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Impact of COVID-19 pandemic on liver, liver diseases, and liver transplantation programs in intensive care units

Emerging worldwide data have been suggesting that coronavirus disease 2019 (COVID-19) pandemic consequences are not limited to the respiratory and cardiovascular systems but encompass adverse gastrointestinal manifestations including acute liver injury as well. Severe cases of liver injury associated with higher fatality rates were observed in critically ill patients with COVID-19. Intensive care units (ICU) have been the center of disposition of severe cases of COVID-19. This review discusses the pathogenesis of acute liver injury in ICU patients with COVID-19, and analyzes its prevalence, consequences, possible drug-induced liver injury, and the impact of the pandemic on liver diseases and transplantation programs.


INTRODUCTION
More than a year ago, the global pandemic started from its epicentre in Wuhan. In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the lung is the main organ targeted by the virus[1]. The organism exhibits a wide range of severity and a diverse disruption of extrapulmonary systems, including gastrointestinal, renal, cardiac[2,3], hepatic [4], and even multi-organ damage [2,5]. Moderate or severe symptoms have been reported in almost 20% of all COVID-19 patients, while 5% progress into critical stages of the disease [6].
The rate of intensive care unit (ICU) admission due to COVID-19 is quite variable, ranging from 3% to 100% in literature [7]. The liver could be affected in COVID-19 through several mechanisms, including virus-related liver cell injury, disorganized immune response, drug-induced liver injury (DILI) and ischemic liver dysfunction in the settings of multisystem organ failure [8]. The reported rate of COVID-19-induced liver injury ranged from 14.8% in one study [9] and up to 74% in another [10]. In a case series of critically ill patients with COVID-19, liver injury was frequent but transient and non-severe [11]. Patients may not be equally affected by the pandemic, certain patient populations are potentially more vulnerable. Immunocompromised patients and patients with cirrhosis are probably more susceptible to worse outcomes after SARS-CoV-2 infection [5]. The data in literature on how chronic immunosuppression can influence COVID-19 outcomes is scarce [6]. This minireview will discuss the pathogenesis of acute liver injury in ICU patients with COVID-19, focusing on its prevalence, consequences, DILI, and its impact on existing liver diseases and liver transplantation programs.

PATHOGENESIS OF LIVER INJURY IN COVID-19
Liver injury in COVID-19 can be related to the direct cytopathic effect of the virus, DILI, uncontrolled immune reaction, or sepsis [12]. SARS-CoV-2 ribonucleic acid has been detected in blood and stool samples of COVID-19 patients who presented with diarrhoea, indicating the liver's probable involvement in the disease pathogenesis [13,14]. It has been suggested that there is a considerable expression of angiotensinconverting enzyme 2 (ACE2) receptors in cholangiocytes, where SARS-CoV-2 binding may adversely affect liver function. Moreover, COVID-19 may worsen the underlying chronic liver disease(s) (CLD), leading to hepatic decompensation or acute-on-chronic liver failure and increasing the risk of mortality, particularly in critically ill patients [12,[15][16][17]. However, in severe COVID-19, liver damage is more likely due to the inflammatory cytokine storm [12,18] rather than the direct cytopathic effects of the virus [12].
The progression of SARS-CoV-2 infection has been divided into four phases: Upper and lower respiratory tract infection, usually treated as outpatients, COVID-19 associated lung injury, usually treated as inpatients, systemic inflammatory response syndrome (SIRS), and systemic failure. Liver involvement is often observed in the latter phases but can also occur in the earlier ones. In SIRS, pro-thrombotic factors accumulate due to bone marrow and liver acute phase response causing thrombosis, whereas in the last phase, multi-organ vascular dysfunction and cytokine storm occur in view of the ongoing interaction between the lung and systemic inflammation [19].
Hypoxic hepatitis (HH), known as shock liver or ischemic hepatitis, is an acute liver injury resulting from liver hypoxia [20]. The extensive complex vascular supply together with high metabolic efficacy results in a liver vulnerable to circulatory disturbances. Critically ill patients with circulatory or respiratory manifestations which may influence liver perfusion are at higher risk of HH [3,21,22]. The mechanism by which SARS-CoV-2 infection leads to HH is not fully understood. Multiple theories have been postulated, including hypoxemia developed due to COVID-19 pneumonia [2] and systemic stress caused by SIRS [19]. Both may provide a route to a compensatory decrease in peripheral and splanchnic blood flow, resulting in decreased hepatic blood flow leading to hepatocellular hypoxia [23]. Reperfusion injury is mediated by the generation of reactive oxygen species when ischemic hepatocytes are re-exposed to oxygen, leading to cell injury via lipid peroxidation [24]. Waseem and Chen[21] defined the diagnostic criteria for HH as circulatory or respiratory failure with a dramatic but transient rise in serum aminotransferases activity when excluding other causes of liver cell necrosis, especially viral or drug-induced hepatitis [21]. A visual summary of liver injury in COVID-19 is presented in Figure 1.

