Skip to main content

COVID-19 and liver diseases

Abstract

Coronavirus causes an outbreak of viral pneumonia that spread throughout the world. Liver injury is becoming more widely recognized as a component of the clinical picture of COVID-19 infection. Hepatitis with serum ALT elevation has been reported in up to half of patients. Patients with CLD were at a higher risk of decompensation with liver failure, hospitalization, and mortality. The percentage of acute liver injury (ALI) varied from 5 to 28%. COVID-19 hinders HCV elimination by 2030. It is recommended to continue treatment of chronic HCV and chronic HBV if already receiving treatment. Consider using antiviral therapy to prevent viral flare-ups in patients with occult or resolved HBV and COVID-19 who are receiving immunosuppressive agents. Patients with AIH do not have an increased risk of adverse outcomes even in high-risk areas. There is an association between MAFLD and disease progression. Patients with any type of cancer are at a higher risk of infection and are more likely to develop more severe clinical outcomes. Most societies advise against immunosuppressant modifications in patients with mild COVID-19, whereas in rare cases such as severe lymphopenia, worsening pneumonia, or bacterial or fungal superinfection, reduction or discontinuation of antiproliferative agents and lymphocyte-depleting therapies has been suggested.

Introduction

Coronaviruses are enveloped single-stranded RNA diverse group of viruses infecting animals and can cause mild to severe respiratory infections in humans. A novel coronavirus designated as SARS-CoV-2 emerged in the city of Wuhan, China, causing an outbreak of viral pneumonia and spread all over the world [1, 2], named “COVID-19” [3]. The virus causes a total of approximately 437,333,859 confirmed cases and nearly 5,960,972 confirmed deaths updated on March 3, 2022 [4]. Recent reports showed that about 2–11% of patients with COVID-19 had underlying chronic liver disease and hepatic dysfunction has been seen in 14–53% of patients with COVID-19 [5].

Pathogenesis

The pathophysiological and immunological mechanisms of liver injury in patients with COVID-19 are poorly understood.

Hepatotropism

Angiotensin-converting enzyme 2 (ACE2), the susceptible receptor for SARS-CoV-2 virus entry into the cells, is highly expressed in the vascular endothelium of small and large arteries and veins but not in the sinusoidal endothelium, Kupffer cells, or T and B lymphocytes [5]. Chai et al. in 2020 [6] reported more abundance of ACE2 receptor in cholangiocytes (59.7%) than hepatocytes (2.6%). While ACE2 in conjunction with transmembrane serine protease2 (TMPRSS2) is considered the predominant receptor for SARS-CoV-2 entry into cells, L-SIGN (CD209L) and CD147 may function as possible alternative cell receptors for SARS-CoV-2 [7].

Mechanisms of liver injury (Fig. 1)

Direct cytopathic effect

Direct hepatic infection was evidenced by showing SARS-CoV-2 particles in the cytoplasm of hepatocytes of COVID-19 patients [7, 8]. Recent evidence suggests upregulated ACE2 expression in hepatocytes, triggered by inflammatory signals, such as type I interferon or IL-6 during SARS-CoV-2 infection [9, 10]. SARS-CoV-2 directly contributed to cytopathy by conspicuous mitochondria swelling, endoplasmic reticulum dilatation, decreased glycogen granule, and impaired cell membranes in the hepatocytes [11].

Fig. 1
figure 1

Cited in the Mediterranean Journal of Hematology and Infectious Diseases, Mechanism of SARS-CoV-2 Invasion into the Liver and Hepatic Injury in Patients with COVID-19 published on January 1, 2022

Abnormal immune response

Crosstalk between hyperinflammation and dysregulated immune responses is characterized into three phases: the immune activation stage, secondary hemophagocytic lymphohistiocytosis (sHLH) stage, and immune suppression stage [7]. In the immune activation stage, replication of SARS-CoV-2 causes cell pyroptosis and releases of proinflammatory cytokines [12]. These inflammatory signals subsequently activate T and B cells and recruit macrophages and monocytes [13]. sHLH is a hyperinflammatory syndrome characterized by activated T cells and NK cells producing large amounts of cytokines to activate monocyte-derived macrophages [14, 15]. Activated macrophages also produce additional IL-6 and other inflammatory factors, resulting in cytokine release syndrome or cytokine storm that causes severe immune damage to the lungs as well as the liver [16, 17]. The immune suppression stage is characterized by a drastic reduction in peripheral lymphocytes [18, 19], T cell apoptosis, and exhaustion [7, 15].

Cytokine release syndrome (CRS)

IL-6 is a potential risk factor in patients with COVID-19 developing severe liver injury [20, 21]. IL-6 signals through two distinct pathways referred to as classic cis signaling or trans-signaling. and results in a systemic cytokine storm [22]. The trans-signaling results in CRS involving the secretion of various proinflammatory cytokines and chemokines, including additional IL-6. Thus, the feedback loop of the IL-6 amplifier (IL-6 Amp) might act as a switch to activate “cytokine storms” [15].

Abnormal coagulation

Abnormal coagulation has been significantly associated with poor prognosis for patients with severe COVID-19 with hepatic dysfunction. Both neutrophils and monocytes are playing a significant role in amplifying blood clotting in response to proinflammatory stimuli [23, 24].

Hepatic ischemia/hypoxia-reperfusion injury

Hepatic ischemia/hypoxia reperfusion injury involves a biphasic process of ischemia-induced cell injury and reperfusion-induced inflammatory response. Both ischemia and reperfusion injury lead to hepatic apoptosis and elevated liver enzymes [25, 26].

Drug-induced liver injury

The mechanisms of liver injury are variable and include dysregulated immune responses with markedly elevated plasma levels of proinflammatory cytokines as IL-6 and TNF-α [27,28,29], direct cytopathic damage [30], the use of antibiotics, antivirals, other traditional Chinese medicines, and secondary bacterial infection [31].

