The effect of metabolic dysfunction-associated steatotic liver disease on the disease progression in patients with COVID-19 associated pneumonia

Introduction

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) [named earlier non-alcoholic fatty liver disease (NAFLD)] is a common form of chronic liver disease, found in more than a quarter of the world population (1-3). Presence of steatosis in >5% of hepatocytes, in addition to inflammation and liver cell damage caused by type 2 diabetes mellitus (T2DM), or obesity or overweight, or metabolic risk abnormalities (4), increases the risk of liver steatosis to develop further into fibrosis (scarring of the liver). Liver histology and imaging techniques are used to establish the degree of fat infiltration and staging of fibrosis (5).

Rationale and knowledge gap

The coronavirus disease 2019 (COVID-19), caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has led to approximately 7 million deaths amongst more than 777 million infected people worldwide during the years 2019 to 2024 (6). Studies have shown that liver steatosis as a hepatic manifestation of metabolic syndrome could be a potential risk factor for the development of severe COVID-19 infection and complications (7-11). People with liver steatosis (≥10%), irrespective of their body weight, were at an increased risk of acquiring SARS-CoV-2 infection [odds ratio (OR) =1.35; P=0.007] and significantly increased the odds of being hospitalised (P=0.003) with a positive test result for COVID-19 (12). Steatosis was the cause of the higher number of abnormal liver test results and a longer duration of the SARS-CoV-2 infection (13). A meta-analysis by Jagirdhar and co-authors, including 32 studies with 43,388 participants, showed that mortality in the NAFLD group was not higher [837 out of 7,950 people (10.52%)] than the mortality in the non-NAFLD group [1,171 out of 34,304 people (3.41%)], OR of 1.38; 95% CI: 0.97–1.95; P=0.07, and the average difference in hospital length of stay between the NAFLD and non-NAFLD groups was 1.99 days (95% CI: 0.71–3.27; P=0.002) (14).

A negative effect of MASLD on the course and clinical outcomes, such as in-hospital mortality, in people with COVID-19 infection was also observed in another study, but the correlation was not statistically significant (15). The effect of COVID-19 on liver function, manifested immediately at the onset of the disease by a mild to moderate increase in the level of alanine aminotransferase (ALT) or aspartate aminotransferase (AST), or both was shown by Chen and co-authors (16). Brilakis and co-authors noted that there was an unmet need for further studies to explore the relationship between MASLD and the course of COVID-19, and how SARS-COV-2 could lead to the onset and progression of MASLD (17). The possible relationship between the presence or absence of liver steatosis and COVID-19-associated pneumonia in Russian patients has not been studied.

Objective

The aim of our Russian cohort study was to evaluate the effect of MASLD as a risk factor for the severity of COVID-associated pneumonia (COVID-AP).

Outcomes

Our primary outcomes were mortality and severity of COVID-AP in people with MASLD, determined by the following parameters: stage of the lesion on the computed tomography (CT) scanning during hospitalisation, stage of deterioration on the CT scanning, the level of C-reactive protein (CRP) and biological therapy requirement. Our secondary outcomes were duration of hospitalisation and prevalence of MASLD in hospitalised people with COVID-AP. We present this article in accordance with the STROBE reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-24/rc) (18).

Methods

Participant’s selection and study design

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Local Ethics Committee of Sechenov University (protocol No. 04-21 of 04/18/2021) and informed consent was obtained from all individual participants. We conducted a cohort prospective study with inclusion of 100 patients (at least 18 years old) in the order admitted to the hospital, of any sex, admitted to the department of infectious diseases at the University Clinical Hospital No. 4, Sechenov University (Moscow), from November 2021 to January 2022, to be treated for COVID-AP. Study participants received information on the study. All had a laboratory-confirmed diagnosis of coronavirus infection and were treated in accordance with the temporary guidelines “Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)” dated 10/26/2020 (19). Biomaterial, a smear from the nasopharynx (from two nasal passages) and the oropharynx, was taken for laboratory research on ribonucleic acid (RNA) SARS-CoV-2. Laboratory research results were due within 48 hours of the immediate receipt of the biological material. Confirmation of the diagnosis of COVID-19 was considered a positive result of a laboratory test for the presence of SARS-CoV-2 of SARS-CoV-2 RNA using nucleic acid amplification methods, SARS-CoV-2 antigen using immunochromatographic analysis, or a positive result for antibodies of the immunoglobulin (Ig)A, IgM and/or IgG SARS-CoV-2. The diagnosis of COVID-associated pneumonia was confirmed with a positive test result combined with pneumonia on CT.

