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      Interrelationship Between Coronavirus Infection and Liver Disease

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      , M.D., M.P.H. 1 , , , M.B.B.S. 1 , , M.D. 1 , , M.D. 1
      Clinical Liver Disease
      John Wiley and Sons Inc.

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          Abstract

          http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-5-interview-schaefer the interview with the author Abbreviations ACE2 angiotensin‐converting enzyme 2 ALT alanine aminotransferase AST aspartate aminotransferase COVID‐19 coronavirus disease 2019 FDA US Food and Drug Administration GGT gamma‐glutamyl transferase GI gastrointestinal OR odds ratio PT prothrombin time SARS severe acute respiratory syndrome The novel coronavirus severe acute respiratory syndrome corona virus 2 (SARS‐CoV‐2) is currently estimated to have infected more than 3 million individuals worldwide and causes the clinical syndrome of coronavirus disease 2019 (COVID‐19). Although the primary clinical manifestation is pulmonary disease, increasing data support the involvement of multiple organ systems, including the gastrointestinal (GI) tract and liver, with more than 60% of patients presenting with GI symptoms (anorexia, diarrhea, nausea, and vomiting) and a significant proportion presenting with elevated liver biochemistries. 1 , 2 , 3 , 4 The SARS‐CoV‐2 virus is an enveloped, single‐stranded virus, and the angiotensin‐converting enzyme 2 (ACE2) receptor is thought to be a major receptor for the viral spike protein and critical for infectivity. 5 , 6 The ACE2 protein is found at high levels in the colon, biliary system, and liver, 7 and RNA shedding in the GI tract is well described. 8 These data suggest that the SARS‐CoV‐2 may have tropism for the GI tract and liver, and that these may be sites of active viral replication and either direct or indirect tissue injury (Fig. 1). Fig 1 SARS‐CoV‐2 and the GI tract and liver. Liver injury in the setting of COVID‐19–related illness poses a unique challenge to the clinician. First, there is often uncertainty whether there is preexisting undiagnosed liver disease. Second, many of the medications used to treat moderate and severe disease have their own profiles of liver toxicity. Finally, in the subset of patients who experience critical illness, multiple factors may influence the trajectory of liver injury. We summarize what is known about liver injury in COVID‐19 and provide diagnostic clues to contributing factors to the liver biochemical profile. Epidemiology and Clinical Associations of Liver Injury in COVID‐19 Several published studies have characterized the frequency and severity of liver biochemistry abnormalities on presentation, and a few have determined whether these abnormalities are associated with increased disease‐related morbidity or death, as summarized in Table 1. 9 , 10 , 12 , 13 , 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 The largest published study to date encompassed 5700 hospitalized patients in New York and examined admission serologies: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were both frequently elevated (58.4% and 39.0% of subjects, respectively), and a separate large cohort found elevations to be more common in severe disease. 9 Two studies suggest that a higher proportion (44%‐81%) of patients with underlying liver disease had abnormal liver biochemistries on admission. 11 , 12 Elevations have been generally modest on admission, but available data suggest they become more frequently (93% in one series) and more severely deranged during the course of hospitalization. 12 , 13 , 14 Furthermore, liver impairment at admission has not been consistently associated with length of hospital stay, 11 , 15 but has been found to correlate with time from illness onset to admission and with adverse outcomes. 14 , 15 Liver biochemistries do not appear to be associated with GI manifestations in COVID‐19. 2 Table 1 Frequency of Liver Biochemistry Abnormalities on Admission and Association With Outcomes Laboratory Test % Patients With Abnormal Value* Association With Severe Disease † Association With Death Comments AST 16%‐58% 9 , 10 , 12 , 16 , 17 , 18 , 19 Yes 13 , 14 , 16 , 18 Yes 21 In 1 review of 12 published and unpublished reports, AST was the most frequently elevated biochemistry, and more frequently abnormal in severe disease 22 ALT 13%‐39% 9 , 10 , 12 , 17 , 23 Yes 13 , 16 , 18 Yes 21 , 23 Risk for in‐hospital death is associated with ALT > 40 (OR: 2.87 [1.48‐5.57]; P = 0.0018) and PT ≥ 16 23 No 20 Alkaline phosphatase 5% 12 Yes 13 TBili 11%‐23% 10 , 12 , 17 Yes 16 No 13 , 18 Albumin 38%‐98% 17 , 18 Yes 16 , 18 , 20 , 24 Yes 23 Murray lung injury score is highly correlated with albumin (r = −0.959, P < 0.001) 24 GGT 16% 12 Yes 13 Increase in GGT in one study was observed despite normal alkaline phosphatase level 12 PT 5%‐6% 17 , 23 Yes 16 Yes 23 Elevated PT on admission significantly associated with risk for death (OR: 4.62 [1.29‐16.50]; P = 0.019) 23 No 18 * Above normal limits, as designated by study authors. † Abnormal laboratory value at any point in disease course. Severe disease is a composite definition composed of author designation of “severe disease,” disease progression, lung injury, and intensive care unit level care. Abbreviation: TBili, Total Bilirubin John Wiley & Sons, Ltd Patterns of Liver Injury Aminotransferase elevation is the most common abnormality in patients presenting with COVID‐19 (Table 1). Published reports suggest that AST is more frequently elevated than ALT. 9 , 10 , 13 , 22 Elevated alkaline phosphatase is rare, and an increase in bilirubin has less commonly been observed. However, interestingly, one report found elevated gamma‐glutamyl transferase (GGT) levels in nearly 50% of subjects. 