key: cord-0754263-ynflssd7
authors: Portincasa, Piero; Krawczyk, Marcin; Smyk, Wiktor; Lammert, Frank; Di Ciaula, Agostino
title: COVID‐19 and nonalcoholic fatty liver disease: two intersecting pandemics
date: 2020-06-26
journal: Eur J Clin Invest
DOI: 10.1111/eci.13338
sha: 551947d3821d07ce0c648442a9f73b38d54f81e5
doc_id: 754263
cord_uid: ynflssd7

BACKGROUND: Initial evidence from China suggests that most vulnerable subjects to COVID‐19 infection suffer from pre‐existing illness, including metabolic abnormalities. The pandemic characteristics and high‐lethality rate of COVID‐19 infection have raised concerns about interactions between virus pathobiology and components of the metabolic syndrome. METHODS: We harmonized the information from the recent existing literature on COVID‐19 acute pandemic and mechanisms of damage in non‐alcoholic fatty liver disease (NAFLD), as an example of chronic (non‐communicable) metabolic pandemic. RESULTS: COVID‐19 patients are more fragile with underlying metabolic illness, including hypertension, cardiovascular disease, type 2 diabetes, chronic lung diseases (e.g., asthma, chronic obstructive pulmonary disease, and emphysema), and metabolic syndrome. During metabolic abnormalities, expansion of metabolically active fat (“overfat condition”) parallels chronic inflammatory changes, development of insulin resistance, and accumulation of fat in configuring NAFLD. The deleterious interplay of inflammatory pathways chronically active in NAFLD and acutely in COVID‐19 patients, can explain liver damage in a subgroup of patients, and might condition a worse outcome in metabolically‐compromised NAFLD patients. In a subgroup of NAFLD patients, the underlying liver fibrosis might represent an additional and independent risk factor for severe COVID‐19 illness, irrespective of metabolic comorbidities. CONCLUSIONS: NAFLD can play a role in the outcome of COVID‐19 illness due to frequent association with comorbidities. Initial evidences suggest that increased liver fibrosis in NAFLD might affect COVID‐19 outcome. In addition, long‐term monitoring of post‐COVID‐19 NAFLD patients is advisable, to document further deterioration of liver damage. Further studies are required in this field.

The global acute pandemic of severe acute respiratory syndrome (SARS) caused by the coronavirus SARS-CoV-2 (COVID-19, Sarbecovirus subgenus, Betacoronavirus genus, Coronaviridae family) has suddenly become a major threat to public health [1, 2] . Since late 2019, more than 3.6 million confirmed cases, more than 250,000 deaths in 213 countries at a world level (at May 5, 2020), and a huge burden of care have been recorded [3] .

Although many subjects remain asymptomatic [4] , the most frequent and critical clinical presentation of COVID-19 is the respiratory involvement, ranging from mild respiratory symptoms to severe pneumonia. However, the infection by SARS-CoV-2 virus represents a systemic disease [5] , which can lead to myocardial injury [6, 7] , heart failure [6] , vascular inflammation, myocarditis, cardiac arrhythmias [7] , hypoxic encephalopathy [8] , multi-organ failure, and ultimately death [9] .

In the first phase of the COVID-19 disease, the pathogenic properties depend on binding of spike viral proteins to angiotensin I converting enzyme 2 (ACE2) receptors [10] [11] [12] , which allow the virus to enter the target cells [13] . Receptors are expressed in the epithelia of the upper respiratory tract (nasopharynx) as major site of replication and, in the human lung, in alveolar epithelial cells (type II) and ciliated cells [11, 14, 15] . ACE2 receptor expression also occur in vascular endothelium, in the brush border of intestinal enterocytes [11, 16] , and in cholangiocytes [11, 17] . Thus, the symptomatic involvement of the gastrointestinal tract is possible with COVID-19 [18] [19] [20] [21] . A recent USA report describes a clinically evident gastrointestinal involvement in 61% of COVID-19 positive subjects. [22] . The presence of ACE2 receptors in the glandular cells of gastric, duodenal and distal enterocytes may result in malabsorption, unbalanced intestinal secretion and activation of the enteric nervous system, leading to gastrointestinal symptoms [23, 24] .

