ACE2 receptor resembles the ACE receptor and plays a crucial role in the renin-angiotensin-aldosterone system (RAAS), including blood pressure control and electrolyte homeostasis. The liver produced angiotensinogen, which is cleaved by renin from the kidney, results in Ang I. After that, ACE catalyzes the conversion of Ang I to Ang II. Ang II is the significant active RAAS portion and exerts its effects via Ang II type 1 receptor. Furthermore, Ang II's main effects include vasoconstriction, renal sodium reabsorption, potassium excretion, aldosterone synthesis, blood pressure elevation, and induction of pro-inflammatory and pro-fibrotic pathways. ACE2 splits Ang II to Ang (1-7) and Ang I to Ang (1-9). Furthermore, Ang (1-9) is cleaved by ACE to Ang (1-7). Ang (1-7) exerts vasodilatation, anti-inflammatory, and anti-fibrotic effects through the Mas receptor to counterbalance Ang II's action. Notably, ACE2 functionally counteracts the physiological role of ACE and creates the tissue balance of ACE and ACE2, which determines the pro-inflammatory, pro-fibrotic, or anti-inflammatory and anti-fibrotic pathways[25,26] (Figure 1). The common drugs prescribed for RAAS blockade in several disease conditions can affect this balance. Moreover, many dietary factors (high sodium, high fat, and high fructose intake) can also shift the ACE/ACE2 balance towards pro-inflammatory and pro-fibrotic[27-29].

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Figure 1 The renin-angiotensin-aldosterone system and the physiology of angiotensin-converting enzyme 2. ACE: Angiotensin-converting enzyme.

In 2004, Hamming et al[30] investigated the immuno-localization of ACE2 in 93 human specimens and found that ACE2 was present in endothelial cells from small arteries, large arteries, and veins in the studied tissues. Marked ACE2 immuno-staining was found in type I and typed II alveolar epithelial cells in normal lungs. ACE2 was abundantly demonstrated in enterocytes of all small intestine but not in the enterocytes of the large intestine. ACE2 was not found in lymphoid tissues and hepatocytes. Recently, Xu et al[31] investigated ACE2 expression in the oral cavity mucosa and various organs, including the intestine, kidney, stomach, bile duct, liver, lungs, thyroid, esophagus, bladder, breasts, uterus, and prostate. They found that ACE2 could be expressed in various organs. The mean expression of ACE2 in the liver, bile duct, and lungs was 6.86 ± 1.35, 7.23 ± 1.16, 5.83 ± 0.71, respectively. This result demonstrated that the expression of ACE2 in the lungs and the liver was not different. Moreover, Zhao et al[32] identified ACE2 expression sparsely in cholangiocytes of human liver ductal organoids cells. Anti-ACE2 immuno-staining further confirmed the presence of ACE2 receptors on those cells. Furthermore, Li et al[33] explored the underlying liver injury mechanism by profiling ACE2 expression with CLD expression data. They found that the liver tissues with chronic diseases, such as cirrhosis, non-alcoholic steatohepatitis, simple steatosis, and dysplasia, could express higher levels of ACE2 than normal liver tissues.

Sinha et al[34] performed in vitro and in vivo studies to identify the clinically approved drugs that could modify ACE2 expression. They found that ACE inhibitors (ACEIs) but not angiotensin II type-I receptor blockers (ARBs) tend to upregulate ACE2 expression, and anti-adrenergic drugs other than alpha/beta-blockers tend to down-regulate ACE2 expression. Moreover, calcium channel blockers (CCBs) do not significantly change ACE2 expression, consistent with the finding that they do not act on the RAAS. This evidence provides preliminary in vitro support for the use of CCBs as an alternative to ACEIs in COVID-19 patients with hypertension. They also studied the 13 approved anti-diabetic drugs related to ACE2 expression, and they could not demonstrate that the drugs significantly altered ACE2 expression. Surprisingly, they reported that intravenous dexamethasone injection could increase ACE2 expression. They also demonstrated the effect of vancomycin, which increased an ACE2 expression. Saheb SharifAskari et al[35] studied the effect of common medications on the expression of ACE2 receptors in human primary hepatocytes. They found that the top three drugs that increased ACE2 expression were penicillamine, ethambutol, and vitamin A. The top five drugs that decreased ACE2 expression were colchicine, acetaminophen, sulindac, diazepam, and nimesulide. The top five drugs that did not change ACE2 expression were ibuprofen, lornoxicam, mefenamic acid, meloxicam, and methyltestosterone.

