Hepatology Communications, VOL. 5, NO. 7, 2021  Impact of COVID-­19 in Liver Disease Progression Miguel Angel Martinez , and Sandra Franco Severe acute respiratory syndrome coronavirus-­2 (SARS-­CoV-­2) is a novel coronavirus that causes coronavirus disease 19 (COVID-­19), which has infected millions of people worldwide in only a few months. A minority, but significant number, of infected individuals require hospitalization and intensive care. From the start of this new virus pandemic, it was apparent that obese and/or diabetic individuals had a bad prognosis for COVID-­19 progression, strongly suggest- ing an association between liver disease and severe COVID-­19. Because chronic liver disease (CLD) is associated with immune dysregulation and inflammation, it is unsurprising that patients with CLD may carry a greater risk of adverse outcomes following SARS-­CoV-­2 infection. Initial COVID-­19 data have also indicated that healthy infected individu- als display abnormal liver function tests, suggesting a possible direct implication of SARS-­CoV-­2 in liver damage. Here we show that COVID-­19 affects the liver metabolism and increases the morbidity and mortality of individuals with underlying CLD. (Hepatology Communications 2021;5:1138-1150). T he severe acute respiratory syndrome coro- and immune-­related symptoms, those who are unable navirus 2 (SARS-­ CoV-­ 2) pandemic clearly to control SARS-­CoV-­2 replication are more likely to highlights the importance of an effective host show pathogenesis-­ associated immune dysregulation immune response.(1) SARS-­CoV-­2 causes coronavirus (Fig. 1). disease 2019 (COVID-­19), which can involve a number There is also an ongoing worldwide obesity pan- of diverse symptoms, including immune dysregulation demic that has led to insulin resistance, diabetes, and and cytokine storm. In COVID-­19, elevated cytokine chronic liver disease (CLD), becoming a major pub- levels have been implicated in lung injury and multi-­ lic health burden.(7,8) CLD is most commonly caused organ failure,(2) and a more severe cytokine storm may by chronic hepatitis B and C, alcohol-­associated liver contribute to COVID-­19 pathogenesis.(3,4) Cytokines disease (ALD), and nonalcoholic fatty liver disease that are elevated in patients with COVID-­19 include (NAFLD). CLD can further progress to inflamma- interleukin (IL)-­1β, interleukin-­6, interferon (IFN)-­ tion (nonalcoholic steatohepatitis [NASH]), fibrosis, γ–­induced protein 10, tumor necrosis factor (TNF), and finally cirrhosis and hepatocellular carcinoma IFN-­γ, macrophage inflammatory protein 1α and 1β, (HCC) as end-­stage diseases. Cirrhosis, viral hepatitis, and vascular endothelial growth factor.(5) In particular, and HCC account for approximately 2 million deaths high IL-­6 levels have been associated with COVID-­19 per year worldwide.(7,8) Liver cells, primarily hepato- severity and mortality.(6) Although patients with cytes, constitute a major source of proteins involved COVID-­19 exhibit highly variable immune responses in innate and adaptive immune responses. The liver Abbreviations: ACE2, angiotensin-­converting enzyme 2; ALD, alcohol-­associated liver disease; ALT, alanine transferase; AST, aspartate transferase; CI, confidence interval; CLD, chronic liver disease; COVID-­19, coronavirus disease 2019; FIB-­4, fibrosis-­4; GGT, gamma-­glutamyltransferase; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; HDL, high-­density lipoprotein; IFN, interferon; IL, interleukin; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OR, odds ratio; SARS-­CoV-­2, severe acute respiratory syndrome coronavirus 2; TIM-­3, T-­cell immunoglobulin and mucin-­domain containing 3; TMPRSS2, transmembrane serine protease 2; TNF, tumor necrosis factor. Received February 26, 2021; accepted April 28, 2021. Supported by the Spanish Ministry of Science and Innovation (PID2019-­103955RB-­100). © 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution-­NonCommercial-­NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-­commercial and no modifications or adaptations are made. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep4.1745 Potential conflict of interest: Nothing to report. 