Trends and Outcomes of Acute Liver Failure in patients with COVID-19 Infection: Insights from National Inpatient Sample Analysis 2020-2022

1. Introduction

Since its emergence in late 2019, COVID-19 infection, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has become a major global health concern, with significant morbidity and mortality affecting 770 million people and resulting in 6.9 million deaths [1]. Although COVID-19 primarily affects the respiratory system, increasing evidence indicates multisystem involvement, including cardiovascular, renal, neurological, hematological, and gastrointestinal complications. Generally, 10.5%–69.0% of hospitalized patients infected with COVID-19 presented with abnormal liver function [2].

Acute liver failure (ALF) is defined as a rapid onset of hepatocellular damage resulting in abnormal liver biochemical tests, particularly Aspartate Aminotransferase and Alanine Aminotransferase (AST and ALT), occurring over days to weeks in patients with or without previously known liver disease. ALF may occur secondary to viral infections, drug-induced hepatotoxicity, ischemia, autoimmune disease, toxins, or systemic inflammatory conditions such as COVID-19 [3,4].

ALI (Acute Liver Injury) is generally distinguished from acute liver failure (ALF) by the absence of hepatic encephalopathy and severe synthetic dysfunction. Progression to ALF occurs when acute liver injury is accompanied by coagulopathy (INR ≥1.5) and hepatic encephalopathy in a patient without preexisting cirrhosis [5].

The pathogenesis of hepatic injury in COVID-19 is multifactorial. Proposed mechanisms include direct viral cytopathic effects through angiotensin-converting enzyme-2 (ACE-2) receptor expression in cholangiocytes and hepatocytes, immune-mediated inflammation, cytokine storm, ischemic hepatitis due to hypoxia and shock, microvascular thrombosis, drug-induced liver injury, and sepsis-associated multiorgan dysfunction [6,7].

Acute liver failure (ALF) is a life-threatening syndrome characterized by rapid hepatic dysfunction, coagulopathy, and encephalopathy in patients without preexisting cirrhosis [8]. Viral infections are recognized causes of acute liver failure, and emerging reports have described SARS-CoV-2 infection precipitating severe acute hepatitis and acute liver failure, even in patients without significant respiratory symptoms [2,9].

Although several studies have evaluated liver enzyme abnormalities in COVID-19, there is limited large-scale national data examining the impact of concurrent COVID-19 infection on outcomes in patients hospitalized with acute liver failure. Understanding this association is important for early recognition, risk stratification, and management of this high-risk population. Therefore, we conducted a retrospective cohort study using the National Inpatient Sample (NIS) database from 2020 to 2022 to evaluate the effect of COVID-19 infection on clinical outcomes, including in-hospital mortality, need for ventilatory support, and length of stay among patients admitted with acute liver failure.

2. Materials and Methods

We conducted a retrospective cohort study using the National Inpatient Sample Database (NIS) from 2020 to 2022. The NIS is the largest inpatient database with a survey design that collects discharged information from non-federal, non-rehabilitation, acute care, and short-term hospitals. Its database is derived from billing data submitted by hospitals to statewide data organizations across the USA, covering more than 97% of the US population. Institutional Review Board (IRB) approval was not required because the NIS is a publicly available deidentified database.

We included all patients admitted from January 2020 to December 2022 with a diagnosis of acute liver failure and COVID-19 infection according to the International Classification of Diseases, 10 revision (ICD-10) codes. Stratification of patients with acute liver failure was based on the presence or absence of concurrent COVID-19 infection.

The primary outcome of interest in this study was to investigate the impact of COVID-19 infection on in-hospital mortality among hospitalized patients with acute liver failure. Secondary outcomes included the need for Invasive Mechanical Ventilation, Non-invasive Ventilation (NIV), and Length of Stay (LOS) in days. Covariates used in this study included age, sex, race, median household income quartile, insurance, Charlson Comorbidity index (derived from diagnosis fields and categorized as 0, 1, 2, >=3), hospital region, hospital location/teaching status and hospital bed size.

The patient information and data were analyzed using StataBE 17.0. The NIS uses a complex sampling design that includes stratification, clustering, and weighting of patient- and hospital-level data to facilitate analyses and produce nationally representative results, variance estimates, and p-values. Continuous variables were presented as median and interquartile range as well as mean and standard error. Categorical/Dichotomous variables were presented as percentages. Survey-weighted multivariate logistic regression analyses estimated adjusted odds ratios for mortality, invasive ventilation, and NIV; multivariate linear regression analysis assessed associations with LOS. Statistical significance was defined as a p-value <0.05.

3. Results

From the 2020-2022 NIS Database, we identified 5,934,565 adult patients with COVID-19 infection and 618,515 adult patients with acute liver failure. Among the patients with acute liver failure, 65,565 patients had concurrent COVID-19 infection, whereas 552,950 patients did not have concurrent COVID-19 infection (Figure 1). Demographic and clinical characteristics are described in Table 1.

