New-Onset Liver Injuries Due to COVID-19: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Sandica Bucurica.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impacted the world and caused the 2019 coronavirus disease (COVID-19) pandemic. The clinical manifestations of the virus can vary from patient to patient, depending on their respective immune system and comorbidities. SARS-CoV-2 can affect patients through two mechanisms: directly by targeting specific receptors or by systemic mechanisms.

  • liver cirrhosis
  • SARS-CoV-2
  • COVID-19
  • cholangitis
  • chronic liver disease

1. Introduction

Coronavirus disease 2019 (COVID-19), caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can affect people of any age and medical history, but it is known that patients with associated comorbidities have a higher risk of developing a more severe form of the disease [1].
The cumulative number of COVID-19 reached more than 604 million confirmed cases, with over 6.4 million deaths, according to published data in September 2022 [2].
SARS-CoV-2 infection may have different clinical manifestations, from asymptomatic to mild forms or severe multisystem involvement [3][4].
In 2021, it was estimated that approximately 1.5 billion patients worldwide suffered from chronic liver disease [5]. The World Health Organization (WHO) estimated in 2019 that 296 million people worldwide were living with hepatitis B and 58 million with hepatitis C, and that almost 1.5 million people for each type are newly infected every year [6][7]. The prevalence of non-alcoholic fatty liver disease (NAFLD) is constantly increasing, matching the rise in the prevalence of obesity [8].
Regarding liver dysfunction during COVID-19, although not all pathways are clear, it has been shown that up to 50% of patients have altered liver enzymes and hepatic impairment [4][9].
Pathophysiologically, SARS-CoV-2 has a direct cytopathic action, binding to the angiotensin-convertase 2 (ACE2) receptors, abundantly expressed in hepatic and biliary epithelial cells.
Histological studies found a variety of liver alterations: slight infiltration of lymphocytes in lobuli associated with a degree of dilation or thrombosis in centrilobular sinusoids, portal inflammation or calcification [10], and variable steatosis degrees going up to the fibrotic stage [11].
Vascular abnormalities and necrosis have been described in a number of studies, which are determined by venous endoluminal obstruction, lymphocytic endotheliosis, and hypoperfusion [12][13]. Fractions of the novel corona virus were identified in hepatic cytoplasm [14], and viral specific proteins were detected in cholangiocytes [15] and hepatocytes even half a year after infection [16].
The affinity of the SARS-CoV-2 virus for cholangiocytes and the biliary tract is high. The viral particles were also present in the gallbladder [17], and congestive alterations with a micro-thrombotic vascular pattern, congestion, and gallbladder mucosa friability were found, similar to SARS-CoV-2 hepatic damage [18].
From an immunological perspective, the relationship between the liver and SARS-CoV-2 is complex and combines the tissue direct viral action with the systemic pro-inflammatory response and “cytokine storm” [19].
ACE-2 receptors (ACE-2R), which are abundant in cholangiocytes and in the cells of the sinusoid endothelium and fewer in the hepatic cells [20], and trans-membrane protease serine 2 (TMPRSS2) are the two most important elements that contribute to SARS-CoV-2 infectiveness [21].
The virus can use an alternative pathway—furin, a protein convertase—to gain access to the host cells. The viral structure is composed of nucleocapsid (N), membrane, envelope, and spike proteins (S) [22]. As a result, the virion spike protein S can bind to the ACE 2 receptors and TMPRSS2 or use furin proteinase cleaving action.
The inflammatory and immune systemic response in SARS-CoV-2 infection is mediated by the breakdown of T cell lymphocytes, flare of interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α). The complement overstimulation pathway appears to be another mechanism that leads to hyperinflammation through the IFN-Janus kinase (JAK) 1/2-signal transducer and activator of transcription (STAT) signaling complex alongside nuclear factor kappa B (NF-kB) [23][24].
Acute liver injury (ALI) during systemic inflammation caused by COVID-19 corresponds to increased c-reactive protein (CRP) levels, elevated interleukin-6, and high ferritin [25]. Pro-thrombotic status induced by SARS-CoV-2 contributes to liver affliction through vessel endothelial injury, intravascular emboli, micro/macro thrombosis induced by immune dysregulation, platelet impairment, and hypoxemia [26].
Hepatic injury in COVID-19 patients can be assessed using liver biochemical tests: serum albumin, cholestasis markers-bilirubin, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), liver transaminases-aspartate aminotransferase (AST/TGO), and alanine aminotransferase (ALT/TGP) [27][28]. A larger study found ALT and AST to be more than 3x the upper limit of normal (ULN) and bilirubin more than 2x ULN in patients with severe COVID-19, and AST to be higher than ALT, which can be a consequence of immune-mediated inflammation or injury [27][29].