1138 Hepatology Communications, Vol. 5, No. 7, 2021 MARTINEZ AND FRANCO regulates immune homeostasis by preventing the sys- demonstrated whether SARS-­ CoV-­ 2 can infect temic spread of microbial and dietary antigens that hepatocytes. Because acute liver injury or cholestasis arrive from the gut, and through the synthesis of sol- can develop in severe cases of cytokine storm,(1,14) not uble molecules that are essential for effective immune related to COVID-­19, it is possible that SARS-­CoV-­ responses.(9) Thus, liver injury can lead to compro- 2-­originated immune dysregulation may play a role in mised immune surveillance by reducing the hepatic COVID-­19-­associated liver pathology. synthesis of proteins involved in innate immunity and We aim here to review and discuss the impli- pathogen-­associated molecular pattern recognition. cations of COVID-­ 19 in healthy liver individ- Both CLD and cirrhosis are characterized by uals as well as the risks of severe COVID-­19 in immune dysregulation.(10) CLD causes impairment of patients with fatty liver disease, viral hepatitis, the liver’s homeostatic role in the systemic immune cirrhosis, HCC, ALD, and liver-­ transplantation response. The molecular patterns from damaged liver recipients. The effect of COVID-­19 antiviral and cells prompt circulating immune cells to induce sys- anti-­inflammatory therapies on the liver will be also temic inflammation, in the form of activated circu- scrutinized and reviewed. lating immune cells and increased serum levels of pro-­ inflammatory cytokines (e.g., TNF and IL-­ 6). Importantly, liver-­associated immune dysfunction can increase susceptibility to infections. In this context, COVID-­19 Impact in it is unsurprising that patients with CLD, especially those with decompensated cirrhosis, are at higher Individuals With Healthy risk of COVID-­ ity.(11) 19-­related morbidity and mortal- The combination of SARS-­ CoV-­ 2 infection Liver and cirrhosis appears to be a lethal duo, likely due to As mentioned previously, patients with COVID-­19 the combination of biological processes characterized commonly exhibit elevated markers associated with by immune dysregulation (Fig. 2). Importantly, liver liver injury, such as AST, ALT, alkaline phosphatase, transplantation restores hepatic function in patients and gamma-­ glutamyltransferase (GGT).(13,15-­17) with decompensated cirrhosis, thus reducing the The prognostic value of elevated liver injury mark- risk of COVID-­19 mortality to that of the general ers in patients with COVID-­19 remains controver- population.(12) sial, as reviewed by Bertolini et al.,(13) with some In addition to the bad prognostic impact of CLD studies showing that elevated AST or ALT values in patients with COVID-­ 19, SARS-­ CoV-­ 2 infec- are correlated with a bad prognosis, while others tion may also negatively affect liver health in previ- find no association with COVID-­19 progression or ously healthy individuals. The available clinical data mortality. indicate that patients with COVID-­ 19 commonly One possible mechanism for the liver injury show abnormal liver function tests, such as aspartate observed in patients with COVID-­ 19 is direct transferase (AST) and alanine transferase (ALT).(13) hepatic infection by SARS-­ CoV-­2. The SARS-­ However, the mechanisms underlying the impact of CoV-­ 2 host cell receptor is angiotensin-­ converting (18) COVID-­19 on liver function are not fully understood enzyme 2 (ACE2), and SARS-­ CoV-­ 2 cellular and may be multifactorial, and it has not been clearly entry also involves transmembrane serine protease 2 ARTICLE INFORMATION: From the IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: Miguel Angel Martinez, Ph.D. E-­mail: mmartinez@irsicaixa.es Fundació irsiCaixa, Hospital Universitari Germans Trias i Pujol Tel.: +34-­934656374 08916 Badalona, Spain 1139 MARTINEZ AND FRANCO Hepatology Communications, July 2021 FIG. 1. Pathophysiological features of SARS-­CoV-­2 infection. Following SARS-­CoV-­2 infection, cytokine storm may occur due to inappropriate or ineffective pathogen recognition, with immune evasion that generates an inappropriate response, including an exaggerated effector response, cytokine production, and/or failure to return homeostasis. The described pathways are based on a report by Fajgenbaum and June.(1) Examples of drugs that can inhibit signaling pathways are shown in red. Abbreviations: JAK-­STAT3: Janus kinase–­signal transducer and activator of transcription 3; MAPK, mitogen-­activated protein kinase; mTOR, mammalian target of rapamycin; NF-­κB, nuclear factor kappa B; Treg, regulatory T cell. (TMPRSS2).