The histologic and molecular correlates of liver disease in fatal COVID-19 including with alcohol use disorder.

Hepatic disease is common in severe COVID-19. This study compared the histologic/molecular findings in the liver in fatal COVID-19 (n = 9) and age-matched normal controls (n = 9); three of the fatal COVID-19 livers had pre-existing alcohol use disorder (AUD). Controls showed a high resident population of sinusoidal macrophages that had variable ACE2 expression. Histologic findings in the cases included periportal/lobular inflammation. SARS-CoV2 RNA and nucleocapsid protein were detected in situ in 2/9 COVID-19 livers in low amounts. In 9/9 cases, there was ample in situ SARS-CoV-2 spike protein that co-localized with viral matrix and envelope proteins. The number of cells positive for spike/100× field was significantly greater in the AUD/COVID-19 cases (mean 5.9) versus the non-AUD/COVID-19 cases (mean 0.4, p < 0.001) which was corroborated by Western blots. ACE2+ cells were 10× greater in AUD/COVID-19 livers versus the other COVID-19/control liver samples (p < 0.001). Co-expression experiments showed that the spike protein localized to the ACE2 positive macrophages and, in the AUD cases, hepatic stellate cells that were activated as evidenced by IL6 and TNFα expression. Injection of the S1, but not S2, subunit of spike in mice induced hepatic lobular inflammation in activated macrophages. It is concluded that endocytosed viral spike protein can induce hepatitis in fatal COVID-19. This spike induced hepatitis is more robust in the livers with pre-existing AUD which may relate to why patients with alcohol abuse are at higher risk of severe liver disease with SARS-CoV2 infection.

Thrombotic sinusoiditis and local diffuse intrasinusoidal coagulation in the liver of subjects affected by COVID-19: the evidence from histology and scanning electron microscopy.

OBJECTIVE: Liver injury has been reported in patients with COVID-19. This condition is characterized by severe outcome and could be related with the ability of SARS-CoV-2 to activate cytotoxic T cells. The purpose of this study is to show the histological and scanning electron microscopy features of liver involvement in COVID-19 to characterize the liver changes caused by the activation of multiple molecular pathways following this infection. PATIENTS AND METHODS: Liver biopsies from 4 patients (3 post-mortems and 1 in vivo) with COVID-19 were analyzed with histology and by scanning electron microscopy. RESULTS: The liver changes showed significant heterogeneity. The first case showed ground glass hepatocytes and scattered fibrin aggregates in the sinusoidal lumen. The second evidenced intra-sinusoidal thrombi. The third was characterized by sinusoidal dilatation, atrophy of hepatocytes, Disse's spaces dilatation and intra-sinusoidal aggregates of fibrin and red blood cells. The fourth case exhibited diffuse fibrin aggregates in the dilated Disse spaces and microthrombi in the sinusoidal lumen. CONCLUSIONS: In COVID-19-related liver injury, a large spectrum of pathological changes was observed. The most peculiar features were very mild inflammation, intra-sinusoidal changes, including sinusoidal dilatation, thrombotic sinusoiditis and diffuse intra-sinusoidal fibrin deposition. These findings suggested that a thrombotic sinusoiditis followed by a local diffuse intra-vascular (intra-sinusoidal) coagulation could be the typical features of the SARS-CoV-2-related liver injury.

Correlation Between Clinical and Pathological Findings of Liver Injury in 27 Patients With Lethal COVID-19 Infections in Brazil.

Liver test abnormalities are frequently observed in patients with coronavirus disease 2019 (COVID-19) and are associated with worse prognosis. However, information is limited about pathological changes in the liver in this infection, so the mechanism of liver injury is unclear. Here we describe liver histopathology and clinical correlates of 27 patients who died of COVID-19 in Manaus, Brazil. There was a high prevalence of liver injury (elevated alanine aminotransferase and aspartate aminotransferase in 44% and 48% of patients, respectively) in these patients. Histological analysis showed sinusoidal congestion and ischemic necrosis in more than 85% of the cases, but these appeared to be secondary to systemic rather than intrahepatic thrombotic events, as only 14% and 22% of samples were positive for CD61 (marker of platelet activation) and C4d (activated complement factor), respectively. Furthermore, the extent of these vascular findings did not correlate with the extent of transaminase elevations. Steatosis was present in 63% of patients, and portal inflammation was present in 52%. In most cases, hepatocytes expressed angiotensin-converting enzyme 2 (ACE2), which is responsible for binding and entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), even though this ectoenzyme was minimally expressed on hepatocytes in normal controls. However, SARS-CoV-2 staining was not observed. Most hepatocytes also expressed inositol 1,4,5-triphosphate receptor 3 (ITPR3), a calcium channel that becomes expressed in acute liver injury. Conclusion: The hepatocellular injury that commonly occurs in patients with severe COVID-19 is not due to the vascular events that contribute to pulmonary or cardiac damage. However, new expression of ACE2 and ITPR3 with concomitant inflammation and steatosis suggests that liver injury may result from inflammation, metabolic abnormalities, and perhaps direct viral injury.