The mean age of patients with acute liver failure was found to be similar in both the cohorts, with a mean age of 62.3 in patients with COVID-19 infection and 61.7 in patients without COVID-19 infection.

The distribution of patients with acute liver failure without COVID-19 infection was 55.8% male and 44.2% female, whereas those with COVID-19 infection comprised 59.0% male and 41.0% female. (Figure 2)

In terms of race distribution, as shown in Figure 3, Caucasians formed the largest group, 65.4%, vs 59.2%, followed by African Americans, 14.7% vs 18.3%, Hispanics, 12.3% vs 19.5%, Asian Pacific Islander, 3.1% vs 3.7%, Native Americans, 1.1% vs 1.2%, and other races, 3.3% vs 4.4%. in non-COVID-19 and COVID-19 cohorts, respectively, with a p < 0.001.

Patients in the lowest national income (Figure 4) quartile of 1-38,999 represented 31.9% with acute liver failure without COVID-19 and 33.4% with COVID-19 infection. The rest of the income quartiles included 39,000-47,999 (26.5% vs 26.6%) and 48,000-62,999 (23.2%) for both cohorts, and the national income quartile >63,000 was the least affected (18.4% vs 16.6%), with p < 0.001.

In terms of insurance coverage, as highlighted in Figure 5, Medicaid patients were amongst the largest group, with 52.5% of patients with acute liver failure without COVID-19 infection and 51.1% with COVID-19 infection. Medicare patients were 20.0% vs 18.5%, private insurance patients were 22.3% vs 26.1%, and uninsured patients were 5.1% vs 4.3%, respectively, with a p <0.001.

The Charlson Comorbid Index (CCI) distribution was based on the CCI scores. CCI scores of >=3 showed 62.9% of patients with acute liver failure without COVID-19 infection and 47.6% with COVID-19 infection, CCI of 2 with 14.9% vs 18.6%, CCI 1 with 14.6% vs 20.6%, and CCI 0 with 7.6% vs 13.2%, respectively, for those without and with COVID-19 infection in patients with acute liver failure, with a p<0.001. This is highlighted in Figure 6.

Most of the hospitalizations were in the Southern region, with 42.1% patients with acute liver failure without COVID-19 and 42.6% with COVID-19 infection. Following this was the Western region with 21.6% vs 21.1%, the Mid-West 20.0% vs 18.6%, and the Northeast 16.3% vs 17.7%, with a p<0.001 as shown in Figure 7.

Figure 8 shows urban teaching hospitals accounted for most patients with 78.8% of acute liver failure without COVID-19 and almost similar at 78.7% with COVID-19 infection, followed by urban, non-teaching hospitals with 15.4% vs 15.8%, and rural hospitals with 5.7% vs 5.4%, with a p value of 0.3.

3.1. Clinical Outcomes

Patients with acute liver failure with COVID-19 infection had worse outcomes as compared to patients without COVID-19, with a mortality rate of 63.7% vs 35.3%, need for invasive ventilation 68.5% vs 40.9%, NIV (non-invasive ventilation)15.0% vs 6.5%, and length of stay 17.1 days vs 10.7 days in patients with acute liver failure with and without COVID-19 infection, respectively, with a p<0.001. (Figure 9).

It was noted that patients with acute liver failure with COVID-19 infection were independently associated with increased odds of adverse outcomes. The adjusted odds ratio (95% CI) for length of stay was 6.33 (5.96-6.69), mortality was 3.28 (3.14-3.42), invasive ventilation was 2.99(2.86-3.12), and NIV was 2.54 (2.39-2.69), respectively, all with a p<0.001. These findings are highlighted in Figure 10 and Figure 11.

3.2. Proportion of Mortality

Figure 12 highlights that among patients with acute liver failure with COVID-19 infection, mortality trends remained high at 69.5% in 2021, and at 69.0% in 2020, and trended down to 51.6% in 2022.

4. Discussion

In our analysis of adult hospitalizations for acute liver failure, concurrent COVID-19 was associated with a worse in-hospital course. Compared with patients without COVID-19, those with COVID-19 had higher in-hospital mortality (63.7% vs 35.3%), greater use of noninvasive ventilation (15.0% vs 6.5%) and invasive mechanical ventilation (68.5% vs 40.9%), and a longer hospital stay (17.1 vs 10.7 days). These differences persisted after adjustment for demographic and clinical factors. COVID-19 remained independently associated with higher odds of death, invasive mechanical ventilation, and noninvasive ventilation, as well as increased length of stay. Notably, patients in the COVID-19 group had a lower proportion of Charlson Comorbidity Index scores ≥3, suggesting that the worse outcomes were not simply explained by a greater baseline burden of comorbidity. Taken together, our findings suggest that concurrent SARS-CoV-2 infection substantially worsens the hospital course of patients admitted with acute liver failure.