Definitions and data collection

All participants gave their consent to participate in the study by signing a consent form. During the history taking, all possible secondary causes of liver steatosis were excluded, and alcohol consumption was assessed. More than 30 g of pure ethanol per day for men and more than 20 g for women was considered excessive alcohol consumption. To exclude alcoholic fatty liver disease, participants were asked to fill out the alcohol use disorders identification test (AUDIT) questionnaire where 0 to 4 for women and 0 to 8 for men were considered a relatively low risk of alcohol-related problems, 5 to 9 and 9 to 13 points were considered dangerous alcohol consumption, 10 and 14 to 16 were considered harmful alcohol consumption, and more than 11 and 17 were considered a risk of possible alcohol dependence (20). During the objective examination, height, body weight, and waist circumference were measured, and body mass index (BMI) was calculated. The presence of obesity was defined as a BMI of more than 30 kg/m² (21). A waist circumference of more than 80 cm in women and more than 94 cm in men was regarded as a central (abdominal) type of obesity, one of the signs of the presence of metabolic syndrome (22,23). The density of the liver and spleen was determined by examining two regions of interest (ROI) in the right lobe of the liver and one ROI in the spleen (24). Several approaches were used to detect significant liver steatosis (more than 30%) using CT: liver density less than 40 Hounsfield units (HU); weakening of liver density by at least 10 HU less than that of the spleen; the ratio of attenuation of liver density to spleen is less than 0.9 (25). The percentage of lung tissue lesions was estimated according to the results of imaging findings from CT of the chest as stage 1 (CT1) 0% to 25%, stage 2 (CT2) 26% to 50%, stage 3 (CT3) 51% to75%, and stage 4 (CT4) 76% to100%. Indicators of prognostic laboratory markers were considered in all participants: general (clinical) blood analysis with determination of the level of erythrocytes, leukocytes, platelets; biochemical blood analysis (ALT, AST); CRP, activated partial thromboplastin time (APTT), and prothrombin index. The exclusion criteria were the presence of markers of viral hepatitis B and/or C, human immunodeficiency virus (HIV) infection, excessive alcohol consumption, the presence of secondary liver steatosis, hereditary diseases, and pregnancy. All participants were prescribed standard glucocorticosteroid therapy and an anticoagulant drug for parenteral administration in a prophylactic dose.

Statistical analysis

Statistical analysis was performed using the SPSS program, Version 22. To select a statistical criterion for evaluating quantitative variables, their distribution was previously compared with the normal one (separately for MASLD and control groups) using the Kolmogorov-Smirnov criterion. Under normal distribution, the Student’s criterion was used to assess the statistical significance of the differences. If the distribution of the parameter in at least one of the groups was statistically significantly different from normal, the Mann-Whitney criterion was chosen. The values of normally distributed variables are represented as the mean ± standard deviation (SD). If the distribution of the variable does not correspond to the normal one, the value of the variable is represented as median [interquartile range (range)]. To assess the statistical significance of the differences in the values of qualitative variables, the Chi-squared test or the Fisher’s exact test was used (if the expected values were less than 5 in more than 25% of the cells). P≤0.05 was taken as the level of significance. To identify the parameters affecting mortality and eliminate possible biases associated with their interfering effect on each other, a multifactorial analysis was carried out with the construction of a logistic regression model, in which the presence of a fatal outcome was used as a dependent variable. Spearman’s correlation coefficient between mortality and potential predictor variables was calculated. The selection condition was P<0.1. The Mantel-Haenszel Chi-squared test was used for this statistical procedure to evaluate the association between two categorical variables while controlling for the effects of a third categorical variable.

