Liver injury after SARS-CoV-2 vaccination: Features of immune-mediated hepatitis, role of corticosteroid therapy and outcome.

BACKGROUND AND AIMS: A few case reports of autoimmune hepatitis-like liver injury have been reported after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. We evaluated clinical features, treatment response and outcomes of liver injury following SARS-CoV-2 vaccination in a large case series. APPROACH AND RESULTS: We collected data from cases in 18 countries. The type of liver injury was assessed with the R-value. The study population was categorized according to features of immune-mediated hepatitis (positive autoantibodies and elevated immunoglobulin G levels) and corticosteroid therapy for the liver injury. We identified 87 patients (63%, female), median age 48 (range: 18-79) years at presentation. Liver injury was diagnosed a median 15 (range: 3-65) days after vaccination. Fifty-one cases (59%) were attributed to the Pfizer-BioNTech (BNT162b2) vaccine, 20 (23%) cases to the Oxford-AstraZeneca (ChAdOX1 nCoV-19) vaccine and 16 (18%) cases to the Moderna (mRNA-1273) vaccine. The liver injury was predominantly hepatocellular (84%) and 57% of patients showed features of immune-mediated hepatitis. Corticosteroids were given to 46 (53%) patients, more often for grade 3-4 liver injury than for grade 1-2 liver injury (88.9% vs. 43.5%, p = 0.001) and more often for patients with than without immune-mediated hepatitis (71.1% vs. 38.2%, p = 0.003). All patients showed resolution of liver injury except for one man (1.1%) who developed liver failure and underwent liver transplantation. Steroid therapy was withdrawn during the observation period in 12 (26%) patients after complete biochemical resolution. None had a relapse during follow-up. CONCLUSIONS: SARS-CoV-2 vaccination can be associated with liver injury. Corticosteroid therapy may be beneficial in those with immune-mediated features or severe hepatitis. Outcome was generally favorable, but vaccine-associated liver injury led to fulminant liver failure in one patient.

Analysis of Outcomes in COVID-19 Patients With Varying Degrees of Hyperlipasemia.

OBJECTIVES: Coronavirus disease 2019 (COVID-19) patients may have varying degrees of hyperlipasemia. The aim was to compare outcomes among different levels of hyperlipasemia in patients with COVID-19. METHODS: This is a retrospective study examining outcomes among hospitalized COVID-19 patients with a lipase <3× upper limit of normal (ULN), asymptomatic hyperlipasemia (>3× ULN), secondary pancreatitis (typical respiratory COVID-19 symptoms and found to have pancreatitis), and primary pancreatitis (presenting with pancreatitis). RESULTS: Of 11,883 patients admitted with COVID-19, 1560 patients were included: 1155 patients had normal serum lipase (control group), 270 had elevated lipase <3× ULN, 46 patients had asymptomatic hyperlipasemia with lipase >3× ULN, 57 patients had secondary pancreatitis, and 32 patients had primary pancreatitis. On adjusted multivariate analysis, the elevated lipase <3× ULN and asymptomatic hyperlipasemia groups had worse outcomes with higher mortality (odds ratio [OR], 1.6 [95% confidence interval [CI], 1.2-2.2) and 1.1 [95% CI, 0.5-2.3], respectively), higher need for mechanical ventilation (OR, 2.8 [95% CI, 1.2-2.1] and 2.8 [95% CI, 1.5-5.2], respectively), and longer length of stay (OR, 1.5 [95% CI, 1.1-2.0] and 3.16 [95% CI, 1.5-6.5], respectively). CONCLUSIONS: Patients with COVID-19 with elevated lipase <3× ULN and asymptomatic hyperlipasemia have generally worse outcomes than those with pancreatitis.

Presentation, patterns and predictive value of baseline liver tests on outcomes in COVID-19 patients without chronic liver disease.

