key: cord-0731661-56j60yj9 authors: Miele, Luca; Napodano, Cecilia; Cesario, Alfredo; De Magistris, Antonio; Pocino, Krizia; Basile, Umberto; Rapaccini, Gian L.; Gasbarrini, Antonio; Grieco, Antonio title: COVID‐19, adaptative immune response and metabolic‐associated liver disease date: 2021-09-28 journal: Liver Int DOI: 10.1111/liv.15061 sha: 2f1d5678cb7ee0dd60365e1ed3b93d7b747d2e25 doc_id: 731661 cord_uid: 56j60yj9 Metabolic diseases are associated with a higher risk of a severer coronavirus disease 2019 (COVID‐19) course, since fatty liver is commonly associated with metabolic disorders, fatty liver itself is considered as a major contributor to low‐grade inflammation in obesity and diabetes. Recently a comprehensive term, metabolic (dysfunction) associated fatty liver disease (MAFLD), has been proposed. The hepatic inflammatory status observed in MAFLD patients is amplified in presence of severe acute respiratory syndrome coronavirus 2 infection. Intestinal dysbiosis is a powerful activator of inflammatory mediator production of liver macrophages. The intestinal microbiome plays a key role in MAFLD progression, which results in non‐alcoholic steatohepatitis and liver fibrosis. Therefore, patients with metabolic disorders and COVID‐19 can have a worse outcome of COVID‐19. This literature review attempts to disentangle the mechanistic link of MAFLD from COVID‐19 complexity and to improve knowledge on its pathophysiology. In December 2019, an outbreak of the novel coronavirus disease 2019 (COVID- 19) was reported in Wuhan, Hubei Province, China, which rapidly spread to other areas and countries. On 11 March 2020, the WHO declared COVID-19 a pandemic. The novel coronavirus was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for its capacity to cause severe acute respiratory syndrome and was isolated from the respiratory samples of patients with pneumonia as shown by sequence analysis of the virus genome obtained. 1, 2 In the majority of patients, infections are mild, but in some individuals, with advanced age or underlying medical comorbidities (obesity, hypertension, diabetes, cardiovascular disease, chronic lung disease and cancer) the virus causes atypical interstitial pneumonia progressing to acute lung injury requiring respiratory support. 3, 4 The onset of COVID-19 presents mainly with fever, cough and dyspnoea, and some patients can progress to acute respiratory distress syndrome (ARDS) and septic shock. In addition to respiratory symptoms, digestive system involvement such as nausea, vomiting and diarrhoea have also been reported. 5 Potential risk factors for Liver enzyme abnormalities are common in COVID-19 patients. Increased liver enzymes were observed more commonly in males and in severe COVID-19 case, 9 aspartate aminotransferase and alanine aminotransferase are considerably elevated, and bilirubin is slightly elevated. 10 Current knowledge about liver injury caused by coronaviruses (SARS-CoV, MERS-CoV and SARS-CoV-2) suggests that it may be a result of direct virus-induced cytopathic effects and/or immunopathology induced by overshooting inflammatory responses. 11, 12 There are several potential contributors to elevated liver enzyme levels in COVID-19 such as immune-mediated inflammatory response, drug-induced liver injury, hepatic congestion and extra-hepatic release of transaminases, 13 or a possible direct infection of hepatocytes. 14 Patients with liver enzyme abnormalities have lower albumin levels, decreased circulating CD4+ T cells and B lymphocytes, higher GGT and alveolar-arterial PO2 difference. 10 Although alterations in liver biochemistries are common in hospitalized patients with COVID- 19 , not all studies show that abnormal liver biochemistries represent a worse course of the disease 15 ; therefore, it is still unclear whether they have prognostic value. Indeed, patients with cirrhosis, and to a lesser degree those with orthotopic liver transplantation, infected with SARS-CoV-2 have a high mortality risk 12, 16 suggesting that SARS-CoV-2 may worse the outcome of end-stage liver disease. The possible pathogenic mechanisms linking cirrhosis with severe COVID-19 are the increased systemic inflammation, cirrhosis-associated immune dysfunction, coagulopathy and intestinal dysbiosis. 