key: cord-0727957-740l3w82 authors: Licata, Anna; Minissale, Maria Giovanna; Distefano, Marco; Montalto, Giuseppe title: Liver injury, SARS‐COV‐2 infection and COVID‐19: What physicians should really know? date: 2021-05-03 journal: GastroHep DOI: 10.1002/ygh2.455 sha: 0551d62cd0375fbed3dad858798795c66401f3dc doc_id: 727957 cord_uid: 740l3w82 BACKGROUND & AIMS: Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) is responsible for coronavirus disease 2019 (COVID‐19), which in males, especially in advanced age, can sometimes evolve into acute respiratory distress syndrome. In addition, mild to moderate alterations in liver function tests (LFTs) have been reported in the worst affected patients. Our review aims to analyse data on the incidence and prognostic value of LFT alterations, the underlying mechanisms and the management of pre‐existing liver disease in COVID‐19 affected patients. METHODS: We searched available literature through online PubMed database using terms as “SARS‐CoV‐2,” “Liver damage,” “Liver Function tests,” “COVID‐19,” “pre‐existing liver disease,” “drug‐induced liver injury.” RESULTS: Available evidence suggest that there could be a relationship between SARS‐CoV‐2 infection and liver damage, although the underlying involved mechanism remains unclear. Cohort studies have shown that high ALT levels, low platelet counts and low albumin levels at admission and during hospitalisation are associated with a high mortality rate. Unfortunately, little is known about the impact of COVID‐19 on pre‐existing liver damage. While chronic viral infections or NAFLD are associated with an increased risk of COVID‐19 progression, patients with cirrhosis may have increased susceptibility to SARS‐CoV‐2 infection due to their systemic immunocompromised status. DILI seems common among hospitalised patient with severe pneumonia. CONCLUSION: Mild to moderate liver impairment during Covid‐19 is common, especially in patients with pre‐existing liver disease. Further studies should be performed in order to understand how pre‐existing liver conditions may influence and worsen progression of liver disease in COVID‐19 patients. Author signs and symptoms, mild to moderate alterations in liver function tests (LFTs) have been reported in the worst affected patients. LFT alterations, and in particular aminotransferase (AST and ALT) values, are a frequent manifestation of SARS-CoV-2 infection and are associated with an increase in lactic dehydrogenase (LDH) and inflammation markers such as C-reactive protein and ferri- It has been clearly shown that the SARS-CoV-2 virus enters cells by binding the angiotensin conversion enzyme-2 (ACE2) receptor similarly to SARS-CoV. 12 Although many studies show that COVID-19 is associated with liver injury, the underlying mechanism is not yet known. However, several hypotheses have been formulated: direct cytopathic effects, immune imbalance and cytokine storm with secondary multi-organ dysfunction, ischaemia and/or hypoxia-reperfusion injury and, finally, drug-induced liver injury ( Figure 1 ). Among the aetiological hypotheses, many authors have argued that liver damage is likely due to the action of immune cells activated in response to the virus and the resulting cytokine activity. 13 In a respiratory viral infection, collateral liver injury has been related to virus-specific effector cells generated in response to pulmonary infection. Analysis of post-mortem liver biopsies of patients infected with SARS-CoV-2 showed hepatocyte degeneration, focal necrosis, inflammation of bile ducts and portal and peri-portal inflammation, as well as fat degeneration, 4 but no viral particles were found. The absence of viral particles in the liver, therefore, indicates that liver damage is probably primarily related to the action of activated T cells, in particular Th-17 and CD8 11 ; a case of microvesicular steatosis was observed with hyperactivation of T cells, reinforcing the hypothesis of immune-mediated damage rather than a cytopathic effect, as has recently been argued. 5 Immune dysfunction (including lympho-penia, a decrease in CD4+ T-cell levels, and abnormal cytokine levels with cytokine storm) in COVID-19 patients is associated with disease severity and mortality. 6 High levels of pro-inflammatory cytokines (TNF-a, IL-6, IL-2, IL-7, IL-11, interferon γ, monocyte chemoattractant protein-1/MCP-1, and macrophage inflammatory protein 1α) are responsible for the cytokine storm, which correlates to increased vascular permeability, Hypoxia and shock induced by acute respiratory distress syndrome, systemic inflammatory response syndrome, and multiple organ failure may cause hepatic hypoperfusion and dysfunction secondary to hypoxia reperfusion. The reduction in oxygen levels (and the consequent lipid accumulation) during shock and other hypoxic conditions, could lead to hepatocyte necrosis. Overall, the damage that occurs, the increase in reactive oxygen species and the products generated during the reactions can activate some transcription factors and act as second messengers, further increasing the release of pro-inflammatory cytokines. 