key: cord-342930-f7cw2ca6
authors: Portincasa, Piero; Krawczyk, Marcin; Machill, Antonia; Lammert, Frank; Ciaula, Agostino Di
title: Hepatic consequences of COVID-19 infection. Lapping or biting?
date: 2020-06-01
journal: Eur J Intern Med
DOI: 10.1016/j.ejim.2020.05.035
sha: 
doc_id: 342930
cord_uid: f7cw2ca6

The outbreak of coronavirus disease 2019 (COVID-19) starting last December in China placed emphasis on liver involvement during infection. This review discusses the underlying mechanisms linking COVID-19 to liver dysfunction, according to recent available information, while waiting further studies. The manifestations of liver damage are usually mild (moderately elevated serum aspartate aminotransferase activities), and generally asymptomatic. Few patients can still develop severe liver problems, and therapeutic options can be limited. Liver dysfunction may affect about one-third of the patients, with prevalence greater in men than women, and in elderly. Mechanisms of damage are complex and include direct cholangiocyte damage and other coexisting conditions such as the use of antiviral drugs, systemic inflammatory response, respiratory distress syndrome-induced hypoxia, sepsis, and multiple organ dysfunction. During new COVID-19 infections, liver injury may be observed. If liver involvement appears during COVID-19 infection, however, attention is required. This is particularly true if patients are older or have a pre-existing history of liver diseases. During COVID-19 infection, the onset of liver damage impairs the prognosis, and hospital stay is longer.

A novel coronavirus was reported to World Health Organization on Dec 30, 2019, as the cause of a 2 cluster of pneumonia cases in China, city of Wuhan, Hubei Province. The first name of 2019-3 nCoV(human) was adopted on Jan 7, 2020, lately changed to severe acute respiratory syndrome 4 coronavirus 2 (SARS-CoV-2). COVID-19 infection became an outbreak throughout China on Feb 5 11, 2020 and subsequently was identified as a global pandemic on March 11, 2020, spreading to 6 more than 120 countries, as a major threat to public health [1] [2] [3] . The COVID-19 pandemic suddenly 7 represented an enormous burden of care [4] , and raised issues related to medical ethics [5] , since 8 specific therapies and/or vaccines are missing, to date. COVID-19 may manifest in different ways. 9 Many subjects may remain asymptomatic [6] , but the exact number is still unknown. Specific 10 settings might facilitate the spread of infection e.g., in skilled nursing facility where more than half 11 of residents with positive test results were asymptomatic at the time of testing and most likely 12 contributed to transmission [7, 8] . The proposed 3-stage classification system of potential increasing 13 severity for COVID-19 infection encompasses stage I (early infection), stage II (pulmonary phase), 14 and stage III (hyperinflammation phase) [9] . Although the most frequent and critical clinical 15 presentation is secondary to the involvement of the lung (fever, cough), the infection by SARS- 16 CoV-2 virus may lead to a systemic and multi-organ disease [10] , also involving the gastrointestinal 17 tract (nausea/vomiting, or diarrhea) [11, 12] . The liver appears to be the second organ involved, 18 after the lung [13] [14] [15] . 19 The present paper explores the available evidences on liver involvement in patients with COVID-19 20 infection, to provide a comprehensive understanding of the phenomenon, and to anticipate effective 21 follow-up. 