There are liver unique concerns in the pharmacologic management of COVID-19. Remdesivir in controlled trials demonstrated no significant impact on liver function tests as compared with placebo contrary to preclinical investigations [32]. The same conclusion came by Wang et al [33]; however, patients with advanced liver disease or with severe baseline derangements in liver biochemistry should be cautious. Tocilizumab use causes mild serum aminotransferase elevations that are self-limited and asymptomatic [34]. However, progressive jaundice requiring liver transplantation (LT) has been reported. HBV reactivation had been reported, and HBV serology should be part of the pre-treatment workup [35]. In patients with IBD, the use of corticosteroids has been associated with ICU admission, ventilator requirement, and/or death [36]. Patients treated with glucocorticoids for rheumatologic conditions have an increased rate of hospitalization following COVID-19 infection [37]. Currently, there is no need to reduce immunosuppression in patients with autoimmune hepatitis or LT recipients including the use of corticoids if required [38]. The use of anticoagulant agents demonstrated no excess of bleeding events in patients with cirrhosis and portal vein thrombosis [39]. Anticoagulation may have antifibrotic properties [40] and confer a survival advantage in patients with cirrhosis [41]. Italian multicenter study confirms this result [42].

Liver histopathology in COVID-19

In a study done by Lagana et al. [43], Macrovesicular steatosis was the most common finding, involving 30 patients (75%). Mild lobular necroinflammation and portal inflammation were present in 20 cases each (50%). Vascular pathology, including sinusoidal microthrombi, was infrequent, seen in six cases (15%). PCR of liver tissue was positive in 11 of 20 patients tested (55%).

COVID-19 and chronic liver disease (CLD)

Patients with CLD per se do not appear to be over-represented in cohorts of patients with COVID-19 where they make up less than 1% of reported cases [44]. Liver injury associated with SARS-CoV-2 infection is usually mild and self-limiting. Severe liver injuries correlate with a more severe clinical course reflected by higher rates of intensive care unit admission, mechanical ventilation, renal replacement therapy, and mortality [21, 45]. There is a higher risk of decompensation and failure with more reduced liver function reserve. Both hepatocellular and ductular injuries had been reported [46]. The main presentation was diarrhea or nausea/vomiting which is more likely to have severe COVID-19 [47].

Liver function test abnormalities: LFT abnormalities ranged from 37 to 69% [48,49,50,51]. The percentage of LFT abnormalities reached 80.5% in patients who died due to SARS-CoV-2 infection [52]. The percentage of ALT elevation ranged from 18.2 to 31.6%, and the percentage of AST elevation ranged from 14.8 to 35.4%. Higher percentages of total bilirubin elevation (5.1 to 11.5%) were reported in several previous studies [48, 49, 53]. The synthetic function of the liver had been affected; serum albumin was less than the normal range and prolonged prothrombin time [28]. Elevated liver enzymes, particularly AST and ALT level elevations greater than five times the upper limit of normal, are associated with an increased risk of death [21, 54, 55]. In a multi-center, observational cohort study across 21 institutions in the United States (US) of adult patients with CLD and laboratory-confirmed diagnosis of COVID-19, the overall all-cause mortality was 14.0% with 61.7% had severe COVID-19. In one of the largest studies of outcomes of SARS-CoV-2 infection in patients with CLDs with and without cirrhosis, SARS-CoV-2 infection in patients with cirrhosis was associated with 2.38 times mortality hazard, and the presence of cirrhosis among patients with CLD infected with SARS-CoV-2 was associated with 3.31 times mortality hazard [56]. In another study, collected by two international registries from the UK, 745 patients were reported from 29 countries including 386 with cirrhosis and 359 without. Mortality was 32% in patients with cirrhosis compared with 8% in those without. There was a significant increase in mortality in cirrhotic patients with CTP-B and CTP-C compared to patients without liver disease [57]. Mortality in cirrhosis increased according to Child-Turcotte-Pugh class: CTP-A 19%, CTP-B 35%, and CTP-C 51%. The main cause of death was respiratory failure (71%) in addition to advanced age, diabetes, hypertension, chronic and current smoker, and alcoholic liver disease. Hispanic ethnicity and decompensated cirrhosis were independently associated with risk for severe COVID19 [47]. The mortality rate in cirrhosis is comparable to the rates reported in smaller studies in Northern Italy (34%) [42] and North America (39%) [58].

The impact of COVID-19 extends beyond the direct morbidity and mortality associated with exposure and infection. The emergence of COVID-19 occurs at a critical moment in the context of hepatitis elimination with only 10 years remaining to reach the Global Health Sector Strategy targets by 2030 [59]. Although the full impact of delaying hepatitis elimination programs is yet to be seen. Blach et al. [60] used mathematical models to evaluate the possible impact on hepatitis disease burden and mortality resulting from programmatic delays. They reported that a 1-year delay in HCV programs could cause excess HCV morbidity and mortality. A 1-year hiatus in HCV elimination programs could result in 72,300 excess liver-related deaths and 44,800 excess liver cancers globally over the next 10 years. Most excess deaths would be in the lower-middle-income and high-income groups.

In addition to standard of care, it is recommended to continue treatment of chronic HCV and chronic HBV if already receiving treatment, use telemedicine/local laboratory testing for follow-up visits in patients receiving antiviral therapy, and send follow-up prescriptions by mail. Treatment for HCV and HBV should be initiated according to the guidelines [61, 62]; avoid interferon α, in patients with COVID-19; and postpone the initiation of treatment for HCV and HBV. Antiviral initiation should be made on a case-by-case basis if there is flare-up. Patients with occult HBV and COVID-19 receiving corticosteroids, tocilizumab, or other immunosuppressive agents should use antiviral therapy to prevent a viral flare-up. Consider early admission for all patients with cirrhosis who become infected with COVID-19 and manage these patients in the non-COVID-19 ward. Patients with new or worsening hepatic decompensation or ACLF should be prioritized for SARS-CoV-2 testing even in the absence of respiratory symptoms [63]. All cirrhotic patients should receive vaccination for Streptococcus pneumonia and influenza [38].