Previous studies have shown that nearly 60% of SARS patients developed a hepatobiliary injury and that SARS-CoV antigens were detected in liver tissues by reverse transcription-polymerase chain reaction[36,37]. Hepatobiliary injury in COVID-19 patients was also demonstrated by abnormal transaminase levels linked to the disease severity and the clinical outcome. Abnormal liver enzymes in COVID-19 patients were first reported by Chen et al[38]. They analyzed data of 99 COVID-19 patients from Wuhan and found that 43 cases (43.4%) had elevated ALT, AST, and lactic dehydrogenase. Most of them had a mild elevation of AST and ALT, and only one patient had very high ALT levels of 7590 U/L and AST levels of 1445 U/L. Recently, Kulkarni et al[39] conducted a systematic review with meta-analysis to evaluate the liver manifestations and clinical outcomes in 20874 COVID-19 patients. They found that the pooled incidence of elevated AST and ALT in COVID-19 was 23.1% (19.3%-27.3%) at initial presentation. Moreover, 24.4% (13.5%-40%) of the patients developed elevated AST and ALT during the illness. They also reported the prevalence of underlying CLD as 3.6% among the 15407 COVID-19 patients. The pooled incidence of drug-induced hepatobiliary injury was 25.4% (14.2%-41.4%). They found that the development of severe COVID-19 in CLD patients had an odds ratio (OR) of 0.81 [95% confidence interval (CI): 0.31-2.09] compared with non-CLD patients. Furthermore, COVID-19 patients with elevated AST and ALT had increased risk of mortality (OR = 3.46, 95%CI: 2.42-4.95, P < 0.001) and severe disease (OR = 2.87, 95%CI: 2.29-3.6, P < 0.001) when compared with the patients without elevated AST and ALT.

Recently, Del Zompo et al[40] conducted a systematic review with meta-analysis to elucidate the prevalence of hepatobiliary injury in 20724 COVID-19 patients with or without pre-existing CLD. They found that the pooled prevalence of abnormal liver function tests (LFTs) on admission was 46.9% [AST 26.5%, ALT 22.8%, gamma-glutamyl transferase (GGT) 22.5%, alkaline phosphatase (ALP) 5.7%, and total bilirubin (tBIL) 8.0%]. The elevation of ALT, AST, and tBIL were independent predictors of disease severity and in-hospital mortality. Wong et al[41] conducted another systematic review with meta-analysis to evaluate the prevalence and degree of liver injury in 5961 severe and non-severe COVID-19. They found that the OR for elevated ALT was 2.5, AST was 3.4, hyperbilirubinemia was 1.7, and hypoalbuminemia was 7.1, which were higher in critical COVID-19. They concluded that hepatobiliary injury is more common in COVID-19 patients with severe clinical outcomes than in COVID-19 patients with non-severe clinical outcomes.

Mao et al[42] conducted another meta-analysis to evaluate the prevalence and prognosis of gastrointestinal symptoms and hepatobiliary injury in 6686 patients with COVID-19. They found that the pooled prevalence of liver co-morbidities was 3%, including chronic hepatitis and liver cirrhosis. The pooled prevalence of liver injury from 12 studies (n = 1267) was 19%. The prevalence of elevated ALT was 18%, AST was 21%, tBIL was 6%, and decreased albumin was 6%. They also reported a higher risk of abnormal LFT in patients with severe COVID-19 than those with the non-severe disease.

Kumar-M et al[43] conducted another meta-analysis to evaluate the overall prevalence, stratified prevalence based on severity, estimated risk ratio (RR), and estimated standardized mean difference (SMD) of liver function parameters in severe compared to non-severe COVID-19 patients with a total number of 28659 subjects. They found that the most frequent abnormalities were hypoalbuminemia (61.27%), elevated GGT = 27.94%, elevated ALT = 23.28%, and elevated AST = 23.41%. Furthermore, the relative risk (RR) of these abnormalities was higher in the patients with severe COVID-19 when compared to non-severe disease (hypoalbuminemia RR = 2.65; GGT RR = 2.31; AST RR = 2.30; and ALT RR = 1.76). The pooled prevalence and RR of CLD as a pre-existing co-morbidity were 2.64% and 1.69%, respectively. They concluded that the most frequent hepatobiliary injury was hypoalbuminemia followed by elevated GGT, elevated AST, and elevated ALT, which were more common in severe COVID-19 patients.

Youssef et al[44] conducted a meta-analysis of 3428 COVID-19 patients to elucidate the relationship between hepatobiliary injuries and the severity of COVID-19 disease. They found that the patients who had severe presentations of COVID-19 had hypoalbuminemia (SMD = 0.68), elevated AST (SMD = 0.36), elevated ALT (SMD = 0.44), and elevated tBIL (SMD = 0.40). They also reported that severe COVID-19 patients had a higher OR of developing acute hepatobiliary injury (OR = 1.93). They concluded that hepatobiliary injury was related to a critical outcome of COVID-19 patients. Close monitoring of the development of liver dysfunction is beneficial in early warning of unfavorable outcomes.

Wang et al[45] conducted a meta-analysis to evaluate the association of liver injury and gastrointestinal symptoms (GIS) with the progression of COVID-19 in 3024 patients. They found that 53% of patients had a hepatobiliary injury, and the degree of hepatobiliary damage was associated with disease severity. The prevalence of GIS was relatively low and was not associated with disease progression, with diarrhea of 9.1%, nausea/vomiting of 5.2%, and abdominal pain of 3.5%.