The liver can also become a target of COVID-19 infection, although major liver damage is uncommon [25] [26] [27] [28] . SARS-Cov-2 might affect the liver by direct (i.e. viral translocation from the gut to the liver) or indirect mechanisms (i.e. systemic inflammation, liver ischemia and hypoxia, effects on pre-existing liver diseases, drug-related liver injury) and represents a new challenge for hepatologists [28] . Notably, nonalcoholic fatty liver disease (NAFLD) is a chronic dysmetabolic pandemic which has become the most

This article is protected by copyright. All rights reserved common liver disease in the world, with a prevalence rate of 30% in the Western population [29, 30] . Moreover, NAFLD does not stands on its own but it is usually associated as "fellow traveler" with a constellation of risk factors, metabolic syndrome, and illness (Figure 1) [31]. Along with this view, the acronym NAFLD has been recently re-visited by coining the acronym MAFLD ("metabolic dysfunction-associated fatty liver disease") [32] . NAFLD/MAFLD can therefore affect the final outcome in COVID-19 patients [33] [34] [35] [36] . In addition, the liver itself has increased susceptibility to drugs in conditions of chronic injury [37] [38] [39] We discuss here the ongoing interaction of two different pandemic conditions: the recent, acute COVID-19 outbreak and the chronic NAFLD as part of an even wider set of metabolic disorders. During COVID-19 infection, the underlying NAFLD could pave the way to more severe hepatic and metabolically-associated complications and become another prognostic marker of viral disease.

In the liver, ACE2 receptors are mainly expressed in cholangiocytes (60% of cells) and in endothelial cells, rather than in hepatocytes (only 3% of cells) or Kupffer cells (where

This article is protected by copyright. All rights reserved ACE2 receptors are absent) [17, 50, 51] . Major factors involved in SARS-CoV-2 infection and liver damage are depicted in Figure 2 .

In Chinese patients, the prevalence of acute liver injury during COVID-19 disease was 15.4% [52] . However, an involvement of the liver has been reported in about 60% of cases [53] , and the risk of liver dysfunction seems to increase in older age [54] . Ji et al. [49] reported on 202 COVID-19 patients and NAFLD status. Liver abnormalities were 50% on admission and 75% during hospitalization, manifesting as hepatocellular pattern (only 3% with ductular or mixed pattern); 33% of the patients had persistent abnormal liver function from admission to last follow-up. COVID-19 progression was associated with male sex, age >60 years, higher BMI, underlying comorbidity, and NAFLD. In this study, univariate and multivariate logistic regression analysis indicated NAFLD as an independent risk factor for COVID-19 progression (OR 6.4; 95% CI 1.5 -31.2). NAFLD was also associated with higher likelihood of abnormal liver function from admission to discharge, and longer viral shedding time. [9] and, thus, the ACE2-mediated liver injury could be mainly secondary to the localization of these receptors in the endothelial cells [17] and NAFLD progression might include exaggerated production of ROS and NO derivatives [64] , inflammatory pathways leading to cellular crosstalk with Kupffer cells [65] and HIF-2α upregulation [66] , through suppression of fatty acid β-oxidation and induction of lipogenesis in the liver via PPARα [63]. This hypothesis is partly supported by liver histology from patients deceased due to severe COVID-19, reporting moderate microvesicular steatosis and mild lobular and portal activity, possibly due to a direct effect of SARS-CoV-2 infection or to drug-induced liver injury (DILI) [67] . c) Dysregulated systemic and hepatic innate immunity [44, 68] . ACE2 receptors in enterocytes [69] would predispose to viral translocation to the liver with potentials for viral circulation via the reticular system [70] . The innate immune cellular cluster in the liver would be activated with inflammatory and changes due to cytokine production ( Figure 3) . Patients with severe COVID-19 infection display elevation of inflammatory biomarkers such as C-reactive protein (CRP), serum ferritin, LDH,

This article is protected by copyright. All rights reserved D-dimer, interleukin (IL)-6, IL-2) [71] . IL-6, in particular, appears as a key factor in the onset and progression of the "cytokine storm" described in COVID-19 patients [54] , and increased IL-6 levels have been reported in subjects with NAFLD [40, 72] .