BACKGROUND: Coronavirus disease 2019 (COVID-19) infection is known to cause abnormal hepatic enzymes. The long term consequences of such elevations are uncertain. AIM: To assessed the prevalence and prognostic value of initial liver enzymes in a large cohort of COVID-19 patients. METHODS: We reviewed electronic medical records of 10614 COVID-19 patients without known chronic liver disease who were admitted to our health system from March 1, 2020, to April 30, 2020. We analyzed baseline demographics and liver chemistries. The primary outcome was in-hospital mortality, and the secondary outcome was a composite of in-hospital mortality or need for mechanical ventilation. RESULTS: Subjects with abnormal liver tests had increased risks of mortality and composite outcome when compared to patients with normal measurements on unadjusted analysis and after adjustment for demographic factors. CONCLUSION: In our diverse patient population, liver enzyme abnormalities are associated with increased mortality and the need for mechanical ventilation in subjects without chronic liver disease. Cholestasis patients are at the greatest risk for poor outcomes.

Impact of COVID-19 Pandemic on Liver Transplantation and Alcohol-Associated Liver Disease in the USA.

BACKGROUND AND AIMS: The surge in unhealthy alcohol use during the COVID-19 pandemic may have detrimental effects on the rising burden of alcohol-associated liver disease (ALD) on liver transplantation (LT) in the USA. We evaluated the effect of the pandemic on temporal trends for LT including ALD. APPROACH AND RESULTS: Using data from United Network for Organ Sharing, we analyzed wait-list outcomes in the USA through March 1, 2021. In a short-period analysis, patients listed or transplanted between June 1, 2019, and February 29, 2020, were defined as the "pre-COVID" era, and after April 1, 2020, were defined as the "COVID" era. Interrupted time-series analyses using monthly count data from 2016-2020 were constructed to evaluate the rate change for listing and LT before and during the COVID-19 pandemic. Rates for listings (P = 0.19) and LT (P = 0.14) were unchanged during the pandemic despite a significant reduction in the monthly listing rates for HCV (-21.69%, P < 0.001) and NASH (-13.18%; P < 0.001). There was a significant increase in ALD listing (+7.26%; P < 0.001) and LT (10.67%; P < 0.001) during the pandemic. In the COVID era, ALD (40.1%) accounted for more listings than those due to HCV (12.4%) and NASH (23.4%) combined. The greatest increase in ALD occurred in young adults (+33%) and patients with severe alcohol-associated hepatitis (+50%). Patients with ALD presented with a higher acuity of illness, with 30.8% of listings and 44.8% of LT having a Model for End-Stage Liver Disease-Sodium score ≥30. CONCLUSIONS: Since the start of COVID-19 pandemic, ALD has become the most common indication for listing and the fastest increasing cause for LT. Collective efforts are urgently needed to stem the rising tide of ALD on health care resources.

Association of non-alcoholic fatty liver disease and COVID-19: A literature review of current evidence.

The coronavirus disease 2019 (COVID-19) pandemic has swept through nations, crippled economies and caused millions of deaths worldwide. Many people diagnosed with COVID-19 infections are often found to develop liver injury, which, in a small portion of patients, progresses to severe liver disease. Liver injury in the form of elevated transaminases, hyperbilirubinemia and alterations in serum albumin has been observed to be higher in patients with severe forms of the disease. Those who already have insult to the liver from chronic disease, such as nonalcoholic fatty liver disease (NAFLD) may be at the greatest disadvantage. The severity of COVID-19 also seems to be driven by the presence of NAFLD and other co-morbidities. About 25% of the global population has NAFLD. With such a widespread prevalence of NAFLD, understanding the disease progression of COVID-19 and the occurrence of liver injury in this vulnerable population assumes great significance. In this review, we present an overview of COVID-19 infection in patients with NAFLD.

Gastrointestinal Sequelae 3 and 6 Months After Hospitalization for Coronavirus Disease 2019.