PREVALENCE AND CONSEQUENCES OF COVID-19-ASSOCIATED LIVER INJURY
The liver injury induced by COVID-19, including its pattern and severity, has not been uniformly defined or well characterized [25,26]. Some definitions reported in the literature, including DILI, are presented in Table 1. Secondary liver injury was the most common, being the first occurrence [3]. Liver injury has been reported as the elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels [25,26]. Thus, the liver injury appears to be of a hepatocellular (56%) rather than cholestatic (24%) or mixed (19%) [34]. Elevation in AST levels is more common than ALT and other LFTs [29,30]. In one report, the acute liver injury occurred on day 17 after the onset of symptoms [28]. In patients with severe COVID-19, the elevation in the transaminases and bilirubin levels was at least double that in patients with mild and moderate disease [33]. Elevation in GGT levels was more noticeable in severe cases, while ALP levels usually remained normal in both mild and severe cases [35]. Variable and inconsistent degrees of LFTs abnormalities, ranging from 3.75% to more than 50% of all patients, have been described [5,25,33,36]. A meta-analysis found a pooled incidence of elevated liver enzymes by 23.1% [37]. Although some studies did not show a statistical difference in abnormal LFTs between patients with severe and non-severe disease [37,38]   , when compared to those without liver diseases, respectively [68]. The presence of CLD was also found to be an independent predictor for ICU admission (adjusted OR 1.77, 95%CI: 1.03-3.04, P = 0.04) and mechanical ventilation need (adjusted OR 2.08, 95%CI: 1.20-3.60, P = 0.0092) [65]. The reported etiologies of the pre-existing liver diseases before COVID-19 included chronic viral hepatitis B and C, alcoholic and metabolic liver disease, cirrhosis of any cause, and others[5,26,31]. Liver cirrhosis is the end-stage of these liver-related diseases [31]. In one study (n = 363), 19% of patients had a pre-existing liver disease with the predominance of non-alcoholic fatty liver disease (NAFLD) (79.7%). Compensated cirrhosis, decompensated cirrhosis, and viral hepatitis B and C accounted for 8.7%, 4.3%, 2.9%, and 8.7% of all patients, respectively [65]. In contrast, the reported rates in one meta-analysis of 107 studies (n = 20874) were, CLD/cirrhosis in 61.1%, NAFLD in 19.5%, hepatitis B in 17.8%, and hepatitis C in 0.73% of patients[5].  Hepatitis B virus co-infection may subject COVID-19 patients to an exacerbated liver injury[30] and a more severe disease [69]. Acute liver injury in COVID-19 patients with hepatitis was significantly higher than that in patients without chronic hepatitis (15.0% vs 7.0%, P < 0.001) [70]. Patients with NAFLD, renamed as metabolic-associated fatty liver disease[26,31], had a significantly higher likelihood of abnormal LFTs, longer viral shedding time, and higher rate of COVID-19 progression (OR: 6.4, 95%CI: 1.5-31.2), compared to those without NAFLD [71]. NAFLD was significantly associated with ICU admissions (adjusted OR: 2.30, 95%CI: 1.27-4.17, P = 0.03) and mechanical ventilation need, (adjusted OR: 2.15, 95%CI: 1.18-3.91, P = 0.02) but not with mortality [65]. Furthermore, NAFLD in younger patients (< 60 years) was associated with the prevalence of severe COVID-19 (adjusted OR: 2.67, 95%CI: 1.13-6.34, P = 0.03) [72]. COVID-19 patients with liver cirrhosis were found to be at increased risk of mortality compared with those without the disease (RR: 4.6, 95%CI: 2.6-8.3, P < 0.0001) [68,71]. Multivariate analysis showed that liver cirrhosis was an independent predictor for mortality (adjusted OR: 12.5, 95%CI: 2.16-72.5, P = 0.009) but not for ICU admission or mechanical ventilation need [65].

