The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a daunting challenge since late 2019, with approximately 600 million confirmed cases and 7 million deaths as of September 1st, 2022 (1). Early on, we learned that while respiratory symptoms may be predominant in COVID-19, the disease affects various organ systems, with gastrointestinal, cardiovascular, neurological, hematological, and renal involvement (2–10). With the growing knowledge of the disease, we learned that in addition to the acute phase, COVID-19 might induce multi-system long-term consequences (i.e., long COVID), such as fatigue, myalgia, psychological symptoms, and hepatitis (11–13).

Liver damage is one of the most important aspects of COVID-19, with elevated liver enzymes appearing in approximately 15–65% of patients in the acute phase (14, 15) and prolonged hepatobiliary complications in some cases (16, 17). In critically ill COVID-19 patients, pathological studies have revealed mild lobular and portal inflammation as well as moderate macrovesicular steatosis (18, 19). Direct viral cytotoxic effects, systemic inflammation, hypoxia, coagulopathy, and drug-induced liver injury are all potential causes of liver damage (4). Notably, viral RNA has been detected in liver samples, and SARS-CoV-2 isolated from liver tissue is infectious (20–22). Angiotensin-converting enzyme 2 (ACE2) is the primary viral receptor for SARS-COV-2. The host transmembrane serine protease 2 (TMPRSS2) is also crucial for viral infectiousness. ACE2 and TMPRSS2 were found to be highly expressed in the liver. Cholangiocytes had the highest levels of ACE2 expression, followed by hepatocytes. Transmembrane serine protease 2 was found to be mainly expressed in cholangiocytes, hepatocytes, periportal liver sinusoidal endothelial cells, and erythroid cells. (23, 24). Interestingly, hypoxia and inflammatory conditions were found to upregulate ACE-2 expression (25, 26).

The liver injury could be more severe in patients with pre-existing chronic liver diseases. This can be partly explained by the increased expression of ACE2 in these patients (26–28). Non-alcoholic fatty liver disease (NAFLD), recently known as metabolic-associated fatty liver disease (MAFLD), is a spectrum of diseases ranging from simple steatosis with or without mild inflammation to a necroinflammatory subtype with the presence of hepatocellular injury (non-alcoholic steatohepatitis (NASH)) and cirrhosis (29, 30). NAFLD is the most common cause of chronic liver disease and is estimated to have affected a quarter of the global population (31, 32). Of note, given the role of cardiometabolic risk factors in the development and progression of the disease, two new position papers (29, 30) proposed the terminology of MAFLD instead of NAFLD in 2020 to better capture the pathophysiology of the disease (33, 34).

Though controversial, early reports during the pandemic indicated that patients with NAFLD have a greater risk of developing a more severe disease course (35–37). Given the association of MAFLD with other cardiometabolic risk factors, which are also well-established predictors of poor prognosis in COVID-19, it remains unclear whether MAFLD is merely associated with poor outcomes or plays a causal role. Moreover, not only can MAFLD influence the course of COVID-19, but it is also important to recognize the effects of the COVID-19 pandemic on the care of patients with MAFLD and the epidemiology of the disease. In addition, given the global scale of COVID-19 vaccination, the focus of research should shift to the safety and efficacy of COVID-19 vaccines in patients with MAFLD.

In this review, we provide a concise yet comprehensive overview of the interplay between MAFLD and the COVID-19 pandemic, focusing on the COVID-19 outcomes in patients with MAFLD, the impact of the COVID-19 pandemic on the care of patients with MAFLD and the epidemiology of the disease, and COVID-19 vaccination in patients with MAFLD (Figure 1). We also pave the way for future research by highlighting the current gaps in the field’s knowledge.

Metabolic factors such as obesity and diabetes are established risk factors for severe COVID-19 (38). Hence, it is only logical to assume that MAFLD is associated with a worse prognosis for COVID-19 (39). While almost all studies show that patients with MAFLD are at a higher risk of severe disease, it is not yet well understood whether MAFLD-related changes can act as an independent prognostic factor and, if they do, to what extent they can impact the clinical course of COVID-19. The following sections review the various aspects of the MAFLD-COVID-19 interaction.

Few studies are available on how MAFLD affects COVID-19 vaccination outcomes.

NASH is one of the most common causes of cirrhosis and the second leading indication for a liver transplant. Patients with cirrhosis require prompt diagnosis and treatment of the relevant complications. Considering the annual cumulative hepatocellular carcinoma (HCC) incidence rate of 2.6% for NASH-related cirrhosis, these patients need routine screening for HCC (31). Notably, a multicenter investigation found a significantly decreased number of HCC diagnoses and an increased rate of HCC treatment delay compared to the same period in the previous year during a high prevalence of COVID-19 (63). Moreover, regular screening for esophageal varices, given the high risk of mortality, is also required in patients with NASH-related cirrhosis (64); however, during the COVID-19 pandemic, most screening procedures were delayed, which presumably has led to undiagnosed cases as we are recovering from the pandemic (65). One such example is screening endoscopy, which was recommended to be performed only in urgent circumstances by the pandemic guidelines. This has most likely resulted in missed esophageal varices due to delayed screening (66, 67), especially in earlier periods of the pandemic, though to the best of our knowledge, no studies have reported the corresponding data. The COVID-19 pandemic has also adversely affected transplantation activity and, in turn, affected the care of patients with NASH-related cirrhosis (68).