(18) Sequencing studies have revealed hepatocytes.(25) These findings strongly suggest that ACE2 messenger RNA (mRNA) expression in a SARS-­CoV-­2 does not directly cause cytopathic liver subpopulation of cholangiocytes, but no or minimal damage. Interestingly, SARS-­CoV-­2 can replicate in expression in hepatocytes, and no expression in other the HCC cell line Huh-­ 7.(26) Additionally, SARS-­ liver cell types.(19-­22) TMPRSS2 mRNA expression CoV-­2 particles without membrane-­ bound vesicles has been found in a subset of hepatocytes and cholan- have been detected in the cytoplasm of hepatocytes giocytes.(23,24) ACE2 protein has not been detected in from 2 patients with COVID-­19 with elevated liver 1140 Hepatology Communications, Vol. 5, No. 7, 2021 MARTINEZ AND FRANCO FIG. 2. Features of immunodeficiency commonly found in patients with cirrhosis. Cirrhosis disrupts the liver architecture and cellular organization, and diminishes the hepatic ability to synthesize proteins. Cirrhosis affects the functions of circulating and intestinal populations of immune cells, resulting in a number of abnormalities that affect cellular and soluble components of the immune response both at the liver and systemically.(10) Abbreviations: CXCR1/2, chemokine receptor 1/2; HLA-­DR, human leukocyte antigen-­DR; IRAK-­M, interleukin receptor-­associated kinase 3; MERTK, c-­mer proto-­oncogene tyrosine kinase; PD-­1, programmed cell death-­1; TGF-­β, transforming growth factor β; TIM-­3, T-­cell immunoglobulin and mucin-­domain containing 3. injury markers(27); however, these samples were not may also be implicated in the disseminated intra- assessed for the presence of viral RNA to exclude vascular coagulation (DIC) and thrombocytopenia, another origin of these particles.(28) Notably, SARS-­ which can worsen the DIC complications, as observed CoV-­ 2 can infect intestine-­ related tissue,(29,30) and in COVID-­19.(34) Patients with COVID-­ 19 have (35) some patients with COVID-­19 (<15%) exhibit viral exhibited endotheliitis in the liver, fibrin micro- RNA in their blood.(31,32) Therefore, it has been sug- thrombi in liver sinusoids,(36,37) and activation of the gested that viruses may enter the portal circulation, complement system.(38) One report demonstrated thus reaching the liver, and Kupffer cells might attempt that, in contrast to patients with mild COVID-­19, to clear the virus and produce local inflammation.(13) patients with non-­ COVID-­ 19 pneumonia did not The liver could also be affected by the hypoxia and exhibit elevated levels of AST, ALT, or GGT,(39) sug- cytokine storm that follows SARS-­CoV-­2 infection, gesting that patients with mild COVID-­19 may have which is associated with multi-­organ failure in some elevated liver damage markers independently of the patients with COVID-­ 19.(1,33) The cytokine storm presence of inflammation. 1141 MARTINEZ AND FRANCO Hepatology Communications, July 2021 The pattern of abnormal liver biochemistries at drugs also caused elevated liver enzyme levels.(45) admission and over the course of illness in hospi- Unfortunately, the former repurposed drugs do not talized patients with COVID-­19 is associated with appear to have an impact on COVID-­19.(51) On the AST-­ predominant aminotransferase elevations.(40) other hand, immunomodulators appear to be a more This finding suggests a virus-­specific mediated mech- effective therapeutic strategy for treating COVID-­19 anism of liver injury. This result is in contrast to that morbidity and mortality—­with corticosteroids, such observed with viral hepatitis, which classically leads to as dexamethasone, significantly increasing survival an ALT-­predominant liver injury. AST is produced in and reducing morbidity among hospitalized patients the muscle, and patients with COVID-­19 have mark- with COVID-­19(52) and in patients with moder- ers of muscle injury. AST-­ predominant elevations ate or severe COVID-­19.(53) Because corticosteroids are also associated with ALD, ischemia and cirrhosis, are derived from cholesterol metabolism, which can revealing the impact of COVID-­19 on the liver. AST interfere with multiple aspects of glucose homeosta- and GGT elevations have been also associated with sis, attention should be paid to the possible effects influenza virus infection and the associated cytokine-­ of these compounds on liver metabolism and hepatic mediated injury.