Gastrointestinal (GI) symptoms are highly prevalent in coronavirus disease 2019 (COVID-19) ranging from 17.6 % to 53 %.1-4 The proposed mechanism for GI symptoms involves SARS-CoV-2 virus binding to the host cell's angiotensin-converting enzyme-2 receptor, commonly found in GI tract epithelial cells.5.

Sex-Based Differences in COVID-19 Outcomes.

Background: Smaller studies suggest lower morbidity and mortality associated with coronavirus disease 2019 (COVID-19) in women. Our aim is to assess the impact of female sex on outcomes in a large cohort of patients hospitalized with COVID-19. Materials and Methods: This is a retrospective observational cohort study of 10,630 adult patients hospitalized with a confirmed COVID-19 polymerase chain reaction between March 1, 2020 and April 27, 2020, with follow-up conducted through June 4, 2020. Logistic regression was used to examine the relationship between sex and the primary outcomes, including length of stay, admission to intensive care unit (ICU), need for mechanical ventilation, pressor requirement, and all-cause mortality as well as major adverse events and in-hospital COVID-19 treatments. Results: In the multivariable analysis, women had 27% lower odds of in-hospital mortality (odds ratio [OR] = 0.73, 95% confidence interval [CI] 0.66-0.81; p < 0.001), 24% lower odds of ICU admission (OR = 0.76, 95% CI 0.69-0.84; p < 0.001), 26% lower odds of mechanical ventilation (OR = 0.74, 95% CI 0.66-0.82; p < 0.001), and 25% lower odds of vasopressor requirement (OR = 0.75, 95% CI 0.67-0.84; p < 0.001). Women had 34% less odds of having acute cardiac injury (OR = 0.66, 95% CI 0.59-0.74; p < 0.001; n = 7,289), 16% less odds of acute kidney injury (OR = 0.84, 95% CI 0.76-0.92; p < 0.001; n = 9,840), and 27% less odds of venous thromboembolism (OR = 0.73, 95% CI 0.56-0.96; p < 0.02; c-statistic 0.85, n = 9,407). Conclusions: Female sex is associated with lower odds of in-hospital outcomes, major adverse events, and all-cause mortality. There may be protective mechanisms inherent to female sex, which explain differences in COVID-19 outcomes.

Risk factors and outcomes for acute-on-chronic liver failure in COVID-19: a large multi-center observational cohort study.

OBJECTIVE: Coronavirus disease 2019 [COVID-19] infection in patients with chronic liver disease [CLD] may precipitate acute-on-chronic liver failure [ACLF]. In a large multi-center cohort of COVID-19-infected patients, we aim to analyze (1) the outcomes of patients with underlying CLD [with and without cirrhosis] and (2) the development and impact of ACLF on in-hospital mortality. DESIGN: We identified 192 adults with CLD from among 10,859 patients with confirmed COVID-19 infection (admitted to any of 12 hospitals in a New York health care system between March 1, 2020 and April 27, 2020). ACLF was defined using the EASL-CLIF Consortium definition. Patient follow-up was through April 30, 2020, or until the date of discharge, transfer, or death. RESULTS: Of the 84 patients with cirrhosis, 32 [38%] developed ACLF, with respiratory failure [39%] and renal failure [26%] being the most common. Hispanic/Latino ethnicity was particularly at higher risk of in-hospital mortality [adjusted HR 4.92, 95% 1.27-19.09, p < 0.02] in cirrhosis despite having lower risk of development of ACLF [HR 0.26, 95% CI 0.08-0.89, p = 0.03]. Hypertension on admission predicted development of ACLF [HR 3.46, 95% CI 1.12-10.75, p = 0.03]. In-hospital mortality was not different between CLD patients with or without cirrhosis [p = 0.24] but was higher in those with cirrhosis who developed ACLF [adjusted HR 9.06, 95% CI 2.63-31.12, p < 0.001] with a trend for increased mortality by grade of ACLF [p = 0.002]. There was no difference in in-hospital mortality between the CLD cohort compared to matched control without CLD (log rank, p = 0.98) and between the cirrhosis cohort compared to matched control without cirrhosis (log rank, p = 0.51). CONCLUSION: Development of ACLF is the main driver of increased in-hospital mortality in hospitalized patients with COVID-19 infection and cirrhosis.