Wu et al[46] conducted a meta-analysis to explore the probable clinical severity and mortality of COVID-19 patients and their liver dysfunction in 3722 COVID-19 patients. They found a significant connection between hepatobiliary dysfunction and mortality in COVID-19 patients with a pooled OR of 1.98. There was a significant association between elevated AST and severity of COVID-19 with a pooled OR of 4.48 and a pooled weighted mean difference of 3.35. They also found a significant difference between elevated tBIL and severe COVID-19 (pooled OR = 1.91 and pooled weighted mean difference = 1.18). They concluded that the mortality and severity of COVID-19 patients are significantly associated with hepatobiliary dysfunction.

Samidoust et al[47] conducted a meta-analysis study to investigate the incidence of liver injury among 4191 COVID-19 patients. They found that the pooled prevalence of liver injury was 19.5%. They concluded that hepatobiliary system is the most frequently damaged outside of the respiratory system. Wu et al[48] conducted the meta-analysis to explore the incidence, risk factors, and prognosis of abnormal liver biochemical tests in 7228 COVID-19 patients. They found that the pooled prevalence of any abnormal liver biochemistry parameters on admission and during hospitalization was 27.2% and 36%, respectively. The most common prevalence was hypoalbuminemia followed by GGT, AST, ALT, tBIL, and ALP (39.8%, 35.8%, 21.8%, 20.4%, 8.8%, and 4.7%). Moreover, severe or critical patients had a significantly higher pooled incidence of abnormal liver biochemistry parameters on admission than mild or moderate patients. Non-survival patients also had a significantly higher incidence of abnormal liver biochemical indicators than survival patients (RR = 1.34). They concluded that abnormal liver biochemical tests are common and are closely related to the severity and prognosis of COVID-19 patients.

Mantovani et al[49] conducted the meta-analysis to assess the overall prevalence of CLD among 2034 COVID-19 patients. They found that the overall prevalence of CLD at baseline was 3%, and patients with severe COVID-19 disease had relevant increases of liver enzymes and coagulation profile due to the innate immune response against the SAR-CoV-2 virus. Sultan et al[50] conducted the meta-analysis to summarize international data on the gastrointestinal (GI) and liver manifestations of SAR-CoV-2 infection and treatment in 10890 COVID-19 patients. They found that elevated AST, elevated ALT, and elevated tBIL are observed in approximately 15%-20% of COVID-19 patients. These findings inform that the clinician should perform a careful evaluation of patients with new-onset GI symptoms for classic and atypical symptoms of COVID-19. All hospitalized COVID-19 patients may benefit from liver enzyme monitoring, particularly in drug treatment with known hepatotoxic potential.

Xu et al[51] reported the first post-mortem findings of a patient who succumbed to severe COVID-19. They found that the liver histology showed moderate microvesicular steatosis and mild inflammatory infiltrates in the hepatic lobule and portal tract. They do not know whether these changes were from the direct viral injury or drug toxicity. Wichmann et al[52] conducted a prospective cohort study to perform the autopsies of 12 consecutive COVID-19 deaths, including post-mortem computed tomography and histopathologic and virologic analyses. The median patient age was 73 years (52 to 87 years), 75% of patients were male, and death occurred in the hospital (n = 10) or outpatient department (n = 2). They did not report the histopathology of the hepatobiliary system; however, they could demonstrate the detection of SARS-CoV-2 ribonucleic acid in the lungs of 12 patients (1.2 × 10⁴ to 9 × 10⁹ copies/mL) and the pharynx of nine patients. In five of these patients, viral ribonucleic acid was also detected in the heart, liver, and kidney. They concluded that SARS-CoV-2 might spread via the bloodstream and infect other organs, including the hepatobiliary system. Tian et al[53] performed post-mortem needle core biopsies of lung, liver, and heart in four patients who died of COVID-19 pneumonia. They found that the liver histopathology showed mild lobular infiltration by small lymphocytes, centrilobular sinusoidal dilatation, focal macrovesicular steatosis, and patchy hepatic necrosis in the periportal and centrilobular areas. Tabary et al[54] reviewed multiple organs, including lung, GI tract, liver, kidney, skin, heart, blood, spleen, lymph nodes, brain, blood vessels, and placenta, in COVID-19-related pathological alterations. The liver found hepatocyte degeneration with lobular focal necrosis, congestion of hepatic sinuses with microthrombus, fibrosis of portal tract, the proliferation of portal vein branches, mononuclear leukocyte, and neutrophil infiltration within the portal area and moderate microvascular steatosis. Yao et al[55] conducted another histopathology of the hepatobiliary system. They found that the liver exhibits mild sinusoidal dilation, with mildly increased small lymphocytes infiltration in sinusoidal spaces. Mild to moderate steatosis and multifocal hepatic necrosis have been reported. These findings confirmed that the hepatocellular injury in COVID-19 patients should be considered as a significant factor in disease severity.