COVID-19 and the liver - Lessons learned.

Liver involvement, indicated by elevated liver function test results, is common in hospitalized patients with coronavirus disease 2019 (COVID-19) and has been linked to disease severity and outcome. A dual pattern of elevated liver function tests can be observed especially in patients with severe or critical COVID-19, characterized by an increase in aminotransferases early in the course of this disease, followed by an increase in cholestasis-associated biochemistry markers at later stages. This dual pattern is associated with inflammatory response markers and poor outcome. Current notions on the mechanisms of liver injury in COVID-19 include direct cytopathic effects of the virus on hepatocytes and cholangiocytes, ischemic and hypoxic liver damage, drug-induced liver injury, activation of hepatic immune cells by excess cytokine production and exacerbation of pre-existing liver disease. Patients with obesity-related non-alcoholic fatty liver disease and, in particular, patients with cirrhosis are at high risk of liver injury and a fatal outcome from COVID-19. In contrast, individuals receiving stable immunosuppressive medication for autoimmune liver diseases or during long-term follow-up after liver transplantation do not have a higher case-to-infection ratio and have a fairly favourable outcome. The present review describes the epidemiology, characteristics and potential pathological mechanisms of COVID-19-related liver injury. Moreover, the influence of pre-existing liver disease on the susceptibility and severity of liver injury in COVID-19 are discussed.

A giant spontaneous subcapsular hematoma of the liver revealing a COVID-19 infection, a coincidence? (A case report).

Hemorrhagic manifestations during COVID-19 infections are increasingly described in the literature. We report the first case of spontaneous subcapsular hematoma of the liver revealing a COVID-19 infection in a 44-year-old woman with no underlying health condition history, a computerized tomography evaluation showed an aspect of lung ground-glass opacities, with moderate impairment estimated at about 20%. Reverse transcription-polymerase chain reaction confirmed the diagnosis of COVID-19 infection. During the COVID-19 pandemic, non-traumatic bleeding such as spontaneous hematomas in patients with no coagulation disorder could be a manifestation of COVID-19 infection.

Chronic liver disease not a significant comorbid condition for COVID-19.

To explore the role of chronic liver disease (CLD) in COVID-19. A total of 1439 consecutively hospitalized patients with COVID-19 from one large medical center in the United States from March 16, 2020 to April 23, 2020 were retrospectively identified. Clinical characteristics and outcomes were compared between patients with and without CLD. Postmortem examination of liver in 8 critically ill COVID-19 patients was performed. There was no significant difference in the incidence of CLD between critical and non-critical groups (4.1% vs 2.9%, p = 0.259), or COVID-19 related liver injury between patients with and without CLD (65.7% vs 49.7%, p = 0.065). Postmortem examination of liver demonstrated mild liver injury associated central vein outflow obstruction and minimal to moderate portal lymphocytic infiltrate without evidence of CLD. Patients with CLD were not associated with a higher risk of liver injury or critical/fatal outcomes. CLD was not a significant comorbid condition for COVID-19.

Effect of COVID-19 on liver abnormalities: a systematic review and meta-analysis.