During COVID-19 infection, patients can be asymptomatic or present clinical symptoms ranging 25 from fever, dry cough, headache to dyspnea and fatigue, to acute respiratory distress syndrome 26 6 (ARDS), shock, and cardiac failure [9, 16] . A nasopharyngeal swab is the collection method used to 1 obtain a specimen for testing. Because the likelihood of the SARS-CoV-2 being present in the 2 nasopharynx increases over time, repeated testing is often used [17] . Multi-organ involvement 3 secondary to COVID-19 infection occurs in a subgroup of patients [10] . COVID-19 infection can be 4 associated with myocardial injury [18] [19] [20] , heart failure [18] , vascular inflammation, myocarditis, 5 cardiac arrhythmias [19] , and hypoxic encephalopathy [21] . The progression and prognosis of 6 COVID-19 infection is worse in the presence of diabetes mellitus [22, 23] . The case-fatality rate 7 increases with age (from 8% to 15% in the age range 70-79 years, and ≥80 years, respectively) and 8 with associated diseases, i.e., 11%. 7%, 6%, 6%, and 6% in patients with cardiovascular disease, 9 diabetes mellitus, chronic respiratory disease, hypertension, and cancer, respectively [ another study in Zhejiang province [26] . Gastrointestinal involvement could be the consequence of 15 COVID-19-Angiotensin-Converting Enzyme 2 (ACE2) receptors at the enterocyte level (i.e. 16 glandular cells of gastric, duodenal and distal enterocytes), resulting in malabsorption, unbalanced 17 intestinal secretion and activated enteric nervous system, therefore diarrhoea) [28, 29] . In human 18 small intestinal organoids, SARS-CoV-2 rapidly infects the enterocytes and strongly induces a 19 generic viral response program, pointing to a marked viral replication in the intestinal epithelium 20 [30] . 21 Notably, continuous viral RNA shedding occurs into feces up to 11 days negativity of respiratory A study reported that the virus can be detected but not cultivated from stool (despite high RNA 1 concentration), consistent with the lack of transmission [33] . In a case-control study from USA 2 (enrolling 278 COVID-19 positive patients and 238 COVID-19 negative patients), the presence of 3 gastrointestinal symptoms was predictive of COVID-19 positivity, and symptoms were associated 4 with slower and less severe disease course [34] . when the virus binds to ACE2 receptors [35] [36] [37] to enter the target cell [38] . Receptors are well 10 expressed in epithelia of the lung, gastrointestinal tract, and vascular endothelium, also in the liver 11 [39]. This early period of COVID-19 infection can evolve to the second stage of viral pneumonia.;

(ii) Extra-pulmonary systemic hyperinflammation syndrome occurs in the minority of infected 13 patients, and is characterized by the so-called "cytokine storm". At this moment, several cytokine 14 levels increase, namely interleukin (IL)-2, IL-6, IL-7, IL-10, and tumor necrosis factor (TNF)α. 15 Additional inflammatory biomarkers include granulocyte-colony stimulating factor, interferon 16 (IFN)-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory Patients with severe and fatal disease had significantly increased white blood cell count, and 24 decreased lymphocyte and platelet counts compared to non-severe disease and survivors.

Biomarkers of inflammation, muscle and cardiac injury, as well as liver and kidney function and year in 43% of the 99 COVID-19 cases from Wuhan [48] . This aspect deserves further attention.

Although the level of serum transaminases could be already elevated before the onset of COVID-14 19, results from clinical reports and autopsy studies [26, 49, 50] suggest that liver dysfunction can 15 be an expression of a worse disease evolution, and that an isolated elevation of transaminases alone 16 is likely to be the indirect expression of a systemic inflammation.