Most prior studies have described liver involvement in COVID-19 as common but usually mild. The updated EASL (European Association for the Study of the Liver) position paper reported acute liver injury in approximately 10% to 65% of infected patients, most often with mild aminotransferase elevations, whereas severe liver injury with hyperbilirubinemia and hepatic synthetic dysfunction was considered uncommon [10]. Similarly, the earlier EASL-ESCMID (European Association of the Study of the Liver-the European Society of Clinical Microbiology and Infectious Diseases) position paper reported abnormal liver biochemistry in 19% to 76% of patients, usually in a hepatocellular pattern [6]. Other reviews have estimated that liver dysfunction occurs in about one-third of patients with COVID-19 and is more often seen in men and older adults [11,14,21,22,23]. Additional studies have shown that abnormal liver tests are more frequent in patients with severe disease and may correlate with worse outcomes, longer hospitalization, organ failure, ICU (intensive care unit) admission, and mortality [15,16,17,18,19,21,24,25,26,27]. Against that background, progression to acute or fulminant liver failure appears to be rare. [10,11,14]

Even so, severe hepatic presentations have been reported. Melquist et al. described acute hepatic failure as the presenting manifestation of COVID-19 in a young woman without significant respiratory symptoms [12]. Matsuki et al. later reported COVID-19-triggered acute liver failure with rhabdomyolysis and reviewed additional cases of SARS-CoV-2-associated acute liver failure in the literature [13]. Our findings build on those reports by showing that, at the national level, patients with both COVID-19 and acute liver failure had markedly worse in-hospital outcomes. [12,13]

The mechanism behind this association is likely multifactorial. Current literature suggests that liver injury in COVID-19 may result from direct viral effects on hepatocytes or cholangiocytes, immune-mediated injury, cytokine-driven inflammation, ischemic or hypoxic hepatitis in severe illness, microvascular thrombosis, drug-induced liver injury, and sepsis-related multiorgan dysfunction [9,10,11,14,22,23,24,25,26,27]. Direct hepatic involvement has also been supported by reports demonstrating SARS-CoV-2 infection in liver tissue.[9] In addition, several studies have shown that the presence and severity of liver injury correlate with overall disease severity and clinical outcomes in COVID-19 [10,15,16,17,18,19,21]. In patients with acute liver failure, who already have limited physiologic reserve, these overlapping insults may further destabilize an already critical condition. This is consistent with the greater need for ventilatory support, and the excess mortality observed in our cohort.

We also found differences in the demographic profile of affected patients. Those with concurrent COVID-19 were slightly older, more often male, and more frequently Hispanic or African American. The male predominance in our cohort is in line with prior reports showing that liver dysfunction during COVID-19 is more common in men and older adults [11,14,15,16,19,21]. The racial and ethnic differences we observed may reflect disparities in exposure risk, severity at presentation, access to care, and broader social determinants of health, although those factors cannot be directly measured in the NIS database.

From a clinical standpoint, these findings support close monitoring for hepatic decompensation in hospitalized patients with COVID-19, especially when mental status changes, coagulopathy, or rapidly worsening liver tests are present. The EASL position paper recommends regular assessment of Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALT), Gamma-Glutamyl Transferase (GGT), Alkaline Phosphatase (ALP), and bilirubin during hospitalization with COVID-19.[10] For patients with both acute liver failure and COVID-19, early intensive care involvement, aggressive supportive management, timely respiratory support, and hemodynamic optimization may be particularly important. Prior studies show that abnormal liver biochemistry in COVID-19 is associated with more severe disease, longer hospitalization, ICU admission, and mortality further support the importance of recognizing hepatic involvement early. [6,15,16,17,18,19,21,23,24,25,26,27]

Limitations:

As a retrospective analysis of an administrative database, it is subject to residual confounding. The NIS database does not provide timing of COVID-19 relative to hepatic injury, medication exposure, ICU-specific interventions, transplant candidacy, vaccination status, viral variant, or post-discharge outcomes. In addition, the database does not allow us to determine whether COVID-19 directly caused liver injury or whether the observed association was mediated through hypoxia, shock, systemic inflammation, drug-induced liver injury, or sepsis-related multiorgan dysfunction. These mechanisms are biologically plausible based on the current liver-COVID literature, but they cannot be separated in this dataset [9,10,11,14,17,22,23,24,25,26,27]. Despite these limitations, the large sample, significant impact on clinical outcomes, mortality trend, and consistency of the adjusted findings suggest that patients with concurrent COVID-19 and acute liver failure represent a particularly high-risk group.

5. Conclusions

Among adults hospitalized with acute liver failure, concurrent COVID-19 was associated with markedly worse in-hospital outcomes, including higher mortality, greater need for ventilatory support, and longer hospitalization. These findings highlight that patients with both conditions (acute liver failure and COVID-19) are a particularly high-risk group who warrant early multidisciplinary management and intensive supportive care. Although severe hepatic involvement through acute liver failure is uncommon in COVID-19, when present, it is associated with substantially worse clinical outcomes in this population. Further studies are needed to clarify the mechanisms underlying this association and to determine whether earlier recognition or targeted treatment can improve outcomes.