2. COVID-19 and Cirrhosis

Cirrhosis is the final stage of long-term liver disease, causing an alteration in liver architecture through processes such as the production of extensive nodules, neo-angiogenesis, vascular restructuring, and newly formed extracellular matrix deposits [30]. Chronic liver disease is characterized by a cyclic process consisting of inflammation leading to the destruction and subsequent regeneration of liver parenchyma [30]. Cirrhosis may develop as a consequence of this process over the years, but at the time the diagnosis is made, it is considered irreversible [30]. Chronic liver disease causes immune dysregulation and inflammation, which can have an augmented effect on the processes present in SARS-CoV-2 infection [31]. The expression of ACE2 in hepatocytes of cirrhotic patients is 30 times higher than in the normal liver, and the association of metabolic syndrome increases the expression of both ACE2 and TMPRSS2 [32]. COVID-19 might affect the liver directly [33] (hepatocyte destruction caused directly by the SARS-CoV-2 virus or through viral translocation from the gut to the liver) or by indirect mechanisms [33] (such as systemic inflammation, hypoxemic effects on preexisting liver diseases, or ICU admission length) [33]. SARS-CoV-2 infection and cirrhosis seem to be a fatal combination, with augmented immune dysregulation being at the core of further biological processes leading to a more severe form of the disease [31]. Inflammation, in this case, is predominantly initiated by circulating active immune cells and pro-inflammatory cytokines [34]. One study from northern Europe found no clear link between COVID-19 and the outcome or evolution of cirrhosis [35]. A meta-analysis that focused on the outcome of COVID-19 infection in cirrhotic and non-cirrhotic patients included 40 studies with more than 900,000 participants. This showed that the COVID-19-cirrhosis association had an increased risk for severity (OR = 2.44; 95% CI, 1.89–3.16) and death (OR = 2.35; 95% CI, 1.85–3.00) [36]. The symptomatology of COVID-19 infection in cirrhotic patients has a specific course. First, acute decompensation is found in 46% of the patients, with formation or worsening of ascites and/or the onset of hepatic encephalopathy. In total, 20–58% of patients can present these alterations without respiratory symptoms connected to COVID-19 [34]. Gastrointestinal manifestations are another possible presentation for these patients, and they are thought to be connected to increased gut permeability, electrolytic changes, and systemic inflammation [37]. A series of severity scoring classifications can be used to assess the cirrhotic patients’ status, showing poorer prognosis for patients with cirrhosis and COVID-19 compared with non-COVID-19 patients [38][39]. A study from India found increased mortality for patients with acute-on-chronic liver failure (ACLF) [40]. The mortality rate of patients with ACLF–COVID-19 association was 55% [39]. ACE2 internalization by SARS-CoV-2 causes reduced ACE2 activity with further alteration in the pathway of angiotensin-II. The role of angiotensin-II in the renin-angiotensin system is essential for vasoconstriction, renal sodium retention, and promoting hepatic fibrogenesis. The reduced number of ACE2 in cirrhotic patients with COVID-19 aggravates hepatic fibrosis and portal hypertension, exacerbating the severity of the disease [41][42][43]. The interaction between SARS-CoV-2 and the liver appears to be a vicious circle, ultimately leading to multiple system organ failure (MSOF) [44]. Another study showed that COVID-19 was found to increase by 5-fold the chance of death among cirrhotic patients, respectively accounting for a 2.2-fold increase in the death risk of those with decompensated cirrhosis [45][46], but the main cause of death in cirrhotic patients infected with COVID-19 was found to be respiratory failure (71% of the cases in the study), while only 19% of the patients died of complications related to the liver [47].