(41) steatosis.(52). Indeed, corticosteroid treatment in severe Liver biochemistries have been associated with COVID-­19 has been associated with significant liver COVID-­19 severity and clinical outcomes. However, injury.(54) Tocilizumab, a humanized monoclonal anti- the impact of COVID-­19 on a healthy liver appears body against the IL-­6 receptor, used to treat rheu- to be negligible, and limited to patients with severe matoid arthritis and now profusely used to counter infection and multi-­organ failure.(42,43) the cytokine-­mediated injury in severe COVID-­19, is also known to induce a significant elevation of ALT.(55) This retrospective, observational cohort Hepatotoxicity of study reported that the tocilizumab group had a sig- nificantly higher elevation of ALT.(55) Finally, antibi- COVID-­19 Antiviral otics, which are one of the most common causes of drug-­induced liver injury, can also contribute to liver and Anti-­inflammatory damage in patients with COVID-­19. Therapies Recently, another retrospective study that included 1,040 patients with COVID-­19 found elevated lev- Another possible source of liver damage in patients els of ALT/AST in 22.6% of the study individuals.(56) with COVID-­19 is drug-­induced liver injury associ- In this cohort, the use of lopinavir–­ritonavir, with or ated with COVID-­19 therapies. One study reports without ribavirin, IFN-­β and/or corticosteroids, was that among patients with COVID-­19 exhibiting nor- independently associated with ALT/AST elevations. mal liver injury markers on admission, nearly half had New specific SARS-­CoV-­2 antivirals are now in phase developed abnormal liver marker levels after 1 week 3 clinical trials (e.g., molnupiravir),(57) and they may following admission.(44) Lopinavir-­ ritonavir treat- enter the clinic soon. Future studies would be worth ment has been associated with elevated levels of AST, conducting in determining the possible effects of new ALT, and bilirubin(45); remdesevir reportedly induces SARS-­CoV-­2 drugs on liver function in patients with AST and ALT elevations(46,47); and acetaminophen COVID-­19. Specifically, individuals with CLD could and hydroxychloroquine are associated with liver be included in these studies. Favipiravir is an oral marker abnormalities.(48,49) The liver toxicity of rem- broad-­ spectrum inhibitor of viral RNA-­ dependent desivir has been widely debated. Randomized trials RNA polymerase that is approved for treatment of have shown that equivalent liver enzyme elevations influenza in Japan and displays a modest effect against between remdesivir-­ treated and control groups.(47) COVID-­19.(58) Favipiravir appeared to be well tol- However, the WHO safety report database indi- erated.(58) However, a case of cholestatic liver injury cates a statistically significant odds ratio for liver induced by favipiravir has been described in an indi- injury with the use of remdesivir.(50) Angiotensin II vidual with previous liver injury due to ALD. This receptor blockers and ACE inhibitors have been also favipiravir case report reveals the relevance of baseline explored as possible COVID-­ 19 treatment. These CLD on future antiviral therapies. 1142 Hepatology Communications, Vol. 5, No. 7, 2021 MARTINEZ AND FRANCO Fatty Liver and COVID-­19 enzymes, and higher C-­reactive protein; and to exhibit lower levels of lymphocytes, platelets, triglycerides, Progression and high-­density lipoprotein cholesterol.(7,8) Moreover, among patients with COVID-­19, the need The high worldwide prevalence of NAFLD and for mechanical ventilation is independently associated NASH, which affect approximately 25% of the global with obesity (OR 4.5), diabetes mellitus (OR 2.55) population, makes it inevitable that NAFLD/NASH and FIB-­4 ≥ 2.67 (OR 3.09), and FIB-­4 ≥ 2.67 is also will overlap with COVID-­ 19. NAFLD is associ- associated with increased 30-­day mortality (OR, 8.4; ated with obesity and other lifestyle-­ related meta- 95% CI, 2.23 to 31.7).(68) bolic disorders (e.g., type 2 diabetes). Since the start The association between NAFLD/NASH and of the COVID-­ 19 pandemic, obesity and diabetes a severe course of COVID-­ 19 suggests the possi- have been linked with a bad disease prognosis.