COVID-19 and acute liver failure

The percentage of acute liver injury (ALI) varied from 5 to 28%. This wide range of differences in the percentage of ALI might be due to differences in the percentage of patients with severe COVID-19 or differences in the percentage of patients with underlying chronic liver diseases [48, 50]. Ji et al. [46] reported studying 140 consecutive COVID-19 patients with pre-existing CLD. They had liver cirrhosis, NAFLD, chronic HBV, and chronic HCV infection. Only one patient with CLD had ACLF. On the day of death, IL-6 and serum ferritin levels increased rapidly reaching the highest levels favoring immune-mediated attacks. Hypoxic hepatitis was another possible cause that was reported in 2.5% of ICU patients [64]. Another study reported acute hepatic decompensation occurred in 179 (46%) of patients with cirrhosis of which 21% had no respiratory symptoms; 89 (50%) of those with hepatic decompensation had ACLF [65].

Autoimmune liver disease (AIH)

Several reviews endorse that even in fairly endemic areas, sufferers with AIH are not displaying extended hazards of detrimental consequences. In a study from Italy, 26% of AIH patients reported COVID-19 that did not require hospitalization. Only 4 confirmed cases, 3 of which were hospitalized and 1 old-aged patient with comorbidities, died [66]. No difference between AIH and non-AIH CLD regarding hospitalization, ICU admission, and/or death in a recent international study involving 70 patients with AIH [67]. No justification for the hypothesis that immunosuppressed patients are more vulnerable to SARS-CoV-2 infection compared to the general population [68]. This supports the idea that immunosuppressive treatment should not be stopped in patients with AIH, but preventive measures remain crucial. The EASL and AASLD recommend the continuation of immunosuppressive regimens without any dose modification in patients without COVID-19. To avoid exposure to high doses of corticosteroids, it is recommended to use budesonide as a first-line agent to achieve remission in non-cirrhotic patients with exacerbation of AIH [38]. This is contrary to patients with AIH who become infected with COVID-19. According to the EASL recommendations, switching to dexamethasone or adding it to the basic corticosteroid should be an option only for patients with severe disease. According to the AASLD, corticosteroids as well as azathioprine or mycophenolate mofetil should be reduced to the lowest possible doses, particularly if the course of COVID-19 is severe [69]. Vaccination for Streptococcus pneumonia and influenza is essential for all patients [38].

Non-alcoholic fatty liver disease (NAFLD)

Obesity represents a great hazard for severe COVID-19 [70]. Hu and his colleagues [71] reported in a study of 58 patients with overweight/obesity and/or abnormal liver function with COVID-19 that obesity is a predisposing factor for prolonged hospitalization in patients with COVID-19 infection. Adipose tissue may serve both as a viral reservoir and also as an immunologic hub for the inflammatory response [72]. Recently, Meijnikman et al. [73] reported that ACE2 is upregulated in the subcutaneous and visceral adipose tissues and liver tissue of individuals with NAFLD; fostering viral penetration into cells identified an additional mechanism that contributes to increased susceptibility to severe COVID-19 in individuals with NAFLD. There is an association between NAFLD and disease progression in a retrospective cohort of 202 patients with COVID [74]. This additional risk has been observed even in younger patients with NAFLD [75] and in the absence of type 2 diabetes mellitus [76]. Within patients with NAFLD, non-invasive fibrosis scores correlate with a better probability of developing severe COVID-19 illness regardless of metabolic comorbidities [77].

Hepatocellular carcinoma (HCC)

Zhang et al. [78] reported that patients with malignancy had poorer outcomes when compared to the general population. They studied 28 cancer patients; 2 of them had HCC. Age of the patients, associated comorbidities, and underlying cirrhosis were risk factors. Anemia and hypoproteinemia affect nutritional status, which compromises their immunity, making them more vulnerable to severe infection. Co-infection with COVID-19 with cancer increased vulnerability to severe disease and increased chance of mortality, as well as ICU admission. Iavarone et al. [79] recommended the use of telemedicine to decrease the risk of the spread of COVID-19. Indications of liver transplantation (LT) and locoregional therapy (LRT) in HCC patients have not changed. It is better to reserve LT for highly progressive cases because of the shortage of ICU beds and to use LRT as a salvage procedure to decrease the risk of HCC progression during the waiting period. Boettler et al. [80] agreed that stereotactic body radiation therapy (SBRT) is another alternative ablative option that can be offered to patients eligible for TACE, especially those with lesions near vascular structures, whom their procedures have been canceled because of COVID-19 [81]. Continuing surveillance imaging of HCC patients with an acceptable delay of a maximum of 2 months is recommended [69]. Local ablative therapies should not be delayed for eligible patients. Post-embolization syndrome can be treated by corticosteroids to minimize hospital stay even in patients proven to have COVID-19 except if there is any other contraindication. TACE is better than SBRT as it can be separated by intervals ranging from 4 to 12 weeks, according to the response and characteristics of the lesion. For patients with resectable HCC whose surgical procedures have been canceled, TACE can be used as a bridge to definitive treatment [82]. Sorafenib is recommended to be continued without any change in its dose [83]. Nivolumab might be temporarily suspended to avoid exposure to COVID-19 at the infusion center [84]. However, Andersen et al. [85] in a retrospective study reported that chronic use of immunosuppressive drugs was neither associated with worse nor better clinical outcomes among adults hospitalized with COVID-19.