3. COVID-19 and Cholangitis

Secondary sclerosing cholangitis is a progressive disease defined by intense fibrosis and destruction of the biliary tract, which can lead to biliary cirrhosis. Secondary sclerosis cholangitis in critically ill patients (SSC-CIP) is a form of secondary cholangiopathy that can cause a rapid deterioration of the patients [47][48]. Cholestasis in critically ill patients is mostly intrahepatic and is a result of the complex pathology behind it, such as systemic inflammatory response syndrome (SIRS), ischemic hepatitis, drug-induced liver injury, parenteral support, and ventilatory support [49]. A cholestatic pattern is less frequent in acute COVID-19 infection [47]. Secondary sclerosis cholangitis in critically ill patients (SSC-CIP) caused by SARS-CoV-2 was defined as a cholestatic liver injury that develops post-COVID-19 infection [50]. Despite emerging reports of secondary sclerosing cholangitis (SSC) in critically ill SARS-CoV-2-infected patients, there are no specific imagistic features that could be associated with the evolution of delayed progressive cholestatic liver injury, leading to cirrhosis [50]. Anatomically, the biliary system receives blood only from the peribiliary vascular plexus, while the liver parenchyma has two major blood supplies. The hypothesis of ischemia has been used to explain that severe hypotension with decreased mean arterial pressure (MAP) and longer time spent in the prone position are the triggers of SSC-CIP [51]. The incidence of SSC-CIP is directly proportional to ICU stay, even in patients without any history of biliary or liver disease. SSC-CIP is defined as a significant complication of ICU stay [52]. This new variant of sclerosis cholangitis provoked by COVID-19 is characterized by liver enzyme elevation even in patients who have not been to the ICU [53]. Pathologists have reported that severe cholangitic injury and intrahepatic microangiopathy are found in COVID-19 infection [53]. When comparing the level of RNA between airway cells and hepatic cells, there is a similar range but a lower median viral RNA in hepatic cells [54]. The binding of SARS-CoV-2 to the ACE2-R from cholangiocytes affects the barrier and the mechanism of transportation of the bile acid by affecting gene regulation. This leads to cholestasis and liver damage [55][56]. A retrospective study conducted in one center in Zurich on 34 patients admitted with COVID-19 to the ICU showed that 14 (41%) had mild cholestasis and 9 (27%) presented with a severe form of cholestasis [49]. Moreover, the ICU stay was prolonged for the last group of patients, and 4 of them developed secondary sclerosing cholangitis [49]. One study showed the case of a 38-year-old male with COVID-19 pneumonia that developed, afterward, hyperbilirubinemia, jaundice, and elevated transaminases [57]. He was hospitalized multiple times for pain, nausea, vomiting, and elevated liver enzymes, which resolved with supportive treatment. The patient underwent magnetic resonance cholangiopancreatography (MRCP), which revealed diffuse intrahepatic biliary distention and irregularity in the extrahepatic common bile duct. After performing the biopsy (cholangiocyte injury, bile ductular proliferation, canalicular cholestasis, fibrosis), the diagnosis of secondary sclerosing cholangitis was taken into consideration [57]. Biliary damage in COVID-19 patients should be taken into consideration when clinical and biological findings reveal jaundice, elevated transaminases, and/or cholestasis. Biliary imaging should be performed to confirm/infirm SSC [57]. One study that enrolled 496 patients showed that 15.4% of patients developed SSC, and patients with both chronic liver disease and COVID-19 pneumonia had a higher risk [58]. The multisystemic effect of SARS-CoV-2 has been intensively studied. The connection between COVID-19 and SSC was underlined, as several case reports have been published [59]. A middle-aged man came to the emergency room after being infected with SARS-CoV-2, with aggravating jaundice, abdominal pain, elevated liver enzymes, and dark-colored urine [59]. He underwent endoscopic retrograde cholangiopancreatography (ERCP) and MRCP, and the diagnosis of SSC was established based on the findings; he was registered for liver transplantation [59].