Results

One hundred participants were screened; one participant was excluded from the study due to alcohol abuse (AUDIT 17). Based on the CT results, 2 groups were identified: 25 (25.25%) participants with MASLD and 74 (74.75%) participants in the control group without signs of significant steatosis. The groups were comparable by sex (P=0.58) and age (56.84±14.93 and 57.00±16.19 years; P=0.96). The incidence of hypertension (HTN) (P=0.52) and T2DM (P=0.06) in the participants’ life history was similar (Tables 1,2).

The BMI was significantly higher in the participants with MASLD than in the control group (32.35±5.05 and 27.87±5.27 kg/m²; P<0.001), and obesity was also more common in the MASLD group than in the control group (68% vs. 29.73%; P=0.001). The MASLD group also had higher waist circumference, considered as one of the criteria for metabolic syndrome (102.84±11.79 vs. 91.05±11.95 cm; P<0.001).

The liver density was lower in the MASLD group than in the control group, which corresponds to the significant presence of fat accumulation (31.68±10.67 vs. 54.44±5.95 HU; P<0.001). The spleen density was comparable in the two groups (47.98±3.87 vs. 47.18±2.72 HU; P=0.34). As a result, the ratio of attenuation of liver density to spleen was lower in the MASLD group than in the control group (0.66±0.22 vs. 1.16±0.13, P<0.001).

A more severe course of COVID-19 pneumonia was observed in the MASLD group on admission (P=0.04). The frequency of deterioration, based on CT data, was comparable in both groups [19 (76%) vs. 45 (60.8%); P=0.16], although its severity based on the percentage of lung damage was higher in the MASLD group (P=0.01) (Table 3). Control CT was not performed in all patients before discharge from the hospital due to the initially low level of lung damage (CT1).

Higher levels of CRP (P=0.01), AST (P<0.001), and ALT (P=0.003) were observed in the MASLD group compared with the control group. The other main prognostic laboratory markers were comparable in both groups during hospitalisation and deterioration (Table 4).

Participants in the MASLD group were more often prescribed biological and antibiotic therapy. We assessed the components of the metabolic syndrome as independent risk factors. No association with T2DM (P=0.61) and HTN (P=0.76) was found. The relationship between the need for biological therapy with steatosis (OR =11.4; 95% CI: 3.1–41.5; P<0.001) and obesity (OR =2.3; 95% CI: 1.02–5.4; P=0.04) has been established. To eliminate the possible impact of obesity and hepatic steatosis on each other, the Mantel-Hensel test was used. The adjusted OR for steatosis was 10.2; 95% CI: 2.6–38.8; P=0.001, the OR for obesity was 1.39; 95% CI: 0.54–3.5; P=0.49. The need for antibiotic therapy was associated with steatosis (OR =3.1; 95% CI: 1.2–8.1; P=0.02) and T2DM (OR =6.8; 95% CI: 1.4–32.7; P=0.008). To eliminate the possible interfering effect of T2DM, the Mantel-Hensel test was used; the adjusted OR for steatosis was 2.6; 95% CI: 0.97–7.03; P=0.057. No association with obesity (P=0.65) and HTN (P=0.77) was found (Table 5).

Amongst patients diagnosed with MASLD, the median of the duration of hospitalisation was 15.00 days (IQR, 12.00–20.50 days) compared to 13.00 days (IQR, 11.00–17.00 days) in the control group (P=0.07). Mortality was increased in the MASLD group with significant steatosis: 12% (3 participants) vs. 0% in control group, P=0.02.

Discussion

Key findings

Participants in the MASLD group had an initially higher stage of CT lesions, a significant increase in CRP and hepatic aminotransferases. The frequency of deterioration of COVID-AP in people on basic therapy was comparable, while in the MASLD group there was a significantly higher stage of CT lung lesions. In the MASLD group, antibiotic and biological therapy were more often prescribed. Liver steatosis, regardless of other metabolic risk factors, increased the need for biological therapy. However, the association of steatosis and the need for antibiotic therapy was a consequence of the confounding factor, T2DM. The duration of hospitalisation did not differ between the groups, which may be due to the epidemiological situation. In the situation of the pandemic, discharge is carried out under conditions that allow continued outpatient treatment, but not until full recovery. In the MASLD group, mortality was higher. Thus, our study showed a more severe course of COVID-AP in people with MASLD.