14 The histological features in COVID-19 patients have been characterized by non-specific findings, including steatosis, mild lobular and/or portal inflammation and vascular pathology 14,17-19 but confirm the presence of massive apoptosis and binuclear hepatocytes in the SARS-CoV-2 infected liver. 10 Liver biopsy from deceased COVID-19 patients showed moderate microvascular steatosis and mild lobular and portal activity indicating that the injury may have been a consequence of SARS-CoV-2 infection, even if druginduced liver disease may be a contributing factor for liver injury ( Figure 1 ). 17 • Metabolic diseases are associated with a higher risk of severe COVID-19. • The hepatic inflammatory status in MAFLD patients is amplified in case of SARS-CoV-2 infection. • One of the determining mechanisms for COVID-19 progression is cytokine release syndrome or cytokine storm syndrome. • In MAFLD, the polarization state of liver macrophages could be distorted by COVID-19 promoting inflammation. • The gut microbiome plays a key role in MAFLD progression. F I G U R E 1 Mechanisms leading from MAFLD to inflammation and disease progression. The development of liver inflammation in MAFLD patients leads to several complications. The factors participating in the amplification of inflammation are different (A, B, C, D) and could also include SARS-CoV-2 infection (E). A, SARS-CoV-2 infection. SARS-CoV-2 binds to target cells through receptor angiotensin-converting enzyme II (ACE2) determining the consequent activation of cells of the immune system and the release of mediators inflammatory. One of the determining mechanisms for COVID-19 progression is cytokine release syndrome or cytokine storm syndrome (CSS). B, NLRP3 inflammasome activation. The Nod-like receptor protein 3 (NLRP3) inflammasome activation is not only an intracellular machinery triggering inflammation but also produces uncanonical effects beyond inflammation. NLRP3 inflammasome activation may play a fundamental role in the development of NASH. C, Macrophages activation. Liver macrophages derive from resident Kupffer cells or recruited monocytes. M1 macrophages initiate inflammatory processes expressing high levels of pro-inflammatory cytokines and producing high amounts of reactive oxygen and nitrogen species. While M2 macrophages have anti-inflammatory function and promote tissue repair and remodelling, they have a clever phagocytic activity and express different chemokines profiles compared with M1 macrophage. D, Gut microbiome. Alteration in commensal microbiome composition, diversity and function may lead to increased gut permeability and production inflammatory factors. Gut dysbiosis is a modification of microbiome and promotes translocation of microorganisms and microbial products into the portal circulation (metabolic endotoxaemia). The gut microbiome plays a key role in MAFLD progression resulting in diversity and composition directly progression to NASH and liver fibrosis. E, Insulin Resistance. During insulin resistance, insulin receptor signalling to the GLUT 4 is inhibited, preventing GLUT 4 from transporting glucose. Thus, glucose is prevented from entering muscle and fat cells. Insulin resistance is one of the hallmarks of MAFLD is pivotal for disease pathogenesis and determines even disease progression. ACE2, angiotensin-converting enzyme 2; PMN, polymorphonuclear; DAMPs, Damage-associated molecular patterns; PAMPs, Pathogen-Associated Molecular Patterns; KC, Kupffer cells; TNFα:Tumour Necrosis Factor; IL, Interleukine; ROS, Reactive oxygen species; M1, Macrophage 1; M2, Macrophage 2; NLRP3, Nod-like receptor protein 3; MAFLD, metabolic-associated fatty liver disease; NASH, non-alcoholic steatohepatitis; CSS, cytokine storm syndrome, GLUT4, Glucose transporter type 4 Therefore, patients with liver damage and SARS-CoV-2 infection require special attention and care. The clinical implication for the management of liver injury during COVID-19 9 includes regular follow-up of liver biochemical parameters, cautious interpretation, and, in the context of a complex multi-organ disease, 15 the serology evaluation for hepatitis B and C and investigation for other causes of liver disease. 