Increased IL-6 levels occur in NAFLD [40, 72] and could represent a marker or mediator of related atherosclerosis [72] and comorbidities often found in COVID-19 patients. The cytokine MCP-1 is often increased in COVID-19 patients [45] and acts as a further hit for steatohepatitis [73] . Although there is no direct evidence that, in the acute phase of the disease, a major liver damage occurs more frequently in COVID-19 infected patients with preexisting NAFLD, the common pathogenic mechanisms involved in COVID-19 and NAFLD could generate, in COVID-19 patients, an increased risk of NAFLD progression to steatohepatitis in the long-term [77] . Thus, in these patients, a close follow-up aimed at explore the long-term outcomes of liver injury is needed.

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Studies from China confirm that most vulnerable subjects to COVID-19 infection suffer from pre-existing illness that includes hypertension, cardiovascular disease, diabetes, chronic lung disease (e.g., asthma, chronic obstructive pulmonary disease, and emphysema), cancer, and chronic inflammation [9, 34, 78, 79] .

Several of such conditions, alone or in combination, predispose or are associated with metabolic changes of the liver, namely NAFLD. Although there is a hope for more specific therapies in COVID-19 infection, including vaccines [80] , a rational approach against future outbreaks must include preventive measures such as lifestyle changes to decrease the burden of chronic metabolic disorders, adiposity, and associated pro-inflammatory status while preserving an healthy immune response [81, 82] .

This conclusion is supported by emerging relationships between COVID-19 outcomes and frequent metabolic abnormalities which coexist with NAFLD.

Diabetes mellitus has been described as an additional risk to the progression of COVID-19 [34, 47], probably also due to the presence of an "overfat" condition (see below), lowgrade chronic inflammation, insulin resistance, obesity [38, [83] [84] [85] , and a dysregulation of ACE2 [61]. Of note, the ACE2 is also expressed in the endocrine pancreas. Thereby, COVID-19 might facilitate a status of insulin resistance and impaired insulin secretion [86] .

Independently from diabetes, the presence of an "overfat" condition (i.e. excess body fat that impairs health [87] ) has developed as a pandemic worldwide and can occur in obesity, overweight, and even normal weight subjects with excess fat involving the liver as well in terms of steatosis (Figure 1) . Several abnormalities can cluster together with overfat, i.e., overweight, obesity, chronic "metabolic" inflammation, and insulin resistance, eventually configuring the metabolic syndrome (MetS) [9, 88, 89] .

Excess body fat can impair immunity, as confirmed by the higher incidence of both autoimmune and immune diseases [90] . A defective immune response (mainly of T lymphocytes, and macrophages) with underlying adiposity, will compromise the immune system to increase the risk of infections, and chronic respiratory diseases [91, 92] .

Notably, the overfat condition appears to be a risk factor in infectious viral diseases [93, 94] . In particular, overfat might negatively affect immune function and host defence

This article is protected by copyright. All rights reserved [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109] . In this case, individuals have increased morbidity in response to COVID-19 infection [110, 111] .

The pandemic characteristics and high-lethality rate of SARS-CoV-2 infection have raised concerns about mechanisms of injury in patients at risk. Initial evidence from China indicated that the subjects most vulnerable to COVID-19 suffer from pre-existing illness.

COVID-19 acute pandemic often develops in patients with major metabolic abnormalities, including fatty liver disease, which is part of a chronic pandemic together with body fat accumulation. During metabolic abnormalities, the expansion of metabolically active fat ("overfat condition") parallels chronic inflammatory changes [9, 34, 78, 79] , the development of insulin resistance, and, in the liver, the accumulation of fat and, possibly, an underlying fibrosis. In this context, the deleterious interplay of the complex inflammatory pathways chronically present in NAFLD can be acutely boosted in the setting of COVID-19, magnifying liver injury and deteriorating outcome in metabolicallycompromised populations. Thus, NAFLD should be considered as prognostic indicator during COVID-19 and, on the other hand, close long-term monitoring of NAFLD patients who experienced COVID-19 might be needed.

Finally, a further challenge in the diagnosis and treatment of NAFLD patients is to reduce the vulnerability from non-communicable diseases, increasing the individual resilience to future outbreaks. macrophage [114] . The pro-inflammatory metabolic status is a factor promoting insulin resistance, as well as defective immune response (poor T cell and macrophage function)

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