Clinical characteristics and risk factors of liver injury in COVID-19: a retrospective cohort study from Wuhan, China

The ongoing outbreak of Coronavirus disease 2019 (COVID-19) has been recently becoming a pandemic [1]. At present, it is believed that SARS-CoV-2 mainly invades the respiratory system. Most patients have fever, cough, chest distress and dyspnea. Furthermore, systemic hyper-inflammation driving hypercoagulability is common in these patients [2].

However, accumulating evidences have suggested that some COVID-19 patients have different degrees of liver dysfunction [3‐6]. Of 99 patients with COVID-19 enrolled in Wuhan Jinyintan Hospital, among whom 43 patients with different degrees of abnormal liver function were admitted to intensive care unit (ICU). One patient presented with obvious liver injury (alanine aminotransferase (ALT) 7590 U/L, aspartate aminotransferase (AST) 1445 U/L) [3]. Huang et al. showed that more patients admitted to ICU had elevated AST levels [4]. Wang et al. showed that patients admitted to ICU had significantly higher ALT levels [5].Moreover, Guan et al. extracted the currently largest cohort regarding 1099 mainly moderate SARS-CoV-2 infected patients and showed 39.4% with severe disease had elevated AST and 28.1% had elevated ALT, and the proportion was 18.2% and 19.8% in patients with non-severe disease [6].Given that the number of patients in these studies is relatively small, information about the clinical characteristics of liver injury in these patients is scarce. So far, to our knowledge, there are few reports that analyzed risk factors of liver injury in COVID-19 patients.

This current study aims to analyze the clinical characteristics of COVID-19 patients with liver injury, and evaluate the potential risk factors for the development of liver injury.

The present study showed that liver injury was more prevalent in male, severe or critically ill patients with percutaneous oxygen saturation ≤ 93% or peak temperature ≥ 38.5 °C on admission, and comprehensively delineated the risk factors for COVID-19-associated liver injury. Liver injury-related inflammations included increased white blood cells, neutrophils and decreased lymphocytes. More patients with liver injury had increased serum IL-2R, TNFα, ferritin, hsCRP, PCT, ESR, γ-GT, and LDH. In addition, male, elevated hsCRP (≥ 10 mg/L) and NLR (≥ 5) were risk factors for COVID-19-associated liver injury. And patients with abnormal liver function tests (LFT) had higher risks of progressing to severe disease.

COVID-19-associated liver injury is defined as any liver damage occurring during disease progression and treatment of COVID-19 in patients with or without pre-existing liver diseases. In our cohort, there were 26 patients with elevated TBIL alone. According to data analysis of these patients, the results showed that the bilirubin elevation was due to direct bilirubin elevation as main body (15 cases) or both direct bilirubin and indirect bilirubin elevation (8 cases) or indirect bilirubin elevation as main body accompanied by the rise of AST (3 cases). Although all the 26 patients showed a degree of liver injury, Hemolytic Jaundice or Gilbert’s disease cannot be entirely excluded and requires further monitor in follow-up study.

Liver injury is not uncommon in previous studies in patients infected with severe acute respiratory syndrome coronavirus (SARS-Cov) and Middle East respiratory syndrome coronavirus (MERS-Cov) [8]. Likewise, abnormal LFTs were frequently seen in patients with COVID-19, with incidence rates exceeding 50% in some studies. Liver injury was presented in 30 out of 113 deceased patients from our previous reports [9]. However, patients with COVID-19 rarely develop acute or acute-on-chronic liver failure [4, 6, 9]. Taken together, these studies demonstrated that the majority of cases of COVID-19-associated liver injury occurred in severe or critically ill patients.

Consistent with the above findings, current study in a relatively larger cohort of severe/critical patients further demonstrated liver injury occurred more frequently in these patients [148/257 (57.6%)] than in moderate ones [155/400 (38.8%)]. Serum ALT, TBIL and γ-GT levels were markedly higher in severe and critically ill patients than in moderate patients, with a peak ALT of 728 U/L and peak TBIL of 174.1 μmol/L, respectively. The increase of ALT from day 5 to day 15 after admission was significantly greater in deceased patients than in discharged patients, and the proportion of cases in deceased patients with serum TBIL levels of 1–2 or above 2 times the ULN was markedly higher than that in discharged patients. These results provided the concrete evidence that impaired liver function was more frequent in severe and critically ill patients.

Moreover, multivariate regression analysis showed that hsCRP ≥ 10 mg/L, NLR ≥ 5 and male were the risk factors for liver injury in our study, which was consistent with Lei’s results [10]. As a traditional inflammatory marker, CRP is an acute-phase protein used for the diagnosis and follow-up of infection or tissue damage. Li et al. [11] showed CRP was independently associated with hepatic injury in patients with COVID-19. NLR, as a reliable marker of systemic inflammation and infection, has been considered as a predictor of bacterial infections, including pneumonia. Liu et al. [12] reported that NLR might predict severe illness in the early stage of COVID-19. Zhang et al. [13] identified NLR as an independent risk factor for severe COVID-19. Current studies indicated that there might be a sex predisposition to COVID-19, with men more prone to being affected likely due to much higher smoking rate in men [14].