(17,59) bility that a genetic risk score for NAFLD, based Elevated levels of the liver enzymes AST/ALT (≥2× on the weighted effect of risk variants in PNPLA3 the upper limit of normal [i.e., 80 U/L]) are com- (patatin-­ like phospholipase domain containing 3)–­ mon, and are independently associated with adverse TM6SF2 (transmembrane 6 superfamily member clinical outcomes among patients with COVID-­ 2)–­MBOAT7 (membrane-­bound O-­acyltransferase 19.(60-­62) In one study, AST/ALT elevations were domain-­ containing protein 7)–­ GCKR (glucokinase observed in 235 patients classified as having severe regulator) on hepatic fat in the general population,(69) COVID-­19.(56) Another study included 31,461 adults may affect COVID-­19 risk.(70) In an analysis of 1,460 with COVID-­ 19, and found that moderate/severe individuals, of whom 526 were positive and 934 were liver disease was significantly associated with mor- negative for SARS-­CoV-­2, the genetic risk score for tality (odds ratio [OR], 2.62; 95% confidence inter- NAFLD was not associated with an increased risk val [CI], 1.53 to 4.47).(63) In a similar investigation of COVID-­19. However, this investigation revealed of 2,780 patients with COVID-­19, liver disease was a trend of protection against COVID-­19 conferred again significantly associated with mortality (OR, 2.8; by the single-­ nucleotide polymorphism rs738409, 95% CI, 1.9 to 4.0).(64) Compared to patients with- which encodes the p.I148M PNPLA3 variant.(70) out NAFLD, patients with NAFLD reportedly show It has been also suggested that obese individuals a higher risk of disease progression (6.6% vs. 44.7%), and patients with NAFLD/NASH may have higher higher likelihood of abnormal liver function from hepatic expression of the SARS-­ CoV-­ 2 receptors admission to discharge (70% vs. 11.1%), and longer ACE2 and TMPRSS2,(71,72) which could explain viral shedding time (17.5 ± 5.2 days vs. 12.1 ± 4.4 the worse clinical course of these patients. One study days).(65) Thus, the high global prevalence of NAFLD found that NAFLD/NASH did not influence the liver suggests that a large proportion of the population is at expression of the ACE2 and TMPRSS2 genes.(72) risk of severe COVID-­19. However, another investigation revealed that obese Because NAFLD prognosis is determined based patients with NASH showed markedly higher expres- on liver fibrosis severity, it has been considered that sions of these genes, suggesting that advanced stages patients with NAFLD with higher noninvasive liver of NAFLD might predispose to COVID-­19.(73) Gut fibrosis scores may carry a greater risk of severe microbiota and incomplete fatty acid oxidation prod- COVID-­19. Indeed, the risk of severe COVID-­19 ucts were also associated with NAFLD/NASH and is significantly higher in patients with NAFLD who severe COVID-­19,(74-­76) possibly by modulating host have been diagnosed with hepatic steatosis based on immune response.(77) computed tomography (OR, 4.32; 95% CI, 1.94 to Within the context of COVID-­ 19, it has been 9.59) or with an intermediate or high fibrosis-­4 (FIB-­ clearly demonstrated that the presence of NAFLD/ 4) index (OR, 5.73; 95% CI, 1.84 to 17.9), regard- NASH predisposes patients to severe COVID-­ 19 (66,67) less of metabolic comorbidities. Compared to morbidity and mortality. Because there are no patients with NAFLD with low FIB-­4 scores or indi- approved therapies for NAFLD/NASH, numerous viduals without NAFLD, patients with NAFLD with trials are being conducted in this clinical research intermediate or high FIB-­ 4 scores are more likely field. However, many such trials have been disrupted to be older and obese; to have diabetes, higher liver due to the COVID-­19 pandemic. The high global 1143 MARTINEZ AND FRANCO Hepatology Communications, July 2021 prevalence of CLD warrants the continuation of immune dysfunction(10) (Fig. 2), which is related to a ongoing NAFLD/NASH trials.(78) bad COVID-­19 prognosis.(1) In patients with severely decompensated cirrhosis, cirrhosis-­associated immune dysfunction can switch from predominantly pro-­ Alcohol-­Associated Liver inflammatory to predominantly immunodeficient.(10) Systemic inflammation can affect the functions of tis- Disease sue somatic cells and modify the clinical manifestation of cirrhosis.