Previous data from COVID-19 outbreak in China found that 2-11% of patients had liver 18 comorbidities, 14-53% of patients presented with abnormal serum aminotransferases levels during 19 the disease, and that the rates of liver dysfunction were more present in subjects with the most 20 severe clinical presentation [26, 49] . In another large series of 417 Chinese COVID-19 patients, 21 abnormal liver tests (AST, ALT, total bilirubin, GGT) were present in 76.3% of patients and 21.5% 16 China, in 6% to 22% and 21% to 28% of patients, respectively. In studies from Wuhan, AST levels 17 were increased in 24% to 37% of patients, a proportion higher than in other Chinese regions 18 (Zhejiang), reporting a proportion of 16%. A gender difference might exist in this respect [62] , since 19 the prevalence of AST increase is higher in men than women, as documented by six case series (i.e., 20 average 66% vs. 35%, respectively). Case reports and case series also suggest that the probability of 21 developing liver dysfunction increases with older age [61] . Notably, the elevation of Additional elements possibly concurring to liver damage are drug-related injury and the progression 14 of underlying liver diseases. 15 It is still under debate if these alterations can really be an expression of a clinically relevant liver 16 injury requiring particular attention in the management of the disease [13, 68]. In one study, patients 17 developing abnormal liver tests had higher risks of progressing to severe disease [51] , and the 18 finding is associated with longer hospital stay [62] . In addition, the more severe form of COVID-19 19 infection is a predisposing condition to a more evident liver damage [10, 49, 69] , and therefore also promoted by systemic sepsis [71] . Viral inclusions seem to be absent in the liver [57] , but this 2 possibility deserves further investigations, because of potential viral RNA translocation from 3 intestine though portal blood. 4 Another possibility is the direct damage from COVID-19. Cholangiocytes express ACE2 receptors 5 (more that 20-fold than in hepatocytes). Although cell damage can also occur at the level of bile COVID-19 infection can progress to the inflammatory cytokine storm [75] , which involve both the 13 innate (Toll-like receptors, TLRs) and the cellular adaptive immunity (killer T lymphocytes) [76, increased neutrophil counts and neutrophil to lymphocyte ratios, as well as hyperferritinemia [10] .

Elderly patients go worse, in this respect [79] . This sudden and immense immune hyperactivation 24 may result in multiple organ failure lungs but also to the liver, heart, and kidneys [75] . Serum levels liver disorder in Western industrialized countries, (prevalence ranging from 10 to 46% in the United 1 States [89-91]) and a median of 20% worldwide with a documented rising trend with time [92] . This 2 trend in North America and Europe is the consequence of the rising prevalence of major risk factors 3 for NAFLD, including obesity, sedentary lifestyles, type 2 diabetes mellitus, dyslipidaemia, and 4 metabolic syndrome [92] [93] [94] [95] . However, lean non-alcoholic steatohepatitis (NASH) can develop as 5 well [94] and is frequent in Asia [96] . Overall, factors contributing to NAFLD include the 6 environment, the gut microbiome, disrupted gluco-lipid metabolic pathways, metabolic was more frequent among those receiving lopinavir/ritonavir after hospital admission [62] . 14 Remdesivir, a nucleoside analog prodrug developed by Gilead Sciences (USA), is effective against 15 COVID-19 replication in vitro [116] and in infected patients [117] . This drug produced similar 16 effects on liver enzymes [118] . Hydroxy Chloroquine sulphate is also effective in vitro [116] and, in 17 COVID-19 patients for short periods, appears to safe. Rare case of fulminant hepatic failure have 18 been described with Hydroxy Chloroquine [119, 120] . Acute liver injury is also possible after 19 azithromycin treatment, with a clinically evident presentation following about two weeks after drug 20 cessation, and after an average duration of treatment of 4 days [121] . Several patients with 21 concomitant diseases (i.e. diabetes type 1 or 2, or hypertensive), undergo antihypertensive therapies 22 with ACE inhibitors and angiotensin II type I receptor blockers. In this context, a possibility is the 23 onset of ACE2 overexpression. Whether this condition will facilitate COVID-19 infection and 24 penetrance, deserves further attention [122, 123] . There is no evidence, however, that ACE 25 inhibitors will worsen the consequence of infection [123] . Many patients with fever use antipyretic 1 agents, namely acetaminophen [124] . This drug might mediate, at least in part, the liver damage [57] . 2 Patients with underlying metabolic abnormalities and NAFLD might be more exposed to drug-3 induced liver damage (DILI) [99, 108]. As mentioned earlier, the cytokine MCP-1 is often increased 4 in COVID-19 patients [42] and act as a further hit for steatohepatitis [125] . In addition, patients with 5 NAFLD/nonalcoholic steatohepatitis (NASH) COVID-19 infection, might be more susceptible to 6 DILI, as well as to therapy with steatogenic drugs (amiodarone, sodium valproate, tamoxifen and 

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We confirm that there are no known conflicts of interest associated with this publication and there has been 3 no significant financial support for this work that could have influenced its outcome. 4 5