15 Another link between COVID-19 and MAFLD could be the evidence that the SARS-CoV-2 harbours the receptor angiotensinconverting enzyme 2 (ACE2). Thus, SARS-CoV-2 binds ACE2 and then, the cellular protease transmembrane protease serine 2 (TMPRSS2) cleaves the SARS-CoV-2 spike protein, allowing fusion of viral and cellular membranes. 20 High-fat diets seem to induce the expression of ACE2 in adipocytes. In the lungs, ACE2 is expressed by 2% of epithelial cells, increasing with cell differentiation, and being located on the apical pole, can serve as an accessible anchor point to airborne contaminants. 21, 22 Under normal conditions, ACE2 has anti-obesity and antiinflammatory effects; therefore, metabolic syndromes are often treated with ACE inhibitors (ACE-Is), which could increase the expression of ACE2 receptors in the liver. Physiologically ACE2 is expressed in low quantities in cholangiocytes and hepatocytes, but an increase in ACE2 is observed in chronic liver damage and in MAFLD. Therefore, treating liver injuries and the metabolic syndrome itself with ACE-Is could probably promote SARS-CoV-2 susceptibility and disease severity of COVID-19. 23 Currently, has not been shown an increased incidence of progressing to severe COVID-19 in hypertension patients treated with ACE-Is/angiotensin receptor blockers drugs compared to the patients taking other anti-hypertensive drugs. 24 The studies about the influence of MAFLD on the hepatic expression of ACE2 and TMPRSS2 25, 26 have shown that MAFLD is not associated with changes in liver expression of genes implicated in SARS-CoV-2 infection. But the SARS-CoV-2 entry factors are affected differently in T2DM and NAFLD. Obsesses women with T2DM have lower levels of ACE2 and TMPRSS2 compared with normoglycaemic obese women. It has been noted that obese patients with non-alcoholic steatohepatitis (NASH) show a higher expression of ACE2 and TMPRSS2, suggesting that the advanced stages of NAFLD could predispose individuals to SARS-CoV-2 entry factors. 26 In patients with metabolic disorders, and in consequence adipocyte dysregulation, the involvement of the angiotensin 1-7 system and its underlying inflammatory environment, SARS-CoV-2 infection leads to more severe outcome. 27 Metabolic diseases have been reported to be risk factors for the severity of COVID-19. The mortality rate of patients with SARS-CoV-2 infection with metabolic comorbidities (ie obesity and diabetes) is significantly higher. 28 MAFLD is a more recent term with a definition for non-alcoholic fatty liver disease (NAFLD), which has been proposed by a panel of international experts to overcome limitations related to the NAFLD definition. 29 The MAFLD definition focuses on metabolic dysfunction as the driver of liver damage based on chronic low-grade inflammation. [29] [30] [31] The nature of inflammation in MAFLD could be an intermittent or chronic relapse, like in other chronic inflammatory liver disorders and could be missed by liver biopsy. 31 In several reports, it had been observed that COVID-19 patients with fatty liver had a four-fold increased risk of severe COVID-19 compared with patients without fatty liver. 32-34 MAFLD patients had a higher likelihood of abnormal liver biochemistries, higher risk of respiratory disease progression, more liver injury during hospitalization and a higher viral shedding time. 34, 35 A recent systematic literature review supports the hypothesis that the presence of metabolic dysfunction-associated fatty liver disease (MAFLD) 32 may represent a risk factor for symptomatic, severe and progressive COVID-19. 16, 33, 34, [36] [37] [38] [39] [40] [41] [42] [43] [44] (Table 1) . A pooled analysis of Sachdeva et al showed the association between MAFLD and increased risk of severe COVID-19 even after adjusting for obesity. 40 The progression of COVID-19 seems to be correlated with age in MAFLD patients. Indeed, a multicentre preliminary analysis reported that COVID-19 patients with MAFLD aged younger than 60 years had a more than two-fold higher prevalence of severe COVID-19 (55.9% of 327 COVID-19 patients) compared with those without MAFLD, moreover the presence of MAFLD in elderly patients was not associated with disease severity in the multivariable analysis. 