4, 8, 18 It is well known that hypoxia is a relevant factor involved in liver damage from COVID-19. Liver injury during SARS-CoV-2 infection may also be related to drug hepatotoxicity, especially 7-10 days after disease onset, which explains the great variability observed in the different cohort studies in the literature, due to the different drugs used to manage COVID-19. Treatment of infection involves the use of multiple medications such as anti-pyretic, anti-microbial, anti-viral and anti-fungal drugs and steroids, which have all been seen to be potential causes of liver damage, although there is still no strong evidence to support this. 19 Consequently, in patients with COVID-19 there has been an increased incidence of liver dysfunction not only directly related to the action of the virus, but also to the side effects of the drugs used in its management 2 (see Table 2 ). Among the drugs initially licensed for use against COVID-19 was chloroquine; in vitro studies have shown its important activity in the inhibition of viral replication and also a certain effectiveness in vivo. 20 Chloroquine acts either by stopping the cytokine storm or by blocking the activation of CD8+ cells. 21 However, its use has been linked in the past to the onset of fulminating hepatitis. 22 In combination with chloroquine, azithromycin, a broad-spectrum macrolide, has been used due to its presumable anti-inflammatory activity, but it is a common cause of hepatotoxicity (DILI) after about 1-3 weeks of treatment. 23 A retrospective cohort study of 134 patients showed that treatment with chloroquine/azithromycin led to a clinical improvement in 26.8% of patients and although ICU transfer rate and mechanical ventilation, as well as mortality at day 28 were higher in the treatment group compared to controls (p 0.03), no differences in LFTs were found between the two groups. 24 In a randomised controlled multicenter trial, 25 The relationship between pre-existing liver disease and COVID-19 The acute Covid-19 pandemic is superimposed on a much slower but equally widespread epidemic, namely metabolic diseases, as It should also be noted that NAFLD promotes the activity of M1 macrophages, which produce pro-inflammatory cytokines, and suppresses the activity of M2 macrophages, thus contributing to the progression of damage from COVID-19. 45 Understanding the role of NAFLD in COVID-19 disease could have important therapeutic and clinical implications. Therefore, patients with COVID-19 with pre-existing liver diseases such as NAFLD, and even more so if they are male and in advanced age, should be closely monitored and strongly supported with heparin at a suitable therapeutic dose. Social distancing needed to fight the pandemic, and stress, isolation and depression caused by the lockdown resulted in a significant increase in alcohol consumption and related diseases (ALD). Alcoholic liver disease is often associated with diabetes and chronic renal failure, both comorbidities that increase the risk of severe Covid-19. In particular, in patients with alcoholic steatohepatitis, the use of corticosteroids could lead to an immunosuppressive effect that would further increase the risk of having a more severe Covid-19. 46 To date, no specific guidelines are available regarding the man- Despite the rearrangements made within hospitals during lockdown, and the consequent reduction in outpatient visits, the commencement of antiviral therapies for HCV and HBV should be promoted, especially in patients with more advanced liver disease and comorbidities. In Patients with cirrhosis or liver cancer could be more prone to developing a SARS-CoV-2 infection and to a more severe course due to their systemic immunocompromised status. However, there are no data regarding severity, mortality and incidence of complications (infections, hepatic encephalopathy, bleeding from varices, liver failure). 47 An Italian study showed that SARS-CoV-2 infection was associated with liver function deterioration and elevated mortality in patients with cirrhosis, whether compensated or decompensated. The main causes of death were respiratory complications but also the sudden worsening of liver function. 55 Further studies should focus on the effect of COVID-19 on existing liver comorbidities and treatment outcomes. In cirrhotic patients, it is essential to continue follow-up to avoid worsening the underlying chronic liver disease or underestimating a liver cancer. Covid-19 in LT recipients is unfortunately responsible for a greater number of cases who are hospitalised in intensive care unit (ICU) due to severe pneumonia requiring mechanical ventilation. These patients also have a higher risk of liver damage, evident from alteration of the LFTs, which depends not only on the state of immunesuppression related to the transplant, but also on comorbidities, such as diabetes, cardiovascular and renal diseases, and the considerable risk of severe drug-drug interactions. One of the few recent studies that analysed this clinical setting highlighted how age, Hispanic race, metabolic syndrome, the use of antibiotics and vasopressor were able to predict the onset of liver damage, and also its multifactorial nature. 56 Furthermore, liver injury was independently associated with increased mortality. Thus, following LFTs in a LT recipient with Covid-19, as a warning of liver damage, could help to identify patients at risk for a poor outcome. 57 In patients with a mild COVID-19, liver injuries are often transient and self-limiting. 58 Average levels of AST, ALT and serum bilirubin are significantly higher in severe or critical cases, 59 such as a reduction in serum albumin. 60 According to recent studies, there is no specific treatment for liver injury during COVID-19, although in patients with severe liver damage it is advisable to administer medications with a hepatic-protective effect. 50 The presence of altered liver enzymes should not be considered a contraindication to the use of experimental or off-label therapies for COVID-19. However, high transaminase levels (five times the baseline value) exclude patients from experimental treatment. In particular, patients treated with remdesevir, ritonar and tocilizumab should be regularly monitored via LFTs, as these drugs have a documented hepatotoxicity. 47 It appears that a greater severity of SARS-CoV-2 infection and advanced age, together with poly-therapy, predisposes patients to a more severe liver dysfunction. The increase in transaminases, in particular AST, is more common in adult males than in female patients. Therefore, COVID-19 patients who have pre-existing liver diseases should be adequately monitored and drug-to-drug interactions should be checked before starting COVID-19 treatments, including antiviral agents, especially in patients with advanced chronic liver. A useful checker tool is available at: https://www.COVID 19-drugi ntera ctions.org/checker The underlying mechanisms of liver injury during SARS-CoV-2 remain unclear. Among the most probable hypotheses are viral cytopathic effects, immune imbalance and cytokine storm, ischaemia and/or hypoxia-reperfusion injury and, finally DILI. A recent metaanalysis reported that incidence of DILI in Covid-19 hospitalised patients was of 25%. From a clinical point of view, great care should be taken when monitoring patients to prevent the onset of liver injury and avoid the administration of hepatotoxic drugs. Some studies have reported an increased incidence of acute kidney injury after COVID-19, possibly due to the presence of SARS-CoV-2-induced inflammation. Damage to the liver and kidneys can affect expectations regarding the metabolism, excretion, dose and concentration of drugs, thus making it difficult to establish the correct therapeutic dose of the drugs without increasing the risk of toxicity. 61, 62 Continuing studies on severity, mortality and the incidence of complications should be performed in order to understand how preexisting liver conditions may influence and worsen the progression of liver disease in patients with SARS-CoV-2 infection. Guarantor of the article: Anna Licata. None to declare. Giuseppe Montalto contributed to concept and study design, helped in drafting the article, collected and analysed data. All authors approved the final version of the manuscript. The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. No ethical approval was required as this is a review article with no original research data. The peer review history for this article is available at https://publo ns.com/publo n/10.1002/ygh2.455. Clinical characteristics of coronavirus disease 2019 in China Clinical features of patients infected with 2019 novel coronavirus in Wuhan COVID-19: abnormal liver function tests Liver impairment in COVID-19 patients: a retrospective analysis of 115 cases from a single centre in Wuhan city Pathological findings of COVID-19 associated with acute respiratory distress