Liver injury may be associated with COVID-19 due to direct damage of the viral infection to liver cells up to 20 months after infection

A study by researchers from the State University of Pará, (UEPA)-Brazil and São Paulo University-Brazil has shown that liver function in patients up to 20 Months of Long COVID still manifest abnormalities indicating liver injury.

The study findings were published on preprint server and is currently being peer reviewed.
https://www.preprints.org/manuscript/202302.0145/v1

In this study, patients with long-term COVID symptoms that lasted up to 20 months were admitted. Alterations were identified in the average levels of ALT, AST, LDH, GGT, and ferritin. The elevation of ferritin, a group of inflammatory markers, was related to the increase in the levels of other liver markers, and ESR was above the reference values in all groups in this study.

In addition, we observed that age > 60 years, male sex, and AST and GGT levels above the reference values were more associated with ALT > 29 U/L. The high correlation between ALT and AST levels also suggests a high risk of liver damage.

An et al. [18] also reported elevated levels of ALT, GGT, and ALP 14 days after hospital discharge within 2 months of the initial infection. According to Gameil et al. [19], ALT, AST, GGT, and ALP levels may be elevated 3 months after the resolution of COVID-19. Such altered markers are the result of direct damage caused by the virus to hepatocytes and a systemic inflammatory process already documented in hospitalised patients whose levels of IFN-λ, interleukin (IL)-6, IL-10, and IL-2 are found to be high [20].

Patients with severe COVID-19 have elevated levels of AST, ALT, and GGT [21] and reduced albumin levels [22]. In the findings of our study, the mean albumin levels were within normal limits.

AST has also been used as a liver marker. Because it is produced in the muscle, and patients with long-term COVID have fatigue and muscle weakness as the most frequent symptoms, the elevation of this marker is questionable as to its hepatic origin [23].

However, the correlation and association between ALT and AST identified in our study suggest that true liver injury is the predominant source of aminotransferase elevation.

Bende et al. [17] identified liver stiffness and viscosity in patients with post-COVID-19 syndrome, whose rates were significantly higher in those with lung in- jury in the acute phase and developed exacerbated clinical manifestations. Liver viscosity appears to be associated with the degree of inflammation and hepatic steatosis [24].

Although ferritin was the only inflammatory marker with differences between the study groups, we observed that the mean ESR values were above the reference values in all groups, which could be explained by a probable residual systemic inflammatory response [19].

In hospitalised patients with COVID-19, liver markers demonstrate a correlation between ALT and AST levels; however, this relationship has not been identified between muscle degradation and inflammatory markers, which suggests that liver damage is directly caused by the presence of the virus in the tissue, whose mechanisms have not yet been fully elucidated [25]. In our study, there was a correlation between markers of muscle degradation (LDH) and inflammation (ferritin).

Alteration of liver markers without concomitant elevation of serum total bilirubin observed in acute and long COVID, as well as the elevated expression of ACE2 in cholangiocytes, suggests a persistent systemic inflammatory response in these patients [26]. ACE2-mediated direct viral invasion of hepatocytes, disrupted immune homeostasis, systemic inflammatory response, concomitant hypotension, pneumonia-associated hypoxia, cytokine storm with increased pro-inflammatory cytokines, and drug use suggest probable pathogenesis of liver injury in long-term COVID [27, 28].

An et al. [18] highlighted that patients in serious conditions during acute COVID-19 used more drug therapies, such as oxygen inhalation, antiviral drugs, anti-infective drugs, vasoactive drugs, hormone therapy, immunoregulatory drugs, drugs to regulate the intestinal flora, and symptomatic treatment drugs. Most of these drugs have hepato- toxic effects and may cause liver damage in patients with long-term COVID [29-30].

In addition, reliable control groups are difficult to obtain because of the pandemic that affects many people. On the other hand, this study evaluates possible liver damage in patients with up to 20 months of long COVID, the first study in the literature, mainly in the Amazon Region.

Changes in liver function markers, such as ALT, AST, LDH, GGT, and ferritin, may be present in patients who have developed long-term COVID, especially those hospital- ised during acute infection. This may be due to the direct injury caused by the virus to hepatocytes and a persistent systemic inflammatory process.

Furthermore, the results of this study suggest that changes in markers of liver injury in patients with long-term COVID may persist for more than 1.5 years after the resolution of COVID-19.

Finally, we suggest that new studies be carried out, especially those that allow monitoring the evolution of these patients for a longer time to identify whether such findings are indelible or transient, which represents one of the main gaps in current scientific knowledge.