(10) An analysis of 745 patients with CLD ALD is independently associated with a 1.8-­ infected with SARS-­CoV-­2 from 29 countries revealed fold increased risk for mortality in patients with that cirrhosis was strongly associated with death (OR, COVID-­19.(11) Furthermore, patients with both ALD 9.32; 95% CI, 4.80 to 18.08).(11) Among the 745 and COVID-­19 appear to exhibit more severe liver patients, 150 (20%) died, of whom 123 had cirrhosis. injury, as the proportion of patients without cirrho- Importantly, the main cause of death was lung injury, sis is only 6% among patients with ALD compared with only 19% of the patients dying due to cirrhosis-­ to 62% among those with NAFLD.(11) A case report related complications. This finding strongly suggests describes 2 patients who were diagnosed with noso- that cirrhosis is a driving force in lung injury develop- comial COVID-­19 infections and severe COVID-­19 ment, and this relationship could be due to cirrhosis-­ pneumonia while hospitalized during treatment for associated immune dysfunction.(1) Cirrhosis has been ALD.(79) Both patients developed multiple-­organ fail- associated with impaired responses to pneumococcus ure and died over a short period of time. An additional and hepatitis B virus (HBV) vaccines,(86,87) suggesting study indicated that the risk of severe COVID-­ 19 a possible poor response to SARS-­CoV-­2 vaccination. was significantly associated with alcoholic liver dam- Potential mechanisms of disease linking cirrhosis with age (OR, 7.05; 95% CI, 6.30 to 7.88) and alcoholic severe COVID-­19 are increased systemic inflamma- liver cirrhosis (OR, 7.00; 95% CI, 6.15 to 7.97).(80) tion, cirrhosis-­associated immune dysfunction, coag- Nevertheless, few studies have explored the impact ulopathy, and intestinal dysbiosis.(88) Because gut of alcohol during the COVID-­19 pandemic, nor the microbiota composition plays a role in regulating the mechanisms through which alcohol consumption and magnitude of COVID-­19 severity, possibly by mod- ALD may impact COVID-­19 pathogenesis.(81) ulating host immune responses, and cirrhosis is char- Excessive alcohol consumption may have immune-­ acterized by changes in gut microbiota composition, modulating effects and predispose individuals to viral we can also speculate about the link among microbi- and bacterial infections.(82,83) It is estimated that ota, cirrhosis, and COVID-­19 severity. An interesting alcohol causes 3.3 million deaths annually.(84) Several aspect of the former study is that patients with cirrho- pathologies are linked to alcohol consumption, with sis were less likely to receive targeted antiviral therapy CLD and cirrhosis being the main alcohol-­associated due to safety concerns, highlighting the importance health problems. Unfortunately, alcohol consump- of evaluating hepatotoxicity during COVID-­19 clini- tion is showing annual increases nearly worldwide.(84) cal trials, and allowing patients with cirrhosis to enter Moreover, social distancing and lockdown measures these studies. are resulting in increased alcohol abuse, which is aggra- Intriguingly, patients with cirrhosis have a reduced vating alcohol-­associated CLD and liver injury.(85) risk of SARS-­ CoV-­ 2 infection.(89) Analysis of 88,747 COVID-­19-­positive individuals revealed that patients with cirrhosis were less likely to test posi- COVID-­19 in Patients tive than patients without cirrhosis (8.5% vs. 11.5%; OR, 0.83; 95% CI, 0.69 to 0.99).(89) As previously With Cirrhosis and Patients described, patients with cirrhosis exhibited increased With Liver Cancer 30-­day mortality and ventilation rates (17.1% and 13.0%, respectively), being 4.1 times more likely to Cirrhosis is a late stage of fibrosis of the liver, caused undergo mechanical ventilation and 3.5 more likely primarily by NAFLD/NASH, ALD, and viral hepati- to die. In another retrospective study, patients with tis. As discussed previously, cirrhosis is associated with cirrhosis and SARS-­CoV-­2 infection had a 30-­day 1144 Hepatology Communications, Vol. 5, No. 7, 2021 MARTINEZ AND FRANCO mortality rate of 34%.(90) This increased mortality rate could be related to the median age of the study Alterations of Lipid population (67 years; interquartile range, 61-­74).