Underlying mechanisms involved in liver injury in patients with COVID-19 are complex and interactive, including immune reconstitution in the presence of SARS-CoV-2, direct drug toxicity, systemic inflammation with liver involvement induced by cytokine storm or pneumonia-associated hypoxia [15]. Previous studies indicated that T lymphocytes particularly CD4⁺T and CD8⁺T cells decreased in severe COVID-19 patients [16], and immune function dysregulation in some cases may be associated with the development of acute respiratory distress syndrome (ARDS), collateral damage to multiple organs, such as liver, kidney and heart as well as death [17]. The exaggerated immune-mediated inflammation is known as “cytokine storm”. Similar to our study, accumulating evidence suggested that patients with severe COVID-19 might have a cytokine storm syndrome. Changes of inflammatory cytokines following SARS-CoV-2 infection may cause or contribute to liver damage. The underlying mechanism involved in cytokine accumulation in COVID-19 and subsequent liver injury warrants further investigation.

Recent study [18] demonstrated no significant increase in ALP and γ-GT in patients with COVID-19. In contrast, among 657 cases in the present study, more severely/critically ill patients [83/257 (32.3%)] than moderate patients [77/400 (19.3%)] had elevated γ-GT level. Previous pathological findings of COVID-19 in the liver showed moderate microvesicular steatosis and active inflammation in the hepatic portal area but no viral inclusions identified in the liver tissue [19]. The latest research showed that angiotensin-converting enzyme 2 (ACE2) was expressed in specific cholangiocytes in healthy liver tissues [20] and suggested liver injury in COVID-19 patients may not be only due to hepatocyte damage but cholangiocyte dysfunction. In our study, elevated γ-GT and bilirubin in patients with COVID-19 suggested that the virus may cause liver impairment by targeting cholangiocytes. The pathogenesis of COVID-19-associated liver injury warrants further investigation.

The impact of preexisting chronic liver diseases on the liver function of COVID-19 patients remains not fully elucidated. Ji et al. recently reported patients with non-alcoholic fatty liver disease (NAFLD) were at higher risk of disease progression, and developing abnormal liver function during hospitalization in COVID-19 patients [21]. Singh et al. [22] found COVID-19 patients with pre-existing liver disease, notably cirrhosis, were at higher risk for hospitalizations and mortality. Guan et al. reported that patients with preexisting chronic hepatitis B did not have more severe disease compared to the overall population [6]. Our study showed that 52 (7.9%) patients with underlying viral hepatitis (hepatitis B and hepatitis C)developed liver dysfunction, and more patients with underlying viral hepatitis developed liver injury than those without [31/303 (10.2%) vs 21/354 (5.9%)], which may be partly due to inflammatory responses and immune disorder of viral hepatitis. Further multivariate regression analysis showed that underlying viral hepatitis and metabolic disorder were not independent risk factors for liver injury, which is consistent with recent report [23], suggesting that liver injury cannot be entirely attributed to the preexisting chronic liver diseases in COVID-19 patients.

Considering the administration of antivirals, antibiotics, NSAIDS and glucocorticoids in the treatment of patients, potential drug-induced liver injury (DILI) deserves special concern. Given data provided is limited, based on recent results, we cannot draw a definitive conclusion about whether Lopinavir/Ritonavir increase the risk of developing liver damage [18, 24, 25]. Our study revealed a higher proportion of patients with liver injury had received systemic glucocorticoid. Nevertheless, we found a slightly reduced risk of hepatic injury in patients treated with Arbidol. This is likely due to the possibility that Arbidol may effectively suppress SARS-CoV-2 replication, which may be a beneficial pathway to lower the risk of the subsequent viral-induced liver injury. It has recently been reported that Arbidol combined with Lopinavir/Ritonavir achieved significantly higher rates of viral clearance and favorable clinical outcome compared with Lopinavir/Ritonavir used alone [26]. These findings further supported the hypothesis that effective antiviral therapy may prove useful in preventing or slowing the progression of the COVID-19 disease.

Our study has some limitations. First, nearly one third of critically ill patients developed disorders of consciousness on admission, which might result in a loss of some information (particularly a detailed history and subjective symptoms). Additionally, some physical examination and laboratory tests were not done in all the patients, and missing data or important tests might lead to bias of clinical characteristics. Second, the impact of COVID-19 in patients with preexisting chronic liver diseases, such as viral hepatitis, NAFLD, and alcohol-related liver disease, remains to be evaluated. Third, in the early period of epidemic, owing to some environmental constraints, such as the explosive growth of the infected population and the shortage of medical supplies, the results may be difficult to interpret accurately. More intensive surveillance or individually tailored therapeutic approach is needed for severe cases, especially among patients with liver or other important organ dysfunction.

In conclusion, immune-mediated inflammation may lead to COVID-19-associated liver injury. The potential risk factors for liver injury include male, hsCRP and NLR score. Moreover, patients with abnormal LFTs had higher risks of progressing to severe disease. Attention should be paid to monitor liver function during the course of COVID-19, especially in severely/critically ill patients. The data provided may be useful in helping us extend our understanding of the disease so that early effective intervention could be carried out promptly. Appropriate intervention and reasonable supportive care are expected to reduce the inflammatory response and then further reduce liver injury of patients with COVID-19.