DILI IN PATIENTS WITH COVID-19
Numerous medications that are currently used to treat SARS-CoV-2 infection carry the risk of hepatoxicity. Given that many medications are being used in combination, the interpretation of the commonly seen raised liver transaminases in patients with COVID-19 can be biased. While the efficacy of these medications towards improving COVID-19's morbidity and mortality is still to be proven, their safety should be monitored closely . A systematic review and network meta-analysis of 110 studies reported no association between a regimen or an agent with non-cardiac severe adverse events [76]. In a multicenter and retrospective study (n = 565) on hospitalized COVID-19 patients, de novo LFTs abnormality was noted with tocilizumab (82% vs 52%; P = 0.009) and lopinavir/ritonavir (64% vs 48%; P = 0.045). Moreover, there was a trend towards an increased composite endpoint of death or transfer to ICU associated with de novo LFTs abnormality with an incidence of 14% vs 5% (P = 0.069) [27]. Although published data regarding the incidence, severity and clinical significance of DILI have not been consistent, it warrants close monitoring of LFTs.

DRUG-DRUG INTERACTIONS BETWEEN IMMUNOSUPPRESSIVE THERAPY AND COVID-19 AGENTS
Calcineurin inhibitors (CNIs), such as cyclosporine and FK506 (tacrolimus), antimetabolite drugs, such as mycophenolate mofetil (MMF), mycophenolic acid, and corticosteroids are commonly used for immunosuppression after liver transplantation (LTX) [96]. Some centres adopted dose modifications based on expert opinion with many uncertainties regarding the best approach for combination therapies and immunosuppressive agents against COVID-19. In two large academic centers in New York City including 90 patients with solid organ transplant, antimetabolite drugs doses were reduced or held in 88% of patients, steroids in 7%, and CNIs in 18%, with no reported acute rejection cases at 20-day follow-up [6]. In a prospective European study of 57 liver transplant patients with COVID-19, immunosuppression therapy doses were reduced in 39% of patients and discontinued in 7%. Reduction or continuation of therapy did not affect mortality, while the discontinuation effect was not assessed [97]. Drug interactions between COVID-19 medications and immunosuppression therapy were also considered. For instance, lopinavir-ritonavir combination interacts with CNIs and MMF, it is not recommended to be used with steroids [98] and has been reported to interact with mechanistic target of rapamycin (mTOR) as well [18]. Moreover, tocilizumab may decrease CNIs plasma concentration, unlike remdesivir which does not interact with the immunosuppressive drugs [98]. Hydroxychloroquine has been reported to interact with CNIs and mTOR [