Strengths and limitations

The strength of our study is the exclusion of the possible effect of alcohol on the development of liver steatosis, not only according to the clinical record (this information may sometimes be missing from the clinical record in a retrospective study of the data), but also due to the survey of each participant of the questionnaire AUDIT. Also, our study allowed to evaluate the independent effect of liver steatosis on the course of COVID-AP in patients with MASLD, regardless of other metabolic risk factors.

Our study has several limitations. On one hand, the limitations are related to the lack of morphological confirmation of liver steatosis, which is the reference standard for verification of MASLD, and on the other hand, the study did not consider the degree of liver steatosis (mild, moderate, and severe). The criteria used for steatosis indices according to CT data correspond to the diagnosis of moderate and severe liver steatosis, which primarily presents a serious problem. It is also important to note that the potential danger of radiation exposure makes CT unsuitable for the primary diagnosis and monitoring of patients with MASLD.

Comparison with similar research

The prevalence of MASLD amongst our sample of 99 patients was 25.25%, which is comparable to the general prevalence of the population (26,27). Our results are also consistent with the theory of intensified cytokine storm in obese COVID-19 patients (28,29). At the same time, the meta-analysis by Singh and co-authors showed an increased risk of severe COVID-19 infection and admission to intensive care unit due to COVID-19, but no difference in mortality between NAFLD and non-NAFLD patients (30).

Explanations of findings

According to available data, MASLD may be a risk factor for the development of severe COVID-19, critical conditions, and mortality. Possible causes of this include increased immunological dysregulation associated with excessive fat accumulation. The mechanisms underlying this relationship are not yet fully understood. It has been proven that MASLD is a chronic inflammation of low severity, which may be a favorable background for the development of a cytokine storm in COVID-19. SARS-CoV-2 infection is determined by the interaction of its spike protein with angiotensin converting enzyme 2 (ACE2) expressed, including in proximal and distal enterocytes and hepatocytes. A recent study showed that the degree of liver steatosis is associated with the presence of the SARS-CoV-2 virus in the liver, and the level of ACE-2 protein is elevated in patients with COVID-19, especially in those with signs of liver damage. These indicators also correlate with the pathophysiological spectrum of MASLD (31). It has been demonstrated that Toll-like receptor (TLR) family signaling can be maintained in MASLD and COVID-19, which leads to hyperactivation of neutrophils and macrophages, the latter producing high systemic levels of proinflammatory molecules (32). The role of changes in adipokines (leptin and adiponectin) negatively affecting lung function is also discussed. The progression of MASLD, among other things, is caused by the adipokine dysregulation, whose receptors are also present in the respiratory tract on bronchial epithelial cells (33). Impaired adipokine levels may also contribute to the development of an inflammatory condition associated with the severe course of COVID-19 (34). Other mechanisms of COVID-19 progression in patients with MASLD include drug-induced liver injury in the treatment of COVID, as well as conditions associated with liver steatosis: alteration in the intestinal microbiota; increased production of proinflammatory cytokines by Kupffer cells and activation of intracellular inflammasomes (35). Moreover, there is evidence that MASLD has demonstrated a negative effect on the SARS-CoV-2 vaccine immunogenicity (36,37).

Implications and actions needed

The presence of MASLD requires closer monitoring and correction of therapy. MASLD increases the burden on healthcare. Assessment of the degree of liver steatosis from CT data, simultaneously with studying the underlying disease, can become an important diagnostic step determining the prognosis of the course of the disease as well as a tool for risk stratification in patients with MASLD. Understanding the etiopathogenetic relationship of MASLD with the development of a complicated course and the long-term consequences of COVID-AP actualises the need to develop comprehensive programmes aimed at treating MASLD, and also focuses on the highest vulnerability of this category of patients and the need for a personalised approach.

Conclusions

Patients with MASLD and COVID-AP had a more severe course and higher mortality than patients without MASLD. The presence of steatosis was an independent risk factor that degraded the prognosis. The results of our Russian population study are comparable to previous non-Russian studies on the relationship between MASLD and the progression of COVID-19.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-24/rc

Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-24/dss

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-24/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-24/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Local Ethics Committee of Sechenov University (protocol No. 04-21 of 04/18/2021) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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