4. COVID-19 and NAFLD (Non-Alcoholic Fatty Liver Disease)

Non-alcoholic fatty liver disease (NAFLD) is defined as hepatic steatosis with or without inflammation and/or fibrosis [60]. The disease is further divided into NAFL—non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), the main difference between them being the presence of inflammation [60]. Liver biopsy is the gold standard method of diagnosing NAFLD (staging from milder forms (steatosis) to severe forms (NASH, advanced fibrosis, cirrhosis)). Histologically, NAFLD has been defined as the presence of hepatic steatosis, ballooning, and lobular inflammation with or without fibrosis [61]. NAFLD is a heterogenous condition, mainly related to the types of lipids that accumulate, their toxicity to the liver, and to the ability of the individual to defend against it. The response of wound healing of individuals determines their capacity to recover from NASH or to develop scarring, cirrhosis, and even hepatocellular carcinoma [61]. NAFLD is becoming a leading cause of chronic liver disease worldwide because of the high incidence of both obesity and metabolic syndrome [62]. While the prevalence of the disease varies with age, sex, and demographics, it is more common in Hispano-American men aged between 40 and 50 years [60]. Patients with NAFLD (particularly those with NASH) often have one or more components of metabolic syndrome, to which NAFLD is linked [63]. SARS-CoV-2 infection is known to have a worse outcome in patients with high BMI or diabetes [64]. The pathophysiological mechanism is related to obesity-related poor immune responses to infection. It has been postulated that there is chronic inflammation in obese patients with pro-inflammatory citokine release mediated by the NLRP3 inflammasome [64]. NAFLD is not only associated with COVID-19, but it can increase the risk of developing all types of infections through systemic alterations, such as hyperglycemia, insulin resistance, alteration of innate immunity, obesity, and vitamin D deficiency [65]. The lockdown caused changes in lifestyle: more coffee and tobacco use and less physical activity [66]. Moreover, during the pandemic era, NAFLD and insulin resistance prevalence worsened as a consequence of the lack of screening and regular monitoring of patients [66]. Research related to fatty liver index was published evaluating 3122 COVID-19 patients from the South Korea database [67]. The aim was to correlate the fatty liver index (FLI) of NAFLD patients with the severity of COVID-19, showing that NAFLD patients have a poorer prognosis and a higher likelihood of needing mechanical ventilation, ICU admission, and high flow oxygen therapy. As a result, FLI can be used to assess the prognosis of COVID-19 [67]. SARS-CoV-2 infection increases the likelihood of developing new types of liver dysfunctions [63]. The majority of the macrophages are hosted in the liver, and as the macrophages have an impeded clearance in the SARS-CoV-2 infection, it leads to further alteration of liver function through augmented cytokine production [63]. In NAFLD patients, the polarization status of macrophages might be affected, influencing the inflammatory response to SARS-CoV-2. A study conducted in central London concluded that there was no statistically significant difference regarding mortality or ICU admissions between patients with NAFLD and those without. The main difference was that patients with NAFLD were younger and had a higher inflammatory response at the time of admission [68]. Excessive weight and NAFLD associate a pro-inflammatory status with high levels of pro-inflammatory cytokines [69] (NLR family pyrin domain containing 3—NLPR3, IL-1 [64]), increasing susceptibility to severe infection. Obese patients with NASH have a higher risk of being infected with COVID-19, as they have higher liver mRNA expression of ACE2 and TMMPRS 2 [70]. NAFLD is frequently present in patients with metabolic syndrome (hyperglycemic syndrome, hypertriglyceridemia, hypertension, raised high-density lipoprotein cholesterol HDL-cholesterol, obesity), and the influence of ACE2-R has been studied in patients with NAFLD and in those with type 2 diabetes [70]. In T2D, it was observed that there are lower amounts of ACE2-R in comparison to TMPRSS2, which showed no statistically significant difference. Furthermore, ACE2-R is more present in men with T2D than in women. WResearchers can theorize, based on the available data, that the main mechanism of the entrance of SARS-CoV-2 is not majorly altered in the livers of obese men with T2D, but there may be a lower susceptibility for liver injury in women [70]. COVID-19 enters the cholangiocytes through ACE2-R and causes direct damage with liver enzyme alteration, including albumin, GGT, ALT, and AST [71][72][73]. Moreover, the cytokine storm activated in COVID-19 affects the liver directly. TNF-α, a pro-inflammatory protein, is produced by adipose tissue and liver macrophages and modifies the immune response in patients with NAFLD. This process has consequences for M1 macrophages, which are suppressed, while M2 macrophages have an intense activation [71][72][73]. Taking this statement into account, it is necessary to identify a targeted treatment to reduce FLI [71][72][73].

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