Severity of liver test abnormalities in coronavirus disease 2019 depends on comorbidities and predicts early in-hospital mortality.

BACKGROUND AND AIMS: Liver chemistry abnormalities (LCA) are common in patients with coronavirus disease 2019 (COVID-19), but their causes and clinical impact have not been adequately studied. We assessed the associations between LCA and clinical characteristics, inflammatory serum markers, in-hospital mortality. METHODS: Ten thousand eight hundred fifty-six adult patients with COVID-19 hospitalized in 13 hospitals in New York (1 March to 27 April 2020) were analyzed retrospectively. Abnormalities of liver chemistries [aspartate aminotransferase (AST), alanine aminotransferase, alkaline phosphatase, or total bilirubin] were defined as absent, mild-moderate (at least one value up to four times elevated), or severe. RESULTS: LCA were mild-moderate in 63.9% and severe in 7.6% at admission. Risk factors for severe LCA were male sex and chronic liver disease. Conversely, hypertension and diabetes mellitus were less likely associated with severe LCA. AST elevation correlated weakly to modestly with inflammatory markers. On adjusted analysis, in-hospital mortality was 1.56 times and 1.87 times increased in patients with mild-to-moderate and severe LCA, respectively. Diabetes, hypertension, male sex, and age greater than 60 years was associated with incremental risk of mortality with increase severity of LCA, especially in the first week of hospitalization. HTN was not associated with increased in-hospital mortality unless LCA was present. CONCLUSION: Increasing severity of LCA on hospital admission predicts early in-hospital mortality in COVID-19 patients. Mortality associated with the known risk factors, hypertension, diabetes, male sex, and old age was accentuated in the presence of LCA. AST correlated modestly with inflammatory markers.

An early experience on the effect of solid organ transplant status on hospitalized COVID-19 patients.

We compared the outcome of COVID-19 in immunosuppressed solid organ transplant (SOT) patients to a transplant naïve population. In total, 10 356 adult hospital admissions for COVID-19 from March 1, 2020 to April 27, 2020 were analyzed. Data were collected on demographics, baseline clinical conditions, medications, immunosuppression, and COVID-19 course. Primary outcome was combined death or mechanical ventilation. We assessed the association between primary outcome and prognostic variables using bivariate and multivariate regression models. We also compared the primary endpoint in SOT patients to an age, gender, and comorbidity-matched control group. Bivariate analysis found transplant status, age, gender, race/ethnicity, body mass index, diabetes, hypertension, cardiovascular disease, COPD, and GFR <60 mL/min/1.73 m2 to be significant predictors of combined death or mechanical ventilation. After multivariate logistic regression analysis, SOT status had a trend toward significance (odds ratio [OR] 1.29; 95% CI 0.99-1.69, p = .06). Compared to an age, gender, and comorbidity-matched control group, SOT patients had a higher combined risk of death or mechanical ventilation (OR 1.34; 95% CI 1.03-1.74, p = .027).

Liver injury in COVID-19: The hepatic aspect of the respiratory syndrome - what we know so far.

The 2019 novel coronavirus disease (COVID-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a serious threat to global public health. Although primarily, the infection causes lung injury, liver enzyme abnormalities have also been reported to occur during the course of the disease. We conducted an extensive literature review using the PubMed database on articles covering a broad range of issues related to COVID-19 and hepatic injury. The present review summarizes available information on the spectrum of liver involvement, the possible mechanisms and risk factors of liver injury due to SARS-CoV-2 infection, and the prognostic significance of the presence of liver injury. Hopefully, this review will enable clinicians, especially the hepatologists, to understand and manage the liver derangements they may encounter in these patients better and provide guidance for further studies on the liver injury of COVID-19.

