A new meta-analysis study by researchers from Department of Hepatology, The First Affiliated Hospital of Fujian Medical University, Fuzhou-China and Mei-Zhu Hong, Department of Traditional Chinese Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou-China on the liver chemistries of severe or non-severe patients of COVID-19 has revealed interesting insights into varying degrees of liver impairment that SARS-CoV-2 infections can cause and also possibly contribute to Long COVID.
The study findings were published in the peer reviewed World Journal of Hepatology.
In this meta-analysis, 56 studies that consisted a total of 11052 patients with COVID-19 from China, United States, Chile, Iran and South Korea were enrolled. According to the pooled analysis, hepatocellular injury, hepatocellular dysfunction, and cholestasis, three patterns of liver impairment, can develop in quite a part of patients with COVID-19 at variable severity.
In brief, the patients with severe COVID-19 tended to have higher ALT/AST, ALP/GGT, and TBIL levels; higher INR; and prolonged PT. However, the severe cases had lower ALB levels than the non-severe cases. Particularly in severe cases of COVID-19, the AST levels were often higher than the ALT levels. We also observed a tendency of the severe cases to arise in the elderly.
Although the liver may act as the latent target of SARS-CoV-2, the actual prevalence of abnormal liver chemistries could be underestimated since many studies did not report cholestasis-related indexes such as ALP and GGT levels, and synthetic function-related indexes such as ALB level and INR.
Moreover, most studies reported ALT/AST levels on the day of admission while not the entire disease course. This issue further compromises the role of liver chemistries in disease monitoring and provides an early warning against severe cases.
As SARS-CoV-2 can lead to bile duct damage by conquering the ACE2 expressed on cholangiocytes and induce a subsequent cholestatic liver injury, cholestasis-related abnormalities could be overlooked.
Cumulating studies have linked abnormal liver chemistries to the severity of COVID-19. It is more likely that patients with abnormal liver test results will progress to severe cases. In fact, coronavirus infection can cause direct damage to liver cells. Moreover, several underlying diseases, comorbidities, and complications that develop in the course of the disease, such as sepsis and multiple-organ failure, and drugs that can cause potential liver damage also increase the risk of liver injury.
Lopinavir/ritonavir use during hospitalization has been reported to possible lead to liver damage[9,19]. The liver chemistry tests in the enrolled studies were all performed on admission, which suggests that the influences of the drugs on the liver tests, if any, should be minor.
ALB level and PT are known to reflect hepatocellular function. Albumin, which has a circulating half-life of 3 weeks, is a plasma protein exclusively synthesized by the liver. Hypoalbuminemia results from and reflects the inflammatory state, which leads to inflammatory exudate. Effective nutrition support helps to correct hypoalbuminemia.
Our meta-analysis revealed that ALB level was lower in the severe cases than in the non-severe cases, which indicated that the severe cases tended to have more intense inflammation and require more solid nutrition support. PT is a far more sensitive measure of hepatocellular function than ALB level because PT may be prolonged in patients with severe liver disease duration of < 24 h.
According to our meta-analysis, another interesting feature of liver impairment related to COVID-19 is that the AST level often overrides the ALT level, especially in severe cases. By contrast, in patients with chronic hepatitis B or nonalcoholic fatty liver disease, the ALT level is generally higher than the AST level.
While ALT is primarily present in the liver and is a more specific indicator for hepatocellular injury, the distribution of AST is far wider than that of ALT, including the cardiac muscle, skeletal muscle, kidney, and brain. An elevated AST level accompanied by a normal ALT level often suggests cardiac or muscle disease. In fact, cardiac injury is frequent in severe cases of COVID-19, especially in deceased patients[22,23].
This study has some substantial merits. First, acomprehensive review of COVID-19 literature, which is rapidly developing and sometimes confusing, was presented in this meta-analysis regarding the manifestation of liver chemistries. The extensive coverage of 37 studies allowed a more precise evaluation of the abnormalities of liver chemistries. Our subgroup analysis revealed that the abnormal liver chemistries were associated with a more severe disease course. It is imperative that liver chemistries should be monitored more closely for diagnostic and prognostic purposes.
Second, this analysis extensively covered hepatocellular injury, hepatocellular dysfunction, and cholestasis, three patterns of liver impairment. Most observations focused on ALT, AST, and ALB levels. However, cholestasis-related impairment (e.g., abnormal ALP and GGT levels) tended to be inadvertently ignored.
Moreover, we also compared hepatocellular dysfunction between the severe and non-severe cases. The alarmingly high prevalence of hypoalbuminemia in the severe cases prompts further nutrition support in severe cases. In addition, coagulation dysfunction in severe cases requires vigilance. Third, the enrolled studies included multiple observations not only from mainland China but also from other ethnic groups.
This facilitates the assessment of abnormal liver chemistries related to COVID-19 in a broader ethnic context. Fourth, eligible studies preprinted in medRxiv and bioRxiv were also covered. As a result, our analysis has a clear leading position. However, our study has a few limitations. As mentioned earlier, cholestasis-related indexes such as ALP/GGT level may be under-reported in quite a number of studies, which may lead to less precise pooled data.
Second, most studies were conducted in mainland China. It was difficult to determine if liver chemistry was abnormal in other ethnic groups. Most of the studies that came from mainland China seem to have an adverse impact. On the contrary, this helps to abate the heterogeneity caused by the disease grouping, as some potential discrepancies may exist in the definition of severe and non-severe cases of COVID-19 between different countries.
Dong X, Zeng DY, Xing QQ, Hong MZ, Pan JS. Liver chemistries in severe or non-severe cases of COVID-19: A systematic review and meta-analysis. World J Hepatol 2022; 14(12): 2012-2024 [PMID: 36618330 DOI: 10.4254/wjh.v14.i12.2012]
An earlier Spanish study had already found the SARS-CoV-2 spike 1 subunit isalso able to bind to albumin and contribute to disease severity.
A study by researchers from UK and Iraq showed persistent levels of hypoalbuminemia in recovered patients.
Studies have also emerged that even those with mild symptomatic COVID-19 infections also exhibit hypoalbuminemia.
Studies have also emerged that even children with mild COVID-19 are also developing hypoalbuminemia.
While many studies have focused on hypoalbuminemia to determine disease progression into severity, not much research have focused on persistent levels of hypoalbuminemia in asymptomatic, mild and all Post COVID-19 individuals.