COVID-19 and the liver: little cause for concern
Authors: Mansoor N Bangash, Jaimin Patel, Dhruv Parekh
Journal: The Lancet. Gastroenterology & hepatology (2020)

The largest study on COVID-19 to date1Guan W-J Ni Z-Y Hu Y et al.Clinical characteristics of 2019 novel coronavirus infection in China.N Engl J Med. 2020; (published online Feb 28.)DOI:10.1056/NEJMoa2002032Crossref Scopus (20278) Google Scholar showed that the prevalence of elevated aminotransferases and bilirubin in people faring worst was at least double that of others. Although clinically significant liver dysfunction was not quantified, this and other studies have led some to suggest that this finding might present clinical challenges.2Zhang C Shi L Wang FS Liver injury in COVID-19: management and challenges.Lancet Gastroenterol Hepatol. 2020; (published online March 4.)http://dx.doi.org/10.1016/S2468-1253(20)30057-1Summary Full Text Full Text PDF Scopus (1321) Google Scholar Close inspection of the available data supports a higher prevalence of abnormal aminotransferase levels in severe COVID-19 disease, but these studies actually suggest that clinically significant liver injury is uncommon, even when data for the most severely ill patients are selected (table).TableLiver test abnormalities from various COVID-19 studies, identifying the most severe disease categories where possibleGroupPatientsAlanine aminotransferase (IU)Aspartate aminotransferase (IU)Prothrombin time (s)Bilirubin (μmol/L)Elevated lactate dehydrogenase, creatinine kinase, or myoglobinMortality (%)Guan et al (2020)ICU or death67Not knownNot knownNot knownNot knownYes22% (day 51)Huang et al (2020)ICU1349 (29–115)44 (32–70)12·2 (11·2–13·4)14·0 (11·9–32·9)Yes38% (day 37)Chen et al (2020)Hospitalised9939 (22–53)34 (26–48)11·3 (1·9)15·1 (7·3)Yes11% (day 24)Wang et al (2020)ICU3635 (19–57)52 (30–70)13·2 (12·3–14·5)11·5 (9·6–18·6)Yes17% (day 34)Shi et al (2020)Hospitalised8146 (30)41 (18)10·7 (0·9)11·9 (3·6)Unclear5% (day 50)Xu et al (2020)Hospitalised6222 (14–34)26 (20–32)Not knownNot knownUnclear0% (day 34)Yang et al (2020)ICU52Not knownNot known12·9 (2·9)*Non-survivor intensive care unit (ICU) group.19·5 (11·6)*Non-survivor intensive care unit (ICU) group.Not described62% (day 28)Extracted from all studies aboveChronic liver disease42Not knownNot knownNot knownNot knownNot known0–2%†One patient was either admitted to an intensive care unit or died. Details of references can be found in the appendix.Data is mean (SD) or median (IQR) depending on the original study.* Non-survivor intensive care unit (ICU) group.† One patient was either admitted to an intensive care unit or died. Details of references can be found in the appendix. Open table in a new tab Data is mean (SD) or median (IQR) depending on the original study. Although high levels of positive end expiratory pressure can contribute to hepatic congestion by increasing right atrial pressure and impeding venous return, data suggest that many patients admitted to hospital with COVID-19 have liver blood test abnormalities without mechanical ventilation. Furthermore, the distribution of aminotransferase levels among patients with COVID-19 do not support hypoxic hepatitis being a common phenomenon, according to the published literature. Drug-induced liver injury is a possible contributing factor to the observed abnormal liver blood test abnormalities after therapeutics begin and should be considered by clinicians, but mild liver test derangement is present at baseline in many patients with COVID-19 before significant medication use. Several studies have reported elevated levels of creatinine kinase and lactate dehydrogenase or myoglobin in association with COVID-19 severity (table). It is therefore possible that aminotransferase elevations do not necessarily arise from the liver alone and that COVID-19 infection might induce a myositis similar to that observed in severe influenza infections. It has been proposed that COVID-19 causes direct liver injury via a viral hepatitis, but we believe that there are alternative explanations. First, the derangement of liver function is clearly mild. Second, when liver function tests for patients with different durations of symptoms are examined, there is no evidence that later presentation is associated with greater liver function derangement.3Shi H Han X Jiang N et al.Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study.Lancet Infect Dis. 2020; (published onilne Feb 24.)http://dx.doi.org/10.1016/S1473-3099(20)30086-4Summary Full Text Full Text PDF Scopus (2575) Google Scholar The only post-mortem liver biopsy from a patient with COVID-19 showed only microvesicular steatosis, a common finding in sepsis.4Koskinas J Gomatos IP Tiniakos DG et al.Liver histology in ICU patients dying from sepsis: a clinico-pathological study.World J Gastroenterol. 2008; 14: 1389-1393Crossref PubMed Scopus (79) Google Scholar Most importantly, other respiratory viruses produce similar elevations of liver function biomarkers, which is thought to relate to hepatic damage from immune interactions involving intrahepatic cytotoxic T cells and Kupffer cells.5Adams DH Hubscher SG Systemic viral infections and collateral damage in the liver.Am J Pathol. 2006; 168: 1057-1059Summary Full Text Full Text PDF PubMed Scopus (111) Google Scholar This phenomenon waxes and wanes in parallel with respiratory viral disease and in the absence of hepatic viral replication, which might explain why worse outcomes were not seen in the 42 patients with chronic liver disease and COVID-19 who had outcome data (table). Hepatic dysfunction in severe COVID-19 is accompanied by greater activation of coagulative and fibrinolytic pathways, relatively depressed platelet counts, climbing neutrophil counts and neutrophil to lymphocyte ratios, and high ferritin levels.6Wang D Hu B Hu C et al.Clinical Characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; (published online Feb 7.)DOI: 10.1001/jama.2020.1585Crossref Scopus (16201) Google Scholar Although these markers are seen as non-specific markers of inflammation, we believe that they fit the paradigm of disease severity coinciding with a failure of innate immune regulation.7Narasaraju T Yang E Samy RP et al.Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis.Am J Pathol. 2011; 179: 199-210Summary Full Text Full Text PDF PubMed Scopus (667) Google Scholar Such unbalanced immunity favours NETosis and coagulation activation and possibly also alters systemic iron metabolism secondary to macrophage activation.8Sapey E Patel JM Greenwood H et al.Simvastatin improves neutrophil function and clinical outcomes in pneumonia. A pilot randomized controlled clinical trial.Am J Resp Crit Care Med. 2019; 200: 1282-1293Crossref PubMed Scopus (70) Google Scholar Notably, this alteration of immune balance occurs with increased age, and older patients might therefore be expected to fare worse, with a greater reliance on this pathway.9Simon AK Hollander GA McMichael A Evolution of the immune system in humans from infancy to old age.Proc Biol Sci. 2015; 28220143085Crossref PubMed Scopus (1134) Google Scholar Clinicians cannot be complacent about the risks of COVID-19 in patients with chronic liver diseases and cirrhosis, because these patients have poor immune function and worse outcomes from acute respiratory distress syndrome than the rest of the critically ill population.10Gacouin A Locufier M Uhel F et al.Liver cirrhosis is independently associated with 90-day mortality in ARDS patients.Shock. 2016; 45: 16-21Crossref PubMed Scopus (44) Google Scholar However, we believe that collateral liver damage from virally induced cytotoxic T cells and the induction of a dysregulated innate immune response is a more probable explanation for the association between deranged liver markers and COVID-19 disease severity. Furthermore, we suspect that what is termed COVID-19-induced hepatic damage is predominantly a clinical distraction. We urge clinicians and the scientific community to focus attention towards viral control and modulating innate immune dysfunction in COVID-19. We declare no competing interests. Download .pdf (.1 MB) Help with pdf files Supplementary appendix