(91) This study showed that the severity of lung and liver Metabolism Induced by diseases independently predicted mortality, and that SARS-­CoV-­2 Infection patients with cirrhosis and COVID-­19 were signifi- Lipids as cell membrane and exosome components, cantly more likely to die than those hospitalized with bacterial infections. and energy storage elements, are closely related to HCC is the sixth-­ most common cancer in virus life cycle. Virus infection usually affects cell lipid the world, accounting for nearly 6% of all can- metabolism and circulating lipids. Viruses manipulate cer occurrences.(92) Based on the immune dys- lipid metabolism to benefit their replication, includ- function generated by SARS-­ CoV-­ 2 infection, it ing the expression and activity of essential enzymes can be hypothesized that patients with HCC may in lipid biosynthesis. Lipid metabolism changes could be more susceptible to the effects of COVID-­19 also be attributed to host response to infection. SARS-­ than patients with other cancers.(93) Overall, cancer CoV-­2 is not an exception, and following infection patients with COVID-­19 appear to have a higher generates important changes in lipid metabolism.(98) chance of requiring invasive ventilation or of death In particular, SARS-­CoV-­2 infection induces an over- (39%) compared to patients with COVID-­19 with- all down-­regulation of over 100 serum lipids, com- out cancer (8%).(94) Furthermore, cancer treatment is prising sphingolipids, glycerophospholipids, and fatty associated with a higher risk of COVID-­19 adverse acids.(98) Lipids are not only altered in COVID-­19 events (hazard ratio = 4.1).(95) HCC is underrep- but are also implicated in pathogenesis and disease resented in the available studies of cancer and progression. The observed down-­regulation of lipids COVID-­19, making it difficult to extract a robust after SARS-­CoV-­2 infection is linked to liver injury, conclusion regarding the impact of COVID-­ 19 which is supported by changes in bilirubin and bile on patients with HCC. Nevertheless, the data acids. Many of the observed lipid and lipoproteins obtained from patients with cirrhosis suggests that alterations in COVID-­19 are associated with hepatic COVID-­19 likely takes a high toll on patients with functions.(99,100) Plasma lipidomic analysis was inves- HCC. One important aspect regarding patients tigated during the course of COVID-­19.(101) Most with HCC is their management during the current of the significantly changed lipids were up-­regulated pandemic. It is expected that a higher proportion of levels of sphingomyelins and monosialodihexosyl patients will suffer advanced HCC as a consequence gangliosides, and reduced amounts of diacylglycer- of interruptions of surveillance programs among ols. Increased levels of monosialodihexosyl ganglio- patients with cirrhosis and high-­risk patients.(93) sides positively correlated with disease severity. Again, Concerns have been raised that patients with liver inflammation and infection could be involved in dis- transplants might have an increased risk of adverse rupting circulating normal lipid profiles. A cytokine outcomes after SARS-­CoV-­2 infection. However, in storm can induce the release of unsaturated fatty acids an international cohort of 151 adult transplant recip- as a defense mechanism. Pro-­inflammatory lipids and ients with COVID-­19, liver transplantation was not lipid mediators could modulate the immune response independently associated with death.(12) On the other during COVID-­19 disease.(98) hand, another study found that liver injury during COVID-­19 is also characterized by a decrease in COVID-­ 19 in liver-­transplantation recipients was serum total cholesterol. Individuals with inflammatory significantly associated with mortality (OR, 6.91; diseases, including sepsis and lower respiratory tract 95% CI, 1.68 to 28.48).(96) Importantly, reduction infections, displayed significant decreases in high-­ of immunosuppression during COVID-­ 19 in these density lipoprotein (HDL) cholesterol and increases liver-­ transplantation recipients did not increase the serum triglyceride levels.(102,103) Similarly, patients risk for mortality or graft failure.(96) Unfortunately, with COVID-­ 19 showed hypolipidemia in associ- in some countries, the COVID-­ 19 pandemic has ation with disease progression and severity.(104,105) reduced (from 25% to 80%) organ donation and liver Compared with the healthy controls, patients with transplantations.