Liver transplantation (LT)

In one of the largest multicenter network studies on LT and COVID-19, Mansoor et al. [86] found LT patients with COVID-19 to have a significantly higher risk of hospitalization but not mortality, thrombosis, or ICU requirement compared to patients without LT and COVID-19. LT reduced even in areas with a low prevalence of COVID-19 [87]. Deceased organs infected with SARS-CoV-2 even mild or asymptomatic infections are no longer used [88]. However, few recommend the usage of COVID-19-positive liver donors in very selected cases [89]. Donor testing should be proofed preferentially by bronchoalveolar lavage in deceased donors or by nasopharyngeal swab in living donors [88]. Liver grafts recovered from COVID-19-positive deceased donors 3–4 weeks after symptom resolution and 2 negative swabs 1 day apart are considered safe for transplantation, otherwise, deferred [90]. It is mandatory to test living donors at least once within 1–3 days before transplantation. It is recommended to do self or hospital-based quarantine for 2–3 weeks with preventive transmission counseling. COVID-19-positive or high-risk living donors should postpone donation until at least 3–4 weeks after symptom resolution and until 2 negative PCR tests have been observed [90]. The recipient should undergo a PCR test within 1 day of transplantation. Recipients with clinical suspicion or active SARS-CoV-2 infection should have transplantation deferred until 4 weeks after symptom resolution and after 2 negative tests at least 1 day apart [88]. Urgent transplantations would proceed first with temporary cessation of elective living donor and non-urgent deceased donor LT during the pandemic [88]. According to the MELD score, risk of dropping out particularly from liver cancer progression, and fulminant hepatic failure, elective cases could be phased later [90].

No great difference in mortality was found in LT patients with COVID-19 whether mild or severe in comparison with the general population. The incidence in a large Italian LT survey was 1.25%, and most patients (75%) had a mild disease [91]. Conversely, a worse outcome was recorded in New York City [92].

In a systematic review, liver transplant patients with confirmed COVID-19 from 15 studies, were more likely to present with concurrent diarrhea [93]. In a nationwide Spanish study, chronic use of immunosuppressive agents did not increase mortality rates; however, at doses higher than 1 mg/day mycophenolate increases the risk of severe COVID-19 among hospitalized LT patients [94]. Mycophenolate produces a cytostatic effect on activated lymphocytes [95]. Mycophenolate and SARS-CoV-2 exert a synergic and deleterious effect on depleting peripheral lymphocytes [96]. Calcineurin inhibitors not only have antiviral effects but also can ameliorate the cytokine storm [97]. It is better to continue the medication even after the COVID-19 diagnosis. However, consider dose reduction or temporary conversion to calcineurin inhibitors or everolimus until complete recovery from COVID-19 in patients receiving mycophenolate [94].

In patients with mild COVID-19, no need to make immunosuppressant modifications. In case of severe lymphopenia, worsening pneumonia, or bacterial or fungal superinfection, reduction or discontinuation of antiproliferative agents and lymphocyte-depleting therapies has been suggested [87].

COVID-19 vaccination in patients with liver diseases and liver transplant recipients

The already licensed COVID-19 vaccines are immunogenic, and the short-term safety record appears excellent in healthy individuals aged 16 years. Based on current knowledge, there is no evidence to contradict the safety and immunogenicity of currently approved vaccines in patients with CLD and hepatobiliary cancer or in immunocompromised patients after liver transplantation. Given the high risk of serious health consequences of SARSCoV-2 infection in such patients, the potential benefits of the vaccine are likely to outweigh the risks associated with vaccination. Therefore, SARS-CoV-2 vaccination is recommended in patients with CLD, hepatobiliary cancer, and candidates for liver transplantation. Optimal timing of vaccination in transplanted recipients is still unestablished but vaccination 3–6 months after transplantation is advisable [98]. Recently, John and his colleagues reported that two doses of a COVID-19 mRNA vaccine are associated with a decrease in COVID-19 infection and death in liver transplant recipients [99].

Availability of data and materials

NA.

Abbreviations

ACE2:

Angiotensin-converting enzyme 2

sHLH:

Secondary hemophagocytic lymphohistiocytosis

NK cells:

Natural killer cells

IL-6:

Interleukin-6

CRS:

Cytokine release syndrome

sIL-6R:

Soluble IL-6Receptor

IL-6 Amp:

IL-6 amplifier

NETs:

Neutrophil extracellular traps

LFT:

Liver function tests

ALI:

Acute liver injury

CLD:

Chronic liver disease

ACLF:

Acute on top of chronic liver disease

NAFLD:

Non-alcoholic fatty liver disease

CTP:

Child-Turcotte-Pugh class

HCC:

Hepatocellular carcinoma

ALD:

Alcohol-related liver disease

AIH:

Autoimmune hepatitis

AASLD:

American Association of Study of Liver Disease

LRT:

Locoregional therapy

SBRT:

Stereotactic body radiation therapy

TACE:

Transarterial chemoembolization

References

  1. Wu JT, Leung K, Leung GM (2020) Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study. Lancet 395:689–697

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. Hui DS, Azhar EI, Madani TA, Ntoumi F, Kock R, Dar O, Ippolito G, Mchugh TD, Memish ZA, Drosten C, Zumla A (2020) The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health—the latest 2019 novel coronavirus outbreak in Wuhan, China. Int J Infect Dis 91:264–266

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  3. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (2020) The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV2. Nat Micro biol 5:536–544

    Article  CAS  Google Scholar 

  4. WHO Coronavirus Disease (COVID-19) Dashboard.

  5. Jothimani D, Venugopal R, Abedin MF, Kaliamoorthy I, Rela M (2020) COVID-19 and the liver. J Hepatol 73:1231–1124

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. Chai X, Hu L, Zhang Y, Han W, Lu Z, Ke A, Zhou J, Shi G, Fang N, Fan J, Cai J, Fan J, Lan F (2020) Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. Bio-Rxiv. https://doi.org/10.1101/2020.02.03.931766

  7. Li D, Ding X, Xie M, Tian D, Xia L (2021) COVID-19-associated liver injury: from bedside to bench. J Gastroenterol 56:218–230

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. Wang Y, Liu S, Liu H et al (2020) SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. J Hepatol 73:807–816

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. Han L, Wei X, Liu C et al (2020) Single-cell atlas of a non-human primate reveals new pathogenic mechanisms of COVID-19. bioRxiv. https://doi.org/10.1101/2020.04.10.022103

  10. Guan GW, Gao L, Wang JW et al (2020) Exploring the mechanism of liver enzyme abnormalities in patients with novel coronavirus infected pneumonia. Zhonghua Gan Zang Bing Za Zhi 28:100–106