Emerging evidence suggest association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with the development of many liver abnormalities. The overarching aim of this study was therefore to assess the available evidence on the clinical effects of SARS-CoV-2 on the profiles of liver chemistries and coagulation in COVID-19 diagnosed patients. We considered all study designs including epidemiological and observational that reported liver function test abnormalities in patients confirmed with SARS-CoV-2 infection. Medline, Embase databases and Google Scholar as well as relevant reviews were searched to identify appropriate studies from inception to 31st of August 2020. We calculated the pooled mean with 95% confidence intervals (95% CI) through a random-effect model meta-analysis. A total of 35 studies with 10,692 participants were considered for the review from which 23 studies with sufficient quantitative data were included in the meta-analysis. The pooled mean for liver enzymes and coagulation parameters did not significantly change in patients diagnosed with COVID-19 and remained within normal range. Notwithstanding potential bias from confounding factors in interpretation of data in this review, findings from the observational studies and case reports suggest that COVID-19 does not appear to have a significant impact on the transaminases or total bilirubin levels of patients with confirmed SARS-CoV-2 infection. Further controlled studies and larger sample size observational studies are needed with adequate reporting of other liver function parameters are warranted.

Liver histopathology in COVID-19 patients: A mono-Institutional series of liver biopsies and autopsy specimens.

Few studies have focused on COVID-19 patients' hepatic histopathological features. Many of the described morphological landscapes are non-specific and possibly due to other comorbidities or to Sars-CoV-2-related therapies. We describe the hepatic histopathological findings of 3 liver biopsies obtained from living COVID-19 patients in which active SARS-CoV-2 infection was molecularly confirmed and biopsied because of significant alterations of liver function tests and 25 livers analyzed during COVID-19-related autopsies. Main histopathological findings were (i) the absence of significant biliary tree or vascular damages, (ii) mild/absent lymphocytic hepatitis; (iii) activation of (pigmented) Kupffer cells, (iv) hepatocellular regenerative changes, (v) the presence of steatosis, (vi) sinusoidal ectasia, micro-thrombosis and acinar atrophy in autopsy specimens No viral particle actively infecting the hepatic or endothelial cells was detected at in situ hybridization. The morphological features observed within the hepatic parenchyma are not specific and should be considered as the result of an indirect insult resulting from the viral infection or the adopted therapeutic protocols.

Biomedical applications of methionine-based systems.

Methionine (Met), an essential amino acid in the human body, possesses versatile features based on its chemical modification, cell metabolism and metabolic derivatives. Benefitting from its multifunctional properties, Met holds immense potential for biomedical applications. In this review, we systematically summarize the recent progress in Met-based strategies for biomedical applications. First, given the unique structural characteristics of Met, two chemical modification methods are briefly introduced. Subsequently, due to the disordered metabolic state of tumor cells, applications of Met in cancer treatment and diagnosis are summarized in detail. Furthermore, the efficacy of S-adenosylmethionine (SAM), as the most important metabolic derivative of Met, for treating liver diseases is mentioned. Finally, we analyze the current challenges and development trends of Met in the biomedical field, and suggest that Met-restriction therapy might be a promising approach to treat COVID-19.

Pathological findings in the postmortem liver of patients with coronavirus disease 2019 (COVID-19).

Although coronavirus disease 2019 (COVID-19) is transmitted via respiratory droplets, there are multiple gastrointestinal and hepatic manifestations of the disease, including abnormal liver-associated enzymes. However, there are not many published articles on the pathological findings in the liver of patients with COVID-19. We collected the clinical data from 17 autopsy cases of patients with COVID-19 including age, sex, Body mass index (BMI), liver function test (alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), alkaline phosphatase (ALP), direct bilirubin, and total bilirubin), D-dimer, and anticoagulation treatment. We examined histopathologic findings in postmortem hepatic tissue, immunohistochemical (IHC) staining with antibody against COVID-19 spike protein, CD68 and CD61, and electron microscopy. We counted the number of megakaryocytes in liver sections from these COVID-19-positive cases. Abnormal liver-associated enzymes were observed in 12 of 17 cases of COVID-19 infection. With the exception of three cases that had not been tested for D-dimer, all 14 patients' D-dimer levels were increased, including the cases that received varied doses of anticoagulation treatment. Microscopically, the major findings were widespread platelet-fibrin microthrombi, steatosis, histiocytic hyperplasia in the portal tract, mild lobular inflammation, ischemic-type hepatic necrosis, and zone 3 hemorrhage. Rare megakaryocytes were found in sinusoids. COVID-19 IHC demonstrates positive staining of the histiocytes in the portal tract. Under electron microscopy, histiocyte proliferation is present in the portal tract containing lipid droplets, lysosomes, dilated ribosomal endoplasmic reticulum, microvesicular bodies, and coronavirus. The characteristic findings in the liver of patients with COVID-19 include numerous amounts of platelet-fibrin microthrombi, as well as various degrees of steatosis and histiocytic hyperplasia in the portal tract. Possible mechanisms are also discussed.