From another perspective, the COVID-19 pandemic caused considerable behavioral changes due to the restrictions, including lockdown, home confinement, and closure of sports facilities. Several studies have shown decreased physical activity and increased prevalence of unhealthy lifestyles, including increased dietary intake, decreased sleep, and increased smoking during COVID-19 lockdowns (69–71). A longitudinal investigation of NAFLD patients showed that the more active patients had lower physical activity than before during the lockdown, while inactive people had higher physical activity (72). Importantly, cohorts of patients with NAFLD showed that COVID-19 lockdown caused a significant increase in body weight, body mass index (BMI), insulin resistance, cholesterol levels, low-density lipoprotein (LDL) levels, and glucose levels. It also led to a reduction in high-density lipoprotein (HDL) levels alongside with progression of fatty liver (73–75). In addition, population-based analyses using the United States (US) national mortality records revealed that the steady increase in NAFLD mortality prior to the COVID-19 pandemic sped up during the pandemic (76). A recently published cohort study comparing patients before and after a COVID-19 lockdown grouped patients with NAFLD according to the level of physical activity. They found that the fatty liver index (FLI) increased in all groups after the lockdown. However, the elevation in the FLI was higher in the medium physical activity than in the low physical activity group (72). In addition to worsening metabolic risk factors and liver involvement in patients with NAFLD, such lifestyle changes may increase the likelihood of an increased incidence of NAFLD in the coming years as we recover from the pandemic, given the strong association of metabolic risk factors with NAFLD development and progression (32).

The COVID-19 pandemic, although catastrophic, provided and continues to provide many valuable lessons to experts and policymakers of all fields, especially medicine. First and foremost, healthcare providers must always anticipate a sudden crisis that halts delivering health services. Although the COVID-19 pandemic pressured organizations into identifying actions and developing protocols to counter the effect of this global crisis, the effort must be continuous and the results have to be updated regularly based on most recent evidence. Telemedicine is an example of a tool that has been extensively studied during the ongoing pandemic and shown to be effective (77, 78) and satisfactory (79); hence, we suggest healthcare facilities commence and test out different telemedicine approaches to identify the most suitable one for their use. Rapid re-initiation of medical practices during crises is of utmost importance; however, this must not result in the normalization of the ongoing calamity. While continuing care for some patients is necessary, some medical practices could be postponed with no or minimal adverse outcomes (80). Comprehensive crisis-management guidelines and protocols are required to stratify medical services based their delay capacity. Undoubtedly, in the unfortunate event of a similar disaster in the future, the world’s response would be much more appropriate given the experience gained from COVID-19, just as it was for COVID-19 because of the previous outbreaks such as Middle East Respiratory Syndrome (MERS) and SARS (81).

Current studies, as presented in this manuscript, provide strong evidence that patients with MAFLD tend to experience worse COVID-19 outcomes. However, literature is short of approaches to mitigate this risk. Consequently, to the best of our knowledge, no specific COVID-19 guidelines have been developed for patients with MAFLD. We believe the focus of future related studies should be on evaluating different care strategies in these patients.

Vaccination and specific antiviral treatments are the current trend in COVID-19 research. To the best of our knowledge, very few studies have evaluated COVID-19 vaccine effectiveness in patients with MAFLD and no studies have evaluated antiviral treatments (such as remdesivir and Paxlovid) in this population. Investigating these subjects in patients with MAFLD is of utmost importance, given the crucial role of the liver in drug metabolization.

Delay in health care and shift of resources toward managing COVID-19 is the pandemic’s predominant impact on other diseases. No comprehensive analyses have yet been performed to check whether MAFLD prevalence and incidence have increased in this period. Furthermore, there are no studies investigating whether MAFLD complications such as esophageal varices and HCC have significantly increased, given the cardinal role of screening in their detection and prevention.

Almost 3 years after the emergence of COVID-19, we very well know that it can affect the liver, and patients with certain comorbidities, such as metabolic dysfunction, are at higher risk for severe disease or mortality. Herein, we concisely reviewed the substantial evidence supporting the mutual association between MAFLD and COVID-19. Patients with MAFLD are at a higher risk of poor outcomes during COVID-19, even after controlling for the confounding effect of the other metabolic abnormalities. COVID-19 caused drastic changes in human lifestyle, screening programs, and transplantation programs, which could adversely affect the care of patients with MAFLD, especially those with NAFLD cirrhosis, or even potentially increase the incidence rate of MAFLD in years to come. Assessment of the efficacy and safety of COVID-19 vaccines in this group of patