol Hepatol. 2020; 18: 2366-2368.e3Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar elevated ALP above 150 IU/L was associated with deterioration (p = 0.048) and became non-significant after adjustment for age and sex (p = 0.13). In our study, GGT was substantially elevated at admission, whereas the increase in ALP was not pronounced in patients with COVID-19. This finding was consistent with other cohorts.3Fan Z. Chen L. Li J. Chen X. Yang J. Tian C. et al.Clinical features of COVID-19-related liver functional abnormality.Clin Gastroenterol Hepatol. 2020; 18: 1561-1566Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar, 4Zhang Y. Zheng L. Liu L. Zhao M. Xiao J. Zhao Q. Liver impairment in COVID-19 patients: a retrospective analysis of 115 cases from a single center in Wuhan city, China.Liver Int. 2020; ([published online ahead of print, 2020 Apr 2])https://doi.org/10.1111/liv.14455Crossref Scopus (339) Google Scholar, 5Chen N. Zhou M. Dong X. Qu J. Gong F. Han Y. et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.Lancet. 2020; 395: 507-513Abstract Full Text Full Text PDF PubMed Scopus (14343) Google Scholar, 6Guan W.J. Ni Z.Y. Hu Y. Liang W.H. Ou C.Q. He J.X. Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; 382: 1708-1720Crossref PubMed Scopus (20258) Google Scholar The patients with COVID-19 showed elevated GGT levels and normal ALP, which may controvert the hypothesis that SARS-CoV-2 directly injures cholangiocytes. Therefore, we agree that ALP or GGT elevation may just be a marker of patient frailty or represent a stronger systemic inflammatory response to SARS-CoV-2 infection, rather than a sign of cholestatic liver injury. Liver and lung injuries share the same underlying mechanism, which may be directly or indirectly induced by SARS-CoV-2 infection. Laboratory liver function tests should thus be interpreted with caution and always in the context of a complex, multi-organ disease. This work is funded by the National Infectious Diseases Clinical Research Center, Funds for the construction of key medical disciplines in Shenzhen, the Sanming Project of Medicine in Shenzhen (SZSM201612014), and the Bill and Melinda Gates Foundation. J Chen designed the study, received the grant support, had full access to all data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. QX Cai and L Xu contributed to the writing and statistical analysis of the report. All authors contributed to data acquisition, data analysis, and data interpretation, and reviewed and approved the final version of the manuscript. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. Download .pdf (.16 MB) Help with pdf files disclosures.pdf