Molecular and cellular mechanisms of liver dysfunction in COVID-19.

Liver injury has been reported as a common complication in Coronavirus disease 2019 (COVID-19). Recently, more and more studies reported that the degree of liver damages was associated with the severity of COVID-19. Although the exact mechanism of liver injury in COVID-19 patients is unknown, recent studies have made some explorations and investigations. In this review, we summarized the potential mechanisms of liver dysfunction in COVID-19 patients gleaned from recently published research reports, which suggested that the progression of pre-existing liver diseases, direct damage of liver by SARS-CoV-2, systemic inflammation caused by SARS-CoV-2 infection, anti-viral drug toxicity, and hypoxia-reperfusion may be associated with liver injury in patients with COVID-19. Hypoxic liver injury due to ischemia and shock, cholestasis-related liver injury due to altered bile metabolism, and hepatocellular injury due to drug toxicity or overwhelming inflammation might occur in severe COVID-19 patients with sepsis. To understand the pathogenesis of liver dysfunction in COVID-19 patients, further research is needed to focus on liver-related comorbidities, the evidence of viral replication in hepatocytes and bile duct cells, histological features of liver injury, and the influence of hepatotoxic antiviral drugs. We also suggested that special attention should be paid to monitoring inflammatory cytokines and hypoxia for the prevention and treatment of liver injury in severe COVID-19 patients. A deep understanding of the mechanism of liver injury is helpful for the management and treatment of COVID-19 patients.

The Fibrosis-4 Index Is Associated With Need for Mechanical Ventilation and 30-Day Mortality in Patients Admitted With Coronavirus Disease 2019.

The Fibrosis-4 Index (FIB-4), developed to predict fibrosis in liver disease, was used to identify patients with coronavirus disease 2019 who will require ventilator support as well as those associated with 30-day mortality. Multivariate analysis found obesity (odds ratio [OR], 4.5), diabetes mellitus (OR, 2.55), and FIB-4 ≥2.67 (OR, 3.09) independently associated with need for mechanical ventilation. When controlling for ventilator use, sex, and comorbid conditions, FIB-4 ≥2.67 was also associated with increased 30-day mortality (OR, 8.4 [95% confidence interval, 2.23-31.7]). Although it may not be measuring hepatic fibrosis, its components suggest that increases in FIB-4 may be reflecting systemic inflammation associated with poor outcomes.

Risk factors of liver injury in patients with coronavirus disease 2019 in Jiangsu, China: A retrospective, multi-center study.

We aimed to describe liver injury and identify the risk factors of liver injury in coronavirus disease (COVID-19) patients without chronic liver diseases (CLD). The clinical data of 228 confirmed COVID-19 patients without CLD were retrospectively collected from ten hospitals in Jiangsu, China. Sixty-seven (29.4%) of 228 patients without CLD showed abnormal liver function on admission, including increased alanine aminotransferase (ALT) (25 [11.0%]) U/L, aspartate aminotransferase (AST) 30 [13.2%]) U/L, gamma-glutamyl transferase (GGT) 28 [12.4%]) U/L, total bilirubin (Tbil) 16 [7.0%] µmol/L, and alkaline phosphatase (ALP) 10 [4.5%]) U/L. During hospitalization, 129 (56.3%) of 228 patients showed abnormal liver function, including elevated ALT (84 [36.8%]), AST (58 [25.4%]), GGT (67 [29.5%]), and Tbil (59 [25.9%]). Age over 50 years (odds ratio [OR], 2.086; 95% confidence interval [CI], 1.030-4.225; p = .041), male sex (OR, 2.737; 95% CI, 1.418-5.284; p = .003), and lopinavir-ritonavir (OR, 2.504; 95% CI, 1.187-5.283; p = .016) were associated with higher risk of liver function abnormality, while the atomized inhalation of interferon α-2b (OR, 0.256; 95% CI 0.126-0.520; p < .001) was associated with reduced risk of liver function abnormality during hospitalization. Mild to moderate liver injury was common in COVID-19 patients in Jiangsu, China. Age over 50 years, male sex, and lopinavir-ritonavir were the independent risk factors of liver impairment in COVID-19 patients during hospitalization.

