Cases of liver damage or dysfunction (mainly characterized by moderately elevated serum aspartate aminotransferase levels) have been reported among patients with COVID-19. However, it is currently uncertain whether the COVID-19-related liver damage/dysfunction is due mainly to the viral infection per se or other coexisting conditions, such as the use of potentially hepatotoxic drugs and the coexistence of systemic inflammatory response, respiratory distress syndrome-induced hypoxia, and multiple organ dysfunction. Based on the current evidence from case reports and case series, this review article focuses on the demographic and clinical characteristics, potential mechanisms, and treatment options for COVID-19-related liver dysfunction. This review also describes the geographical and demographic distribution of COVID-19-related liver dysfunction, as well as possible underlying mechanisms linking COVID-19 to liver dysfunction, in order to facilitate future drug development, prevention, and control measures for COVID-19.
Angiotensin-converting enzyme (ACE)2-mediated liver dysfunction
Whether SARS-CoV-2 has direct adverse effects on liver function is currently not known. Some studies have suggested that SARS-CoV-2 predominantly enters alveolar epithelial cells through the human ACE2 receptor.19,20 Therefore, the lung is considered the main target organ of SARS-CoV-2 infection. However, previous studies have found that bile duct epithelial cells may also express ACE2 receptor at a concentration 20 times higher than in hepatocytes and these findings suggest that SARS-CoV-2 infection might also cause bile duct epithelial cell damage.21,22 However, significant increases in circulating levels of serum alkaline phosphatase, bilirubin or gamma-glutamyltransferase (that may reflect bile duct injury) have been rarely reported in COVID-19 patients.9 Liver histopathologic features from COVID-19 patients also did not show any significant damage in hepatocytes or bile duct cells.23 For this reason, it is reasonable to assume that COVID-19-related liver dysfunction is more likely due to secondary liver damage than the use of hepatotoxic therapies or the coexistence of systemic inflammatory response, respiratory distress syndrome-induced hypoxia, or multiple organ dysfunction.
During the course of the COVID-19 epidemic, many infected patients have been treated with antipyretic agents. Most of these medications contain acetaminophen, which is a drug recognized as being able to cause significant liver damage or induce liver failure.23 It is known that an acute ingestion of >7.5 to 10 g of acetaminophen in adults or 150 to 200 mg/kg in children is likely to cause hepatotoxicity.24 Although the US Food and Drug Administration Advisory Committee has proposed a decrease in the maximum daily dosage of acetaminophen from 4 to 3 g, and the maximum individual dosage from 1 to 0.65 g, (relegating 500-mg tablets to prescription status), these recommendations have not been implemented worldwide.25 In addition, although there is currently no targeted antiviral treatment for COVID-19, many infected patients have also been treated with some antiviral drugs, such as oseltamivir, abidol or lopinavir, which may have some hepatotoxic effects.
Systemic inflammatory response syndrome
Although many COVID-19 patients were not too unwell, this infection in some patients has resulted in sudden deterioration, ending in multiple organ failure. Most experts believe that the occurrence of multiple organ failure is mainly related to the sudden initiation of an inflammatory “storm” in the critically ill COVID-19 patients.26 The so-called inflammatory “storm”, or systemic inflammatory response syndrome, is strongly related to activation of both natural and cellular immunity that is triggered by COVID-19 infection.27 In fact, the virus is able to directly induce multiple proinflammatory signals via toll-like receptors (TLRs) and activation of killer T lymphocytes.28 The activated T lymphocytes then attack the infected body cells, leading to their apoptosis and necrosis, until T lymphocytes are depleted. Damage-related pattern molecules released by dead infected cells can further amplify some inflammatory signals, such as TLRs. At the same time, T-lymphocyte depletion cannot control viral and bacterial infections, thereby activating multiple inflammatory signaling pathways, which lead to macrophage activation and secondary inflammatory reactions. Subsequently, when more inflammatory cytokines are released, more cell damage and necrosis are observed (Fig. 3). Such a vicious cycle is capable of causing multiple injuries, not only to the lungs but also to the liver, heart, and kidneys.
Our review shows the following: (1) In highly epidemic areas of COVID-19 infection, such as Wuhan, China, the proportion of infected patients with abnormal liver function test results (mainly elevated serum AST levels) is greater than that observed in regions where a smaller proportion of cases of COVID-19 infection in the population have occurred. (2) The proportion of infected patients with elevated serum transaminase levels is higher in adults than in children and in men than in women, respectively. However, we suggest that further studies are needed to confirm these preliminary observations. In the meantime, we believe that the front-line medical staff should pay attention to liver function tests in patients infected with COVID-19. For those patients with a pre-existing history of liver diseases (especially older patients), special attention should be paid to monitoring hepatic changes caused by COVID-19, whilst carefully identifying the cause of the liver dysfunction.39 We also recommend that front-line medical staff should assess the use of appropriate hepatoprotective therapies, especially in patients with pre-existing liver disease, in order to attenuate the potentially deleterious impact of COVID-19-related liver damage/dysfunction.
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