Cytokine-induced liver injury in coronavirus disease-2019 (COVID-19): untangling the knots.

Liver dysfunction manifesting as elevated aminotransferase levels has been a common feature of coronavirus disease-2019 (COVID-19) infection. The mechanism of liver injury in COVID-19 infection is unclear. However, it has been hypothesized to be a result of direct cytopathic effects of the virus, immune dysfunction and cytokine storm-related multiorgan damage, hypoxia-reperfusion injury and idiosyncratic drug-induced liver injury due to medications used in the management of COVID-19. The favored hypothesis regarding the pathophysiology of liver injury in the setting of COVID-19 is cytokine storm, an aberrant and unabated inflammatory response leading to hyperproduction of cytokines. In the current review, we have summarized the potential pathophysiologic mechanisms of cytokine-induced liver injury based on the reported literature.

Gastrointestinal bleeding in hospitalized COVID-19 patients: a propensity score matched cohort study.

BACKGROUND AND AIMS: Gastrointestinal (GI) bleeding has been observed amongst patients hospitalized with COVID-19. Recently, anticoagulation has shown to decrease mortality, but it is unclear whether this contributes to increased GI bleeding. The aims of this study are: (i) to examine whether there are risk factors for GI bleeding in COVID-19 patients and (ii) to study whether there is a mortality difference between hospitalized patients with COVID-19 with and without GI bleeding. METHODS: This is a propensity score matched case-control study from a large health system in the New York metropolitan area between March 1st and April 27th. COVID-19 patients with GI bleeding were matched 1:1 to COVID-19 patients without bleeding using a propensity score that took into account comorbidities, demographics, GI bleeding risk factors and length of stay. RESULTS: Of 11, 158 hospitalized with COVID-19, 314 patients were identified with GI bleeding. The point prevalence of GI bleeding was 3%. There were no identifiable risk factors for GI bleeding. Use of anticoagulation medication or antiplatelet agents was not associated with increased risk of GI bleeding in COVID-19 patients. For patients who developed a GI bleed during the hospitalization, there was an increased mortality risk in the GI bleeding group (OR 1.58, P = 0.02). CONCLUSION: Use of anticoagulation or antiplatelet agents was not risk factors for GI bleeding in a large cohort of hospitalized COVID-19 patients. Those with GI bleeding during the hospitalization had increased mortality.

Role of Nutraceuticals in COVID-19 Mediated Liver Dysfunction.

COVID-19 is known as one of the deadliest pandemics of the century. The rapid spread of this deadly virus at incredible speed has stunned the planet and poses a challenge to global scientific and medical communities. Patients with COVID-19 are at an increased risk of co-morbidities associated with liver dysfunction and injury. Moreover, hepatotoxicity induced by antiviral therapy is gaining importance and is an area of great concern. Currently, alternatives therapies are being sought to mitigate hepatic damage, and there has been growing interest in the research on bioactive phytochemical agents (nutraceuticals) due to their versatility in health benefits reported in various epidemiological studies. Therefore, this review provides information and summarizes the juncture of antiviral, immunomodulatory, and hepatoprotective nutraceuticals that can be useful during the management of COVID-19.

What GI Physicians Need to Know During COVID-19 Pandemic.