Liver injury with COVID-19 based on gastrointestinal symptoms and pneumonia severity.

BACKGROUND/AIM: The coronavirus disease 2019 (COVID-19) had become a big threat worldwide. Liver injury is not uncommon in patients with COVID-19, and clarifying its characteristics is needed. This study aimed to identify factors associated with liver injury and to develop a new classification of predictive severity in patients with COVID-19. METHODS: Confirmed patients with COVID-19 (n = 60) were recruited retrospectively from Musashino Red Cross Hospital. The factors of liver injury especially on the elevation of liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were analyzed. Grading was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: During a median hospitalization follow-up of 15 (4-41) days, 51 (85.0%) patients had COVID-19 pneumonia. In clinical courses, oxygenation was needed for 25 (41.6%) patients and intubation was needed for 9 (15.0%) patients. A total of 27 (45.0%) patients had gastrointestinal symptoms (GS), such as appetite loss, diarrhea, and nausea. A logistic regression analysis revealed that C-reactive protein (CRP) at baseline, oxygenation, intubation, and GS were significant factors of liver injury. Based on these results, patients were classified into three groups: group 1, no oxygenation pneumonia; group 2, pneumonia with oxygenation or GS; and group 3, intubation. We classified 25 (41.7%), 26 (43.3%), and 9 (15.0%) patients into mild, moderate, and severe groups, respectively. The peak of AST and ALT levels was significantly stratified with this criteria (mild [median AST, 28 IU/L; median ALT, 33 IU/L], moderate [median AST, 48 IU/L; median ALT, 47.5 IU/L], and severe [median AST, 109 IU/L; median ALT, 106 IU/L]; P<0.001 and P = 0.0114, respectively). CONCLUSION: COVID-19-related liver injury was significantly stratified based on GS and severity of pneumonia.

COVID-19-associated gastrointestinal and liver injury: clinical features and potential mechanisms.

Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection is spreading globally and poses a huge threat to human health. Besides common respiratory symptoms, some patients with COVID-19 experience gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and loss of appetite. SARS-CoV-2 might infect the gastrointestinal tract through its viral receptor angiotensin-converting enzyme 2 (ACE2) and there is increasing evidence of a possible fecal-oral transmission route. In addition, there exist multiple abnormalities in liver enzymes. COVID-19-related liver injury may be due to drug-induced liver injury, systemic inflammatory reaction, and hypoxia-ischemia reperfusion injury. The direct toxic attack of SARS-CoV-2 on the liver is still questionable. This review highlights the manifestations and potential mechanisms of gastrointestinal and hepatic injuries in COVID-19 to raise awareness of digestive system injury in COVID-19.

Incidence, patterns, risk factors, and histopathological findings of liver injury in coronavirus disease 2019 (COVID-19): a scoping review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) exhibits many extrapulmonary manifestations, including liver injury. This scoping review aimed to provide insight into the incidence, patterns, risk factors, histopathological findings, and relationship with disease severity of COVID-19-associated liver injury. Furthermore, we identified existing gaps in the research on the hepatic manifestations of COVID-19 and highlighted areas for future investigations. METHODS: A scoping review was conducted following the methodological framework suggested by Arksey and O'Mallay. Five online databases, along with grey literature, were searched for articles published until 22 May 2020, and we included 62 articles in the review. The research domains, methodological characteristics, and key conclusions were included in the analysis. RESULTS: Retrospective observational studies comprised more than one third (41.9%) of the included publications, and 77.8% were conducted on living patients. The incidence of liver injury varied widely across the studies (4.8%-78%), and liver injury was frequently associated with severe COVID-19. We identified the following risk factors for liver injury: male sex, lymphopoenia, gastrointestinal involvement, old age, increased neutrophil count, and the use of hepatotoxic drugs. Histopathological findings indicate that COVID-19 has direct cytopathic effects and causes liver function test derangements secondary to inflammation, hypoxia, and vascular insult. CONCLUSIONS: Liver injury following COVID-19 infection is common and primarily hepatocellular, with a greater elevation of aspartate aminotransferase tahn of alanine aminotransferase. However, the evidence regarding hepatic failure secondary to COVID-19 is insufficient. Standardised criteria to diagnose liver injury need to be devised. Current use of hepatotoxic drugs necessitates close monitoring of liver function.