syndrome Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients Clinical features of COVID-19-related liver functional abnormality Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study Liver injury during highly pathogenic human coronavirus infections Systemic viral infections and collateral damage in the liver Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection Angiotensin receptor blockers as tentative SARSCoV-2 therapeutics Recapitulation of SARS-CoV-2 infection and cholangiocyte damage with human liver ductal organoids COVID-19 cytokine storm: the interplay between infammation and coagulation Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury Clinical implications of COVID-19 in patients with chronic liver disease and liver tumor Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Insights from nanomedicine into chloroquine efficacy against COVID-19 Fulminant hepatic failure secondary to hydroxychloroquine Clinical and histologic features of azithromycin-induced liver injury Clinical outcomes and adverse events in patients hospitalised with COVID -19, treated with off-label hydroxychloroquine and azithromycin Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19 Krenzelok EP, The FDA. Acetaminophen Advisory Committee Meeting -what is the future of acetaminophen in the United States? The perspective of a committee member A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19 COVID-19 in a designated infectious diseases hospital outside Hubei Province High rates of drug-induced liver injury in people living with HIV coinfected with tuberculosis (TB) irrespective of antiretroviral therapy timing during antituberculosis treatment: results from the starting antiretroviral therapy at three points in TB tri COVID-19 and drug-induced liver injury: a problem of plenty or a petty point? COVID-19: consider cytokine storm syndromes and immunosuppression Short-course tocilizumab increases risk of hepatitis B virus reactivation in patients with rheumatoid arthritis: a prospective clinical observation Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection Renal and liver injury following the treatment of COVID-19 by remdesivir Liver injury in remdesivir-treated COVID-19 patients Systematic review with meta-analysis: liver manifestations and outcomes in COVID-19 A randomized trial of convalescent plasma in covid-19 severe pneumonia A review of COVID-19 convalescent plasma use in COVID-19 with focus on proof of efficacy REGN-COV2, a neutralizing antibody cocktail, in outpatients with covid-19 SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19 Obesity, diabetes and COVID-19: an infectious disease spreading from the east collides with the consequences of an unhealthy western lifestyle MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease Non-alcoholic fatty liver diseases in patients with COVID-19: a retrospective study COVID-19 and liver dysfunction: current insights and emergent therapeutic strategies Macrophages in obesity and non-alcoholic fatty liver disease: crosstalk with metabolism Coronavirus disease 2019 hangover: a rising tide of alcohol use disorder and alcohol-associated liver disease Clinical best practice advice for hepatology and liver transplant providers during the COVID-19 pandemic: AASLD expert panel consensus statement Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists Covid-19: ibuprofen can be used for symptoms, says UK agency, but reasons for change in advice are unclear Liver injury in COVID-19: management and challenges Clinical characteristics in patients with SARS-CoV-2/HBV co-infection Longitudinal changes of liver function and hepatitis B reactivation in COVID-19 patients with pre-existing chronic hepatitis B virus infection Characteristics of liver function in patients with SARS-CoV-2 and chronic HBV coinfection Rates and characteristics of SARS-CoV-2 infection in persons with hepatitis C virus infection High rates of 30-day mortality in patients with cirrhosis and COVID-19 Liver injury in liver transplant recipients with coronavirus disease 2019 (COVID-19): U.S. multicenter experience COVID-19 in hospitalized liver transplant recipients: an early systematic review and meta-analysis COVID-19 and the liver: little cause for concern Preliminary study of the relationship between novel coronavirus pneumonia and liver function damage: a multicenter study Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Liver injury in COVID-19: the current evidence Identification of a potential mechanism of acute kidney injury during the COVID-19 outbreak: a study based on single-cell transcriptome analysis Liver injury, SARS-COV-2 infection and COVID-19: What physicians should really know?