    PubMed  CAS  Google Scholar 

  11. Wang Y, Lu F, Zhao J (2020) Reply to: Correspondence relating to “SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19.”. J Hepatol 73:996–998

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. Merad M, Martin JC (2020) Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol 20:355–362

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. Feng G, Zheng KI, Yan QQ et al (2020) COVID-19 and liver dysfunction: current insights and emergent therapeutic strategies. J Clin Transl Hepatol 8:18–24

    PubMed  PubMed Central  Article  Google Scholar 

  14. Rasouli J, Ciric B, Imitola J et al (2015) Expression of GM-CSF in T cells is increased in multiple sclerosis and suppressed by IFNbeta therapy. J Immunol 194:5085–5093

    PubMed  Article  CAS  Google Scholar 

  15. Moore JB, June CH (2020) Cytokine release syndrome in severe COVID-19. Science 368:473–474

    PubMed  Article  CAS  Google Scholar 

  16. Crayne CB, Albeituni S, Nichols KE, Cron RQ (2019) The immunology of macrophage activation syndrome. Front Immunol 10:119

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. Mehta P, McAuley DF, Brown M et al (2020) COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395:1033–1034

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. Chen G, Wu D, Guo W et al (2020) Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 130:2620–2629

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. Li H, Liu L, Zhang D et al (2020) SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet 395:1517–1520

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. Zhan K, Liao S, Li J et al (2020) Risk factors in patients with COVID19 developing severe liver injury during hospitalisation. Gut. https://doi.org/10.1136/gutjnl-2020-321913

  21. Phipps MM, Barraza LH, LaSota ED et al (2020) Acute liver injury in COVID-19: prevalence and association with clinical outcomes in a large US cohort. Hepatology 72:807–817

    PubMed  Article  CAS  Google Scholar 

  22. Hunter CA, Jones SA (2015) IL-6 as a keystone cytokine in health and disease. Nat Immunol 16:448–457

    PubMed  Article  CAS  Google Scholar 

  23. von Bruhl ML, Stark K, Steinhart A et al (2012) Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 209:819–835

    Article  CAS  Google Scholar 

  24. Barnes BJ, Adrover JM, Baxter-Stoltzfus A et al (2020) Targeting potential drivers of COVID-19: neutrophil extracellular traps. J Exp Med 217:e20200652

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. Peralta C, Jimenez-Castro MB, Gracia-Sancho J (2013) Hepatic ischemia and reperfusion injury: effects on the liver sinusoidal milieu. J Hepatol 59:1094–1106

    PubMed  Article  Google Scholar 

  26. Zhai Y, Petrowsky H, Hong JC, Busuttil RW, Kupiec-Weglinski JW (2013) Ischaemia-reperfusion injury in liver transplantation–from bench to bedside. Nat Rev Gastroenterol Hepatol 10:79–89

    PubMed  Article  CAS  Google Scholar 

  27. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B (2020) Clinical course and risk factors for mortality of adult in patients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395:1054–1062

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z et al (2020) JAMA 23(11):1061–1069

    Article  CAS  Google Scholar 

  29. Cao X (2020) COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol 20:269–270

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. Chai X, Hu L, Zhang Y, Han W, Lu Z, Ke A, Zhou J, Shi G, Fang N, Fan J, Cai J, Fan J, Lan F et al (2020) BioRxiv. https://doi.org/10.1101/2020.02.03.931766

  31. Zhang C, Shi L, Wang FS (2020) Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol 5:428–430

    PubMed  PubMed Central  Article  Google Scholar 

  32. Remdesivir. (2006) Drugs and Lactation Database (LactMed). National Library of Medicine (US), Bethesda

    Google Scholar 

  33. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, Hu Y (2020) Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 395(10236):1569–1578

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. Maini RN, Taylor PC, Szechinski J, Pavelka K, Bröll J, Balint G, Emery P, Raemen F, Petersen J, Smolen J, Thomson D, Kishimoto T (2006) Double blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 54:2817–2829

    PubMed  Article  CAS  Google Scholar 

  35. Chen LF, Mo YQ, Jing J, Ma JD, Zheng DH, Dai L (2017) Short-course tocilizumab increases risk of hepatitis B virus reactivation in patients with rheumatoid arthritis: a prospective clinical observation. Int J Rheum Dis 20:859–869

    PubMed  Article  CAS  Google Scholar 

  36. Brenner EJ, Ungaro RC, Gearry RB, Kaplan GG, Kissous-Hunt M, Lewis JD, Ng SC, Rahier J, Reinisch W, Ruemmele FM, Steinwurz F, Underwood FE, Zhang X, Colombel J, Kappelman MD (2020) Corticosteroids, but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: results from an international registry. Gastroenterology 159:481–491.59

    PubMed  Article  CAS  Google Scholar 

  37. Gianfrancesco M, Hyrich KL, Al-Adely S, Carmona L, Danila MI, Gossec L, Izadi Z, Jacobsohn L, Katz P, Lawson-Tovey S, Mateus EF (2020) Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis 79(7):859–866

    PubMed  Article  CAS  Google Scholar 

  38. Boettler T, Marjot T, Newsome PN, Mondelli MU, Maticic M, Cordero E, Jalan R, Moreau R, Cornberg M, Berg T (2020) Impact of COVID-19 on the care of patients with liver disease: EASL-ESCMID position paper after 6 months of the pandemic. JHEP Rep 2:1-10. 100169

  39. Loffredo L, Pastori D, Farcomeni A, Violi F (2017) Effects of anticoagulants in patients with cirrhosis and portal vein thrombosis: a systematic review and meta-analysis. Gastroenterology 153:480–487

    PubMed  Article  CAS  Google Scholar 

  40. Turco L, de Raucourt E, Valla DC, Villa E (2019) Anticoagulation in the cirrhotic patient. JHEP Rep 1:227–239

    PubMed  PubMed Central  Article  Google Scholar 

  41. Villa E, Cammà C, Marietta M, Luongo M, Critelli R, Colopi S, Tata C, Zecchini R, Gitto S, Petta S, Lei B, Bernabucci V, Vukotic R, De Maria N, Schepis F, Karampatou A, Caporali C, Simoni L, Del Buono M, Zambotto B, Turola E, Fornaciari G, Schianchi S, Ferrari A, Valla D (2012) Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 143:1253–1260