(97) COVID-­ 19 had decreased concentrations of serum 1145 MARTINEZ AND FRANCO Hepatology Communications, July 2021 total cholesterol, HDL-­ cholesterol, and low-­ density duration of hospitalization.(115,116) Lymphopenia lipoprotein cholesterol. Decreased serum HDL cho- induced by SARS-­CoV-­2 or by the use of immuno- lesterol was associated with the severity of COVID-­19 suppressive therapies (e.g., corticosteroids) may con- infection.(104,105) The molecular mechanism explain- stitute a risk for patients with active or past HBV ing the functional role of lipids during SARS-­CoV-­2 infection. A prospective cohort study reported a low infection is still unknown. Previous work described risk of HBV reactivation in patients with severe HLD cholesterol as an essential part in host defense COVID-­19 and resolved HBV infection who were and anti-­ inflammatory responses.(98,106) Notably, undergoing immunosuppressive therapy.(117) However, HDL cholesterol has been proposed as a predictive the authors still suggested that a short course of anti- marker of an increased risk of infection-­related hos- viral prophylaxis may be a safe option. pitalizations.(107,108) An interesting finding was that Viral hepatitis is an example of how the effects patients on statins had a better COVID-­19 course.(109) of the SARS-­ CoV-­ 2 pandemic extend beyond the It could be hypothesized that reduction in membrane-­ direct morbidity and mortality associated with expo- associated cholesterol may affect the interaction of sure and infection. Disruptions to hepatitis program- ACE2 and virus spike protein. Lipid-­lowering thera- ming across the continuum of care have already been pies such as statins have been suggested as a possible documented. The SARS-­CoV-­2 pandemic may have therapeutic approach to reduce the clinical complica- profound and unexpected short-­term and long-­term tions of COVID-­19.(110) effects on mortality from liver disease, through the limitation of access to health care services for HCV treatment. Mathematical models estimate that a 1-­year Impact of COVID-­19 on delay of HCV treatment administration will yield an excess mortality of 44,800 for HCC and 72,300 for Viral Hepatitis liver-­related deaths.(118) These models emphasize the necessity of mitigating the impact of COVID-­19 on HBV and hepatitis C virus (HCV) cause chronic viral hepatitis programing and treatment. hepatic infection and disease, and constitute two of the main sources of liver disease, infecting 300 million and 70 million people worldwide, respectively.(111,112) HBV and HCV, respectively, account for nearly 12% Conclusions and 11% of the underlying causes of CLD. It remains Liver injury and CLD are associated with unclear whether HBV and/or HCV per se can impact COVID-­19 severity and mortality, such that deter- susceptibility to SARS-­CoV-­2.(113) It appears that mination of indicators of liver disease—­ including HBV and HCV show low prevalence rates among liver enzymes, liver fibrosis, and liver steatosis—­could patients hospitalized with COVID-­19(11,17); however, be prioritized as prognostic markers of COVID-­19 few studies have analyzed viral hepatitis incidence. severity. The immune inflammatory status of individ- Similarly, the scarcity of available data makes it dif- uals with liver disease is particularly consequential in ficult to estimate the influence of HBV and/or HCV other infectious diseases. This is particularly relevant infection on COVID-­19 severity. Liver fibrosis and considering the current co-­occurring worldwide pan- liver injury status are presently the best prognostic demics of NAFLD/NASH and COVID-­19. Special factors for SARS-­ CoV-­ 2-­ infected individuals with attention must be also paid to the screening and treat- viral hepatitis. ment of individuals with CLD (HCC, viral hepatitis, A Chinese study detected HBV infection in 12.2% NAFLD/NASH, and ALD). Patients with CLD, par- (15 of 123) of patients with COVID-­19 and found ticularly those with cirrhosis or advanced liver injury, that HBV infection was associated with a more severe should be prioritized for SARS-­CoV-­2 vaccination. course and higher mortality rate (13.3% vs. 2.8%).(114) Follow-­ up of vaccinated patients with CLD may However, two other retrospective studies from China reveal further clues regarding the impaired immune (where there is a high incidence of HBV infec- response of these individuals. 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