39 The presence of fibrosis assessed by fibrosis-4 (FIB-4) index and NAFLD fibrosis score (NFS), rather than the presence of MAFLD, was associated with increased risk for the worse outcome of COVID-19 (with mechanical ventilation, development of acute kidney injury and higher mortality). 45 47 The findings suggested that GRS was not associated with an increased risk of severe COVID-19 progression. Therefore, the genetic predisposition to liver fat accumulation could not increase predisposition to severe COVID-19 and the MAFLD does not play a causal role in this condition. 47 To date, larger studies with well-characterized cases are needed in order to understand the impact of genetic predisposition of MAFLD in relation to susceptibility and severity of COVID-19, and in particular, the risk of hospitalization and mortality, which also includes the relation to obesity, dyslipidaemia and T2DM. 40 Therefore, MAFLD subjects should be classified as high risk for COVID-19, intensifying preventive measurements, and prioritized for vaccination. 48 In fact, the COVID-19 vaccine appears to give a good immunogenicity in patients with NAFLD, with titres of neutralizing antibodies that persisted over time. 49 Finally, we should consider gut dysbiosis as a powerful activator of the pro-inflammatory cytokine production in the liver macrophages. 56 Gut dysbiosis is a perturbartion of microbiome and promotes translocation of micro-organisms and microbial products into the portal circulation (metabolic endotoxaemia). The gut microbiome plays a key role in MAFLD progression resulting in NASH and liver fibrosis. 61 The pathogenesis of fatty liver postulates the involvement of 'multiple parallel hits' suggesting that molecular mediators from various organs, particularly the adipose tissue and the gut, participate in triggering inflammation pathways, which may later progress to fibrosis and, finally cirrhosis and carcinogenesis. 62 The small intestine has a high expression of ACE2, and a high viral load has been found in faeces of COVID-19 patients, suggesting a central role in viral infection and inflammation. Gastrointestinal symptoms, which are common in COVID-19 patients, are related to liver injury markers indicating an increase in pathogen-associated molecular patterns to the liver, which are a possible cause for CSS amplification. 46 The role of the intestinal microbiota influencing lung diseases has been well discussed, and it is known that respiratory virus infection causes perturbations. 63 Furthermore, the intestinal microbiota has a possible protective role against coronavirus disease infections, which might explain why some COVID-19 patients are asymptomatic. 64 The severity of diges- This process may also explain the increased risk of COVID-19 progression in obesity, T2DM and even IBD which are associated with similar gut microbiota, gut inflammation and barrier integrity disorders. 46 The gut-liver axis alterations, because of metabolic diseases, can contribute to severe COVID-19 progression. Therefore, the study of the gut microbiota can be of considerable help both to understand the pathogenesis and evolution of COVID-19, but also and above all to apply therapies and personalized nutrition. 38, 46 Moreover, the researches on the gut microbiota could be helpful in order to prevent the amplification of the inflammatory signal and the onset of NASH, especially in COVID-19 subjects. 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JGH Open Metabolic dysfunction associated fatty liver disease increases risk of severe Covid-19 MAFLD in COVID-19 patients: an insidious enemy NAFLD and COVID-19: a pooled analysis How to cite this article COVID-19, adaptative immune response and metabolicassociated liver disease We thank Franziska M. Lohmeyer, PhD, Fondazione Policlinico Universitario A. Gemelli IRCCS, for her support in revising our manuscript. The authors declare no competing interests. All authors contributed to editing and discussion of content. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.