General measures
The unprecedented disturbance created by the COVID-19 pandemic has impacted different sectors of health care systems worldwide. For instance, elective services were cancelled or postponed while lifesaving transplant programs, including those for a liver transplant, have been continued. However, the non-lifesaving transplant services October 27, 2021 Volume 13 Issue 10 Case series: Elevated aminotransferases in 23 % discontinuation in 4% of patients [87] RCT (n = 237) in severe COVID-19: Elevated TB versus placebo (10% vs 9%) and AST (5% vs 12%), hypoalbuminemia (13% vs 15%). Discontinuation in 1% of patients [88] Open-label, phase 3 trial: Elevated ALT (5%-6%) and AST (7%-8%) [89] Meta Retrospective study (n = 1827): AST > 5 × ULN in 69.1%, and ALT > 5 × ULN in 72.1% of patients [75] Observational study (n = 104): Minor increase of AST, ALT (P < 0.001) and GGT (P = 0.003; no safety concerns on follow up [93] RCT (n = 243): ALT elevation versus placebo (5% vs 4.9%), AST elevation in 3.7% were frequently delayed, exposing patients to emergency situations [101]. LTX is the most common solid organ transplantation procedure after the kidney, with a global rate of 3.7 per million population [102]. The indication of LTX in the acute phases of liver diseases includes acute liver cell failure, metabolic liver diseases, advanced October 27, 2021 Volume 13 Issue 10 complicated cirrhosis, and CLD associated with systemic complications [103]. Elective LTX indications include advanced cirrhosis associated with deteriorating synthetic function, renal function, and the related complications [104]. The general precautions before LTX currently comprise a COVID-19 testing for both donors and recipients awaiting transplant and consenting for the possible hazard of acquiring nosocomial COVID-19[100]. The standard method of COVID-19 testing is through a nasopharyngeal swab or intraoperative bronchoalveolar lavage. Viral load should be measured in positive cases. The transplant team should be adequately screened, and the risk of exposure identified [101]. Hollander and Carr [105] advised on the use of telemedicine, such as virtual clinics or via phone calls, to minimize both healthcare providers and patient's exposure to COVID-19 [105]. The success of telemedicine in the Chinese territory during the peak of the pandemic could be transposed to future networking to use information and communication technology extensively during the care of patients with COVID-19 [106].

ICU care of liver transplant patients in the era of COVID-19
Strict infection control measures are required in the post-operative care of LTX patients to prevent nosocomial infections that include COVID-19 [107]. During the admission of LTX patients, they should be directed to separate rooms away from the general wards, and strict disinfection and isolation practices should be in place.
Medical and surgical rounds should be minimized, and laboratory testing and radiological studies should be reduced to the least required [108]. Acquiring symptoms suggestive of COVID-19 in a LTX patient should prompt urgent evaluation with the relevant investigations [105]. Other challenges prompted by the COVID-19 pandemic include the increased demand for ICU beds, requiring health care practitioners to work in a dynamic way to maximize ICU bed utilization [109]. During the pandemic, the settings required for ICU should include separate units equipped with highefficiency particulate air filters [110]. The goals of ICU disposition for LTX patients comprise neurological monitoring, hemodynamic monitoring and support, early weaning from the mechanical ventilator, preventing nosocomial infections and graftrelated complications and enhancing early graft recovery [111]. Some institutes screen for COVID-19 in LTX recipients [112]. Simple and effective measures could be implemented to shorten the ICU stay for LTX patients through fast-track procedures, including operating room early extubation, reduction of ventilation time, and direct transfer from the recovery room to surgical wards [113,114]. Transplant services constantly demand resources, which have become extremely limited with the emergence of the COVID-19 pandemic due to staff shortage, saturation of the ICU, and drainage of supplies. Exceptional scarcity of donors and demand for organs also aggravate this problem [115,116].

Transplantation outcome during COVID-19 pandemic
Reports regarding the outcomes of LTX patients have been inconsistent. Although early reports have not found more severe or worse outcomes among immunosuppressed patients [117], subsequent data showed that solid organ transplant recipients diagnosed with COVID-19, including LTX, seemed to be at increased risk of severe disease, morbidity, and poor outcomes[6,118], such as high mortality with an inhospital mortality rate of 29% [119]. Bossini et al[120] reported a higher rate of acute respiratory distress syndrome (ARDS) and death among patients who received solid organs[120], while others reported similar outcomes in COVID-19 patients with and without solid organ transplant [121]. In a multi-centre study of ICU patients after solid organ transplant, the rate of ARDS, duration of mechanical ventilation, vasopressors requirements, and death were similar between groups[122].