12 The trajectory of liver biochemistry changes during hospitalization for COVID‐19 infection is marked by elevation in aminotransferases, with rare severe liver injury, and liver test abnormalities are more frequent in patients with more severe COVID‐19. 12 , 14 This pattern of liver injury is unlike that commonly observed in other forms of viral hepatitis, such as hepatitis B and C, but at least one report describes a similar pattern during influenza A/H1N1 influenza infection. 25 , 26 In the prior severe acute respiratory syndrome (SARS) outbreak of 2003, a similar pattern of liver injury was observed. 27 The pattern of abnormal liver biochemistries characterized by an AST level greater than ALT, with accompanying GGT elevation, is also commonly encountered in both alcoholic liver disease and ischemic or congestive liver injury. 28 Thus, the liver injury observed in COVID‐19 may reflect a direct viral effect, but other potential contributors must be considered, both at the time of initial presentation and during disease progression and management. Potential Causes of Liver Injury in COVID‐19 Hepatic injury from SARS‐CoV2 infection is observed from the time of initial contact with the medical system, suggesting that the primary insult is unrelated to medical management but rather due to either direct effect of the virus or a consequence of the systemic disease. However, the trajectory of liver injury is likely influenced by multiple additional factors (Fig. 2). Fig 2 Potential mechanisms of liver injury and abnormal biochemistries. There may be a direct viral cytopathic effect, given the known presence of the ACE2 receptor in the liver. 5 , 29 In SARS infection, viral RNA was detected in liver tissue. 30 , 31 Further, recently published data suggest that mitochondrial proteins may directly interact with the virus, 32 providing a potential mechanistic explanation for the AST‐dominant injury profile. Alternatively, the robust inflammatory response seen in COVID‐19 may play a central role. The immune response to SARS‐CoV‐2 is characterized by very high levels of IL‐6, 33 which has been implicated in both the inflammatory and the repair responses in liver disease. 34 Cardiomyopathy is a well‐described consequence of COVID‐19, occurring in 33% of individuals in one US series. 35 Thus, it is possible that cardiac dysfunction and hepatic congestion contribute to hepatic injury in severe COVID‐19 infection. Congestive hepatopathy may occur as a consequence of an acute cardiomyopathy, and it is commonly associated with elevations in aminotransferases and GGT. 36 , 37 Severe ischemic hepatitis is a condition characterized by severe AST‐predominant hepatitis 38 and may be observed in critically ill patients with COVID‐19. The infrequently observed alkaline phosphatase elevation occurs late in COVID‐19 disease progression and could reflect the cholestasis of sepsis, critical illness, 39 or medication effect. An increasing number of drugs are being investigated and empirically used in hospitalized patients with COVID‐19. Many of these medications have a distinct risk, time course, and pattern of liver injury, as summarized in Table 2. 41 Remdesivir (a nucleoside analog inhibitor of viral RNA polymerase, recently approved for use under a US Food and Drug Administration [FDA] Emergency Use Authorization) is experiencing growing use in COVID‐19 trials and was associated with a 23% increase in liver enzymes in one small published report. 40 Table 2 Drugs Commonly Used in COVID‐19 and Hepatotoxicity Profile Drug Liver Toxicity Score Pattern of Injury Time Frame of Injury Comments Acetaminophen A Hepatocellular Protracted therapy (>4 g daily): 3‐7 days Injury due to overdose is often associated with jaundice, confusion, renal insufficiency, and hepatic failure, at 48‐96 hours Single overdose: 24‐72 hours Azithromycin A Cholestatic > hepatocellular Cholestatic: 1‐3 weeks Associated with fatigue, jaundice, abdominal pain, and pruritus Hepatocellular: 1‐3 days Statins A/B Hepatocellular > cholestatic 6 months to several years Hydroxychloroquine C Very rare NR* Case report level data Lopinavir/ritonavir D Hepatocellular/cholestatic/mixed 1‐8 weeks May exacerbate underlying chronic viral hepatitis Remdesivir NA** Hepatocellular 5‐25 days ALT elevation observed in the majority of healthy patients; FDA recommends hepatic function testing prior to initiating, and then daily while on therapy; stop drug if ALT > 5 times the upper limit of normal 41 a Not reported. b Not applicable. Data are adapted from LiverTox (livertox.nih.gov). 43 John Wiley & Sons, Ltd Conclusions There is a high prevalence of abnormal liver biochemistries on presentation in patients with COVID‐19. In light of the risk for additional injury due to the complications and management of moderate‐to‐severe disease, it is important to monitor hepatic enzymes during the course of disease. 42 If biochemistries worsen during disease progression, consideration must be given to possible contributors, including cardiac dysfunction, cytokine storm, ischemia, sepsis, and medication effect.