    PubMed  Article  CAS  Google Scholar 

  42. Iavarone M, D’Ambrosio R, Soria A, Triolo M, Pugliese N, Del Poggio P, Perricone G, Massironi S, Spinetti A, Buscarini E, Viganò M (2020) High rates of 30-day mortality in patients with cirrhosis and COVID-19. J Hepatol 73(5):1063–1071

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. Lagana SM, Kudose S, Iuga A, Lee MJ, Fazlollahi L, Remotti HE, Del Portillo A, De Michele S, de Gonzalez A, Saqi A, Khairallah P, Chong AM, Park H, Uhlemann A, Lefkowitch JH, Verna EC (2020) Hepatic pathology in patients dying of COVID-19: a series of 40 cases including clinical, histologic, and virologic data. Mod Pathol 33:2147–2155

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. Williamson E, Walker AJ, Bhaskaran KJ, Bacon S, Bates C, Morton CE, Curtis H, Mehrkar A, Evans D, Inglesby P, Cockburn J, McDonald H, MacKenna B, Tomlinson L, Douglas I, Rentsch C, Mathur R, Wong A, Grieve R, Harrison D, Forbes H, Schultze A, Croker R, Parry J, Hester F, Harper S, Perera R, Evans S, Smeeth L, Goldacre B (2020) Open SAFELY: factors associated with COVID-19 death in 17 million patients. Nature 584:430–436

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. Piano S, Dalbeni A, Vettore E et al (2020) Abnormal liver function tests predict transfer to intensive care unit and death in COVID-19. Liver Int 40(10):2394–2406

    PubMed  Article  CAS  Google Scholar 

  46. Ji D, Zhang D, Yang T, Mu J, Zhao P, Xu J, Li C, Cheng G, Wang Y, Chen Z, Qin E, Lau G (2020) Effect of COVID-19 on patients with compensated chronic liver diseases. Hepatol Int 14:701–710

    PubMed  Article  Google Scholar 

  47. Kim D, Adeniji N, Latt N, Kumar S, Bloom PP, Aby ES, Perumalswami P, Roytman M, Li M, Vogel AS, Catana AM (2021) Predictors of outcomes of COVID-19 in patients with chronic liver disease: US multi-center study. Clin Gastroenterol Hepatol 19(7):1469–1479

    PubMed  Article  CAS  Google Scholar 

  48. Cai Q, Huang D, Yu H et al (2020) COVID-19: abnormal liver function tests. J Hepatol 73:566–574

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. Fan Z, Chen L, Li J et al (2020) Clinical features of COVID-19-related liver functional abnormality. Clin Gastroenterol Hepatol 18:1561–1566

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. Bloom PP, Meyerowitz EA, Reinus Z et al (2021) Liver biochemistries in hospitalized patients with COVID-19. Hepatology 73:890–900

    PubMed  Article  CAS  Google Scholar 

  51. Li L, Li S, Xu M, Yu P, Zheng S, Duan Z, Liu J, Chen Y, Li J (2020) Risk factors related to hepatic injury in patients with corona virus disease 2019. MedRxiv. https://doi.org/10.1101/2020.02.28.20028514

  52. Zhang B, Zhou X, Qiu Y, Song Y, Feng F, Feng J, Song Q, Jia Q, Wang J (2020) Clinical characteristics of 82 cases of death from COVID-19. PLoS One 15(7):e0235458

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. Xie H, Zhao J, Lian N et al (2020) Clinical characteristics of non-ICU hospitalized patients with coronavirus disease 2019 and liver injury: a retrospective study. Liver Int 40:1321–1326

    PubMed  Article  CAS  Google Scholar 

  54. Tapper EB, Sengupta N, Bonder A (2015) The incidence and outcomes of ischemic hepatitis: a systematic review with meta-analysis. Am J Med 128:1314–1321

    PubMed  Article  Google Scholar 

  55. Lei F, Liu Y, Zhou F, et al (2020) Longitudinal association between markers of liver injury and mortality in COVID-19 in China. Hepatology 72(2):389–98

  56. Ge J, Pletcher MJ, Lai JC (2021) N3C Consortium. Outcomes of SARS-CoV-2 infection in patients with chronic liver disease and cirrhosis: a national COVID cohort collaborative study. Gastroenterology 161:1487–1501

    PubMed  Article  CAS  Google Scholar 

  57. Marjot T, Moon AM, Cook JA, Abd-Elsalam S, Aloman C, Armstrong MJ, Pose E, Brenner EJ, Cargill T, Catana MA, Dhanasekaran R (2021) Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study. J Hepatol 74(3):567–577

    PubMed  Article  CAS  Google Scholar 

  58. Bajaj JS, Garcia-Tsao G, Biggins SW, Kamath PS, Wong F, McGeorge S, Shaw J, Pearson M, Chew M, Fagan A, de la Rosa RR (2021) Comparison of mortality risk in patients with cirrhosis and COVID-19 compared with patients with cirrhosis alone and COVID-19 alone: multicentre matched cohort. Gut 70(3):531–536

    PubMed  Article  CAS  Google Scholar 

  59. WHO (2016) Global Health Sector Strategy on Viral Hepatitis 2016–2021: towards ending viral hepatitis. World Health Organization, Geneva

    Google Scholar 

  60. Blach S, Kondili L, Aghemo A, Cai Z, Dugan E, Estes C, Gamkrelidze I, Ma S, Pawlotsky J, Razavi-Shearer D, Razavi H, Waked I, Zeuzem S, Craxi A (2021) Impact of COVID-19 on global HCV elimination efforts. J Hepatol 74:31–36

    PubMed  Article  CAS  Google Scholar 

  61. Lampertico P, Agarwal K, Berg T, Buti M, Janssen HLA, Papatheodoridis G, Zoulim F (2017) EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 67:370–398