The worldwide pandemic of COVID-19, caused by the virus SARS-CoV-2, continues to cause significant morbidity and mortality in both low- and high-income countries. Although COVID-19 is predominantly a respiratory illness, other systems including gastrointestinal (GI) system and liver may be involved because of the ubiquitous nature of ACE-2 receptors in various cell lines that SARS-CoV-2 utilizes to enter host cells. It appears that GI symptoms and liver enzyme abnormalities are common in COVID-19. The involvement of the GI tract and liver correlates with the severity of disease. A minority (10-20%) of patients with COVID-19 may also present initially with only GI complaints. The most common GI symptoms are anorexia, loss of smell, nausea, vomiting, and diarrhea. Viral RNA can be detected in stool in up to 50% of patients, sometimes even after pharyngeal clearance, but it is unclear whether fecal-oral transmission occurs. Liver enzymes are elevated, usually mild (2-3 times), in a substantial proportion of patients. There are many confounding factors that could cause liver enzyme abnormalities including medications, sepsis, and hypoxia. Although infection rates in those with preexisting liver disease are similar to that of general population, once infected, patients with liver disease are more likely to have a more severe disease and a higher mortality. There is a paucity of objective data on the optimal preventive or management strategies, but few recommendations for GI physicians based on circumstantial evidence are discussed.

Prevalence of chronic liver disease in patients with COVID-19 and their clinical outcomes: a systematic review and meta-analysis.

Abnormal liver enzymes are seen in 20% of hospitalized patients with COVID-19. The etiology of elevated liver enzymes is thought to be multifactorial including medications and underlying liver disease. The true prevalence and clinical significance of underlying chronic liver diseases (CLD) in COVID-19 remains poorly defined. In this systematic review and meta-analysis, we included 74 clinical studies that were identified after a thorough literature search across three databases. The prevalence of CLD patients (73 studies, 24,299 patients) was 3% among all COVID-19 patients. The prevalence of CLD patients was similar in COVID-19 positive and negative population (pooled OR 0.79 [95% CI 0.60, 1.05], p = 0.10). The presence of CLD was significantly associated with more severe COVID-19 infection (pooled OR 1.48 [95% CI 1.17, 1.87], p = 0.001) and overall mortality (pooled OR 1.78 [95% CI 1.09, 2.93], p = 0.02). Additionally, there was a non-significant trend noted for increased ICU admissions and need for invasive mechanical ventilation among COVID-19 patients with CLD. To date, the clinical importance of chronic liver diseases among COVID-19 infection has remained undefined. In this novel systematic review and meta-analysis, the presence of underlying chronic liver disease was significantly associated with more severe COVID-19 infections and mortality.

Elevated Liver Biochemistries in Hospitalized Chinese Patients With Severe COVID-19: Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Several recent studies have reported an abnormal liver chemistry profile among patients with coronavirus disease 2019 (COVID-19), although its clinical significance remains unknown. APPROACH AND RESULTS: This systematic review and meta-analysis identified six studies of 586 patients delineating liver chemistries among patients with severe/critical illness versus mild cases of COVID-19 infection. Patients with severe/critical illness with COVID-19 infection have increased prevalence of coronary artery disease, cerebrovascular disease, and chronic obstructive pulmonary disease as compared with mild cases. A significant association between severe/critical COVID-19 infections with elevations in aspartate aminotransferase (pooled mean difference [MD], 11.70 U/L; 95% confidence interval [CI], 2.97, 20.43; P = 0.009), elevated total bilirubin (pooled MD, 0.14 mg/dL; 95% CI, 0.06, 0.22; P = 0.0005), and decreased albumin (pooled MD, -0.68 g/L; 95% CI, -0.81, -0.55; P < 0.00001) was noted. There was also a trend toward elevated alanine aminotransferase levels among these severe cases (pooled MD, 8.84 U/L; 95% CI, -2.28, 19.97; P = 0.12); however, this did not reach statistical significance. More severe/critically ill cases were associated with leukocytosis, neutrophilia, lymphopenia, elevated creatinine kinase, elevated lactate dehydrogenase (LDH), and elevated prothrombin time (PT). CONCLUSIONS: Comorbidities, including coronary artery disease, cerebrovascular disease and chronic obstructive pulmonary disease, are more prevalent in hospitalized Chinese patients with severe/critical illness from COVID-19, and these patients are more likely to manifest with abnormal liver chemistries. Further prospective studies are crucial to understand the pathophysiologic mechanisms underlying the hepatic manifestations of the novel COVID-19 infection and its clinical significance.