Vaccination considerations
It was reported that in liver transplant recipients, COVID-19 infection was not associated with increased mortality. However, these patients are subjected to severe disease, as evidenced by a higher rate of both ICU admission and mechanical ventilation use [123]. COVID-19 pandemic has disrupted various healthcare services worldwide, limiting the services offered to urgent and emergent cases. These changes in services, clinician behaviour and re-organization of hospital activities can indirectly affect morbidity and mortality [129]. delaying or halting diagnostic and therapeutic services for diseases with a high global burden such as cardiovascular diseases can contribute to long-term and indirect adverse health outcomes. For example, cardiac diagnostics procedures, stress tests[129], emergency department (ED) and hospital admissions, procedures and treatments were markedly declined during the pandemic year as compared with that of the previous years [130]. In 909 inpatient and outpatient centres from 108 countries, the rate of cardiac diagnostic procedures decreased by 42% and 64% as of March and April 2020, respectively, with the highest reduction of 78% observed for the stress tests, as compared with March 2019. [130]. A further 22% reduction was noted in low and low-middle income countries, which might be attributed to inaccessible personal protective equipment and telehealth services [130].
In United Kingdom, a cross-sectional study conducted in nine hospitals compared the hospitals' cardiovascular activity data between October 2019 and May 2020 with the respective weeks in 2018 and 2019. There was a marked decline in ED attendances, admissions and hospital procedures and treatments [129]. Patients with other chronic diseases which require close follow up have been negatively affected as well. A crosssectional study of six referral centres in France showed that in 2020 significantly fewer patients with HCC were referred to the multidisciplinary tumour board (P = 0.034) and fewer received the first diagnosis of HCC (P = 0.083) compared with 2019[131]. Therapy optimization and frequency of follow-up visits were also affected by the global pandemic in response to social distancing and re-allocation of services towards fighting COVID-19. A delay in therapy modification for more than one month was noted in 21.5% vs 9.5% of patients during 2020 compared with 2019 (P < 0.001), respectively [131]. In patients with hepatitis C virus who were following up for HCC, there was significant reduction in their scheduled visits, i.e., by before 75%, 63.0%, and 49.1% in March to May 2020, respectively, compared with 97% before February 2020 [132]. Surgical interventions for HCC have significantly declined or stopped across many centers in the world due to increased risk of blood transfusion, ICU stay, prolonged hospitalization and developing COVID-19 after surgery [133]. In a national survey by the Italian Association for the Study of the Liver, HCC treatment was affected; where surgical treatment was reduced in 44% and suspended in 44% of the participating centres, while the loco-regional treatment was reduced in 34% and suspended in 8% of the centres[134].

CONCLUSION
The pathogenesis and characteristics of COVID-19-related multifactorial liver injury October 27, 2021 Volume 13 Issue 10 can be explained by multiple mechanisms. The knowledge about the full spectrum of SARS-CoV-2 infection is being accumulated, given the novelty of the disease and the constantly reported new data. Liver dysfunction is commonly seen in patients presenting with the severe form of COVID-19. Various therapeutic options used for COVID-19 can lead to DILI and contribute to the exacerbation of the existing liver injury. It is challenging to identify the causal factor in the settings of infection, sepsis, and/or hypoxia, especially when the liver enzymes abnormalities are non-specific. The underlying liver disease has not been linked with poor outcomes. Hospitalized patients or those with liver comorbidities should be monitored closely. Patients with COVID-19 and LTX must maintain strict infection control and monitor drug interactions while maintaining immunosuppressive therapy at regular doses. Future research would help explain liver injury associated with SARS-CoV-2 infection and design specific guidelines for the management of COVID-19 in these patients.