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          Most cited references36

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Clinical Characteristics of Coronavirus Disease 2019 in China

            Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)
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              Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

              Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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                Author and article information

                Contributors
                eschaefer@partners.org
                Journal
                Clin Liver Dis (Hoboken)
                Clin Liver Dis (Hoboken)
                10.1002/(ISSN)2046-2484
                CLD
                Clinical Liver Disease
                John Wiley and Sons Inc. (Hoboken )
                2046-2484
                21 May 2020
                May 2020
                : 15
                : 5 , COVID‐19 and Liver Disease ( doiID: 10.1002/cld.v15.5 )
                : 175-180
                Affiliations
                [ 1 ] Liver Center and GI Division Massachusetts General Hospital Harvard Medical School Boston MA
                Author notes
                [*] [* ] Correspondence

                Esperance A. K. Schaefer, M.D., M.P.H., Liver Center and GI Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114. E‐mail: eschaefer@ 123456partners.org

                Author information
                https://orcid.org/0000-0002-7198-3863
                https://orcid.org/0000-0003-1911-5396
                https://orcid.org/0000-0003-3188-7188
                Article
                CLD967
                10.1002/cld.967
                7242011
                32489653
                fbad6c50-394d-4d0a-9b04-f6d3cb293d46
                © 2020 by the American Association for the Study of Liver Diseases
                History
                : 04 May 2020
                : 07 May 2020
                : 08 May 2020
                Page count
                Figures: 2, Tables: 2, Pages: 6, Words: 8845
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases , open-funder-registry 10.13039/100000062;
                Award ID: 1R01AI36715‐01
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                May 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.2 mode:remove_FC converted:21.05.2020

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