    Article  Google Scholar 

  62. Pawlotsky J-M, Negro F, Aghemo A, Berenguer M, Dalgard O, Dusheiko G, Marra F, Puoti M, Wedemeyer H (2018) EASL recommendations on treatment of hepatitis C 2018. J Hepatol 69:461–511

    Article  Google Scholar 

  63. Moon AM, Webb GJ, Aloman C, Armstrong MJ, Cargill T, Dhanasekaran R, Genescà J, Gill US, James TW, Jones PD, Marshall A (2020) High mortality rates for SARS-CoV-2 infection in patients with pre-existing chronic liver disease and cirrhosis: preliminary results from an international registry. J Hepatol 73(3):705

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. Fu Y, Zhu R, Bai T, Han P, He Q, Jing M, Xiong X, Zhao X, Quan R, Chen C, Zhang Y (2021) Clinical features of COVID-19-infected patients with elevated liver biochemistries: a multicenter, retrospective study. Hepatology 73(4):1509-20

  65. Yadav DK, Singh A, Zhang Q, Bai X, Zhang W, Yadav RK, Singh A, Zhiwei L, Adhikari VP, Liang T (2021) Involvement of liver in COVID-19: systematic review and meta-analysis. Gut 70(4):807–809

    PubMed  Article  Google Scholar 

  66. Di Giorgio A, Nicastro E, Speziani C, Di Giorgio M, Pasulo L, Magro B, Fagiuoli S, D’Antiga L (2020) Health status of patients with autoimmune liver disease during SARS-CoV-2 outbreak in northern Italy. J Hepatol 73:702–705

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. Marjot T, Buescher G, Sebode M et al (2021) Contributing Members and Collaborators of ERN RARE-LIVER/COVID-Hep/ SECURE-Cirrhosis, Moon AM, Webb GJ, Lohse AW. SARSCoV-2 infection in patients with autoimmune hepatitis. J Hepatol 74:1335–1343

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. D’Antiga L (2020) Coronaviruses and immunosuppressed patients: the facts during the third epidemic. Liver Transpl 26:832–834

    PubMed  Article  Google Scholar 

  69. Fix OK, Hameed B, Fontana RJ et al (2020) Clinical best practice advice for hepatology and liver transplant providers during the COVID-19 pandemic: AASLD expert panel consensus statement. Hepatology 72:287–304

    PubMed  Article  CAS  Google Scholar 

  70. Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L (2020) Features of 20133 UK patients in hospital with COVID-19 using the ISARIC WHO Clinical Characterization Protocol: prospective observational cohort study. BMJ 369:m1985

    PubMed  PubMed Central  Article  Google Scholar 

  71. Hu X, Pan X, Zhou W, Gu X, Shen F, Yang B, Hu Z (2020) Clinical epidemiological analyses of overweight/obesity and abnormal liver function contributing to prolonged hospitalization in patients infected with COVID-19. Int J Obes (Lond) 44:1784–1789

    Article  CAS  Google Scholar 

  72. Ryan PM, Caplice NM (2020) Is adipose tissue a reservoir for viral spread, immune activation, and cytokine amplification in coronavirus disease 2019? Obesity 28:1191–1194

    PubMed  Article  CAS  Google Scholar 

  73. Meijnikman AS, Bruin S, Groen AK, Nieuwdorp M, Herrema H (2021) Increased expression of key SARS-CoV-2 entry points in multiple tissues in individuals with NAFLD. J Hepatol 74(3):748

    PubMed  Article  CAS  Google Scholar 

  74. Ji D, Qin E, Xu J, Zhang D, Cheng G, Wang Y, Lau G (2020) Non-alcoholic fatty liver diseases in patients with COVID-19: a retrospective study. J Hepatol 73:451–453

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. Zhou YJ, Zheng KI, Wang XB, Yan HD, Sun QF, Pan KH, Wang TY, Ma HL, Chen YP, George J, Zheng MH (2020) Younger patients with MAFLD are at increased risk of severe COVID-19 illness: a multicenter preliminary analysis. J Hepatol 73(3):719–721

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. Gao F, Zheng KI, Wang XB, Yan HD, Sun QF, Pan KH, Wang TY, Chen YP, George J, Zheng MH (2021) Metabolic associated fatty liver disease increases coronavirus disease 2019 disease severity in nondiabetic patients. J Gastroenterol Hepatol 36(1):204

    PubMed  Article  CAS  Google Scholar 

  77. Targher G, Mantovani A, Byrne CD, Wang XB, Yan HD, Sun QF, Pan KH, Zheng KI, Chen YP, Eslam M, George J (2020) Risk of severe illness from COVID-19 in patients with metabolic dysfunction-associated fatty liver disease and increased fibrosis scores. Gut 69(8):1545–1547

    PubMed  Article  CAS  Google Scholar 

  78. Zhang L, Zhu F, Xie L, Wang C, Wang J, Chen R, Jia P, Guan H, Peng L, Chen Y, Peng P, Zhang P, Chu Q, Shen Q, Wang Y, Xu S, Zhao J, Zhou M (2020) Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China. Ann Oncol 31:894–901

    PubMed  Article  CAS  Google Scholar 

  79. Iavarone M, Sangiovanni A, Carrafiello G, Rossi G, Lampertico P (2020) Management of hepatocellular carcinoma in the time of COVID-19. Ann Oncol 31(8):1084–1085

    PubMed  Article  CAS  Google Scholar 

  80. Boettler T, Newsome PN, Mondelli MU et al (2020) Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID Position Paper. JHEP Rep 2:100113

    PubMed  PubMed Central  Article  Google Scholar 

  81. Tchelebi LT, Haustermans K, Scorsetti M, Hosni A, Huguet F, Hawkins M, Dawson L, Goodman K (2020) Recommendations for the use of radiation therapy in managing patients with gastrointestinal malignancies in the era of COVID-19. Radiother Oncol 148:194–200

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. Kudo M, Kurosaki M, Ikeda M, Aikata H, Hiraoka A, Torimura T, Sakamoto N (2020) Treatment of hepatocellular carcinoma during the COVID-19 outbreak: the Working Group report of JAMTT-HCC. Hepatol Res 50(9):1004–1014

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. Denys A, Guiu B, Chevallier P, Digklia A, de Kerviler E, De Baere T (2020) Interventional oncology at the time of COVID-19 pandemic: problems and solutions. Diagn Interv Imaging 101(6):347–353

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. Bollipo S, Kapuria D, Rabiee A, et al (2020) One world, one pandemic, many guidelines: management of liver diseases during COVID-19. Gut 69(8):1369-72

  85. Andersen KM, Mehta HB, Palamuttam N, Ford D, Garibaldi BT, Auwaerter PG, Segal J, Alexander GC (2021) Association between chronic use of immunosuppresive drugs and clinical outcomes from coronavirus disease 2019 (COVID-19) hospitalization: a retrospective cohort study in a large US health system. Clin Infect Dis 73(11):e4124-e4130

  86. Mansoor E, Perez A, Abou-Saleh M, Sclair S, Cohen S, Cooper G (2021) Clinical characteristics, hospitalization, and mortality rates of coronavirus disease 2019 among liver transplant patients in the United States: a multicenter research network study. Gastroenterology 160:459–462

    PubMed  Article  CAS  Google Scholar 

  87. Di Maira T, Berenguer M (2020) COVID-19 and liver transplantation. Nat Rev Gastroenterol Hepatol 17:526–528

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. Ritschl PV, Nevermann N, Wiering L, Wu H, Moroder P, Brandl A, Hillebrandt K, Tacke F, Friedersdorff F, Schlomm T, Schöning W, Öllinger R, Schmelzle M, Pratschke J (2020) Solid organ transplantation programs facing lack of empiric evidence in the COVID-19 pandemic: a by-proxy society recommendation consensus approach. Am J Transplant 00:1826–1836

    Article  CAS  Google Scholar 

  89. Kates OS, Fisher CE, Rakita RM, Reyes JD, Limaye AP (2020) Use of SARS-CoV-2 infected deceased organ donors: should we always “just say no?”. Am J Transplant 20:1787–1794

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  90. Kumar D, Manuel O, Natori Y, Egawa H, Grossi P, Han SH, Fernández-Ruiz M, Humar A (2020) COVID-19: a global transplant perspective on successfully navigating a pandemic. Am J Transplant 20(7):1773–1779

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. Donato MF, Invernizzi F, Lampertico P, Rossi G (2020) Health status of patients who underwent liver transplantation during the coronavirus outbreak at a large center in Milan, Italy. Clin Gastroenterol Hepatol 18:2131–2133

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  92. Pereira MR, Mohan S, Cohen DJ, Husain SA, Dube GK, Ratner LE, Arcasoy S, Aversa MM, Benvenuto LJ, Dadhania DM, Kapur S (2020) COVID-19 in solid organ transplant recipients: initial report from the US epicenter. Am J Transplant 20(7):1800–1808

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  93. Johanna FJ, Mousley TA, Catherine O, Anoop S, Koshy N (2020) Clinical presentation, treatment, and mortality rate in liver transplant recipients with coronavirus disease 2019: a systematic review and quantitative analysis. Transplant Proc 52:2676–2683

    Article  CAS  Google Scholar 

  94. Colmenero J, Rodríguez-Perálvarez M, Salcedo M, Arias-Milla A, Muñoz-Serrano A, Graus J, Nuño J, Gastaca M, Bustamante-Schneider J, Cachero A, Lladó L (2021) Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients. J Hepatol 74(1):148–155

    PubMed  Article  CAS  Google Scholar 

  95. Allison AC, Eugui EM (2000) Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 47(2-3):85–118

    PubMed  Article  CAS  Google Scholar 

  96. Brennan DC, Legendre C, Patel D, Mange K, Wiland A, McCague K, Shihab FS (2011) Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: pooled analysis of three clinical trials. Am J Transplant 11(11):2453–2462

    PubMed  Article  CAS  Google Scholar 

  97. Willicombe M, Thomas D, McAdoo S (2020) COVID-19 and calcineurin inhibitors: should they get left out in the storm? J Am Soc Nephrol 31:1145–1146

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. Cornberg M, Buti M, Eberhardt CS, Grossi PA, Shouval D (2021) EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients. J Hepatol 74(4):944–951

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  99. John BV, Deng Y, Khakoo NS, Taddei TH, Kaplan DE, Dahman B (2021) COVID-19 vaccination is associated with reduced SARS CoV2 infection and death in liver transplant recipients. Gastroenterology. https://doi.org/10.1053/j.gastro.2021.11.001

Download references

Acknowledgements

No acknowledgements.

Funding

No funding.

Author information

Authors and Affiliations

Authors

Contributions

Conceptualization: MTE and MHH. Data curation: MTE and MDE-T. Formal analysis: MHH and ET. Funding acquisition: NA. Investigation: NA. Methodology: MTE. Article administration: GME. Resources: NA. Software: YAA and AAE. Supervision: MTE and GME. Validation: YAA and MDE-T. Visualization: AAE and ET. Writing—review and editing: all authors. Final approval of manuscript: all authors. All authors contribute equally like the corresponding author in creating the idea of the article, gathering the information, drafting, and writing, reviewing, and editing the manuscript in the final shape. All authors are in agreement with the content of the manuscript. There is no conflict of interest, and we do not have any financial support. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The author(s) read and approved the final manuscript.

Corresponding author

Correspondence to Maged T. Elghannam.

Ethics declarations

Ethics approval and consent to participate

NA.

Consent for publication

NA.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Elghannam, M.T., Hassanien, M.H., Ameen, Y.A. et al. COVID-19 and liver diseases. Egypt Liver Journal 12, 43 (2022). https://doi.org/10.1186/s43066-022-00202-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s43066-022-00202-2

Keywords

  • Coronaviruses
  • SARS-CoV-2
  • Liver diseases
  • Hepatocellular carcinoma
  • Autoimmune liver disease
  • Liver transplantation
  • COVID-19 vaccination