Clinical outcomes of coronavirus disease 2019 in patients with pre-existing liver diseases: A multicenter study in South Korea.

BACKGROUND/AIMS: Although coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, the implication of pre-existing liver disease on the outcome of COVID-19 remains unresolved.
. METHODS: A total of 1,005 patients who were admitted to five tertiary hospitals in South Korea with laboratory-confirmed COVID-19 were included in this study. Clinical outcomes in COVID-19 patients with coexisting liver disease as well as the predictors of disease severity and mortality of COVID-19 were assessed.
. RESULTS: Of the 47 patients (4.7%) who had liver-related comorbidities, 14 patients (1.4%) had liver cirrhosis. Liver cirrhosis was more common in COVID-19 patients with severe pneumonia than in those with non-severe pneumonia (4.5% vs. 0.9%, P=0.006). Compared to patients without liver cirrhosis, a higher proportion of patients with liver cirrhosis required oxygen therapy; were admitted to the intensive care unit; had septic shock, acute respiratory distress syndrome, or acute kidney injury; and died (P<0.05). The overall survival rate was significantly lower in patients with liver cirrhosis than in those without liver cirrhosis (log-rank test, P=0.003). Along with old age and diabetes, the presence of liver cirrhosis was found to be an independent predictor of severe disease (odds ratio, 4.52; 95% confidence interval [CI], 1.20-17.02;P=0.026) and death (hazard ratio, 2.86; 95% CI, 1.04-9.30; P=0.042) in COVID-19 patients.
. CONCLUSION: This study suggests liver cirrhosis is a significant risk factor for COVID-19. Stronger personal protection and more intensive treatment for COVID-19 are recommended in these patients.

COVID-19 and multiorgan failure: A narrative review on potential mechanisms.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in December 2019 form Wuhan, China leads to coronavirus disease 2019 (COVID-19) pandemic. While the common cold symptoms are observed in mild cases, COVID-19 is accompanied by multiorgan failure in severe patients. The involvement of different organs in severe patients results in lengthening the hospitalization duration and increasing the mortality rate. In this review, we aimed to investigate the involvement of different organs in COVID-19 patients, particularly in severe cases. Also, we tried to define the potential underlying mechanisms of SARS-CoV2 induced multiorgan failure. The multi-organ dysfunction is characterized by acute lung failure, acute liver failure, acute kidney injury, cardiovascular disease, and as well as a wide spectrum of hematological abnormalities and neurological disorders. The most important mechanisms are related to the direct and indirect pathogenic features of SARS-CoV2. Although the presence of angiotensin-converting enzyme 2, a receptor of SARS-CoV2 in the lung, heart, kidney, testis, liver, lymphocytes, and nervous system was confirmed, there are controversial findings to about the observation of SARS-CoV2 RNA in these organs. Moreover, the organ failure may be induced by the cytokine storm, a result of increased levels of inflammatory mediators, endothelial dysfunction, coagulation abnormalities, and infiltration of inflammatory cells into the organs. Therefore, further investigations are needed to detect the exact mechanisms of pathogenesis. Since the involvement of several organs in COVID-19 patients is important for clinicians, increasing their knowledge may help to improve the outcomes and decrease the rate of mortality and morbidity.

Hepatic pathology in patients dying of COVID-19: a series of 40 cases including clinical, histologic, and virologic data.

The novel coronavirus SARS-CoV-2 (coronavirus disease 19, or COVID-19) primarily causes pulmonary injury, but has been implicated to cause hepatic injury, both by serum markers and histologic evaluation. The histologic pattern of injury has not been completely described. Studies quantifying viral load in the liver are lacking. Here we report the clinical and histologic findings related to the liver in 40 patients who died of complications of COVID-19. A subset of liver tissue blocks were subjected to polymerase chain reaction (PCR) for viral ribonucleic acid (RNA). Peak levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were elevated; median ALT peak 68 U/l (normal up to 46 U/l) and median AST peak 102 U/l (normal up to 37 U/l). 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%). In conclusion, we found patients dying of COVID-19 had biochemical evidence of hepatitis (of variable severity) and demonstrated histologic findings of macrovesicular steatosis and mild acute hepatitis (lobular necroinflammation) and mild portal inflammation. We also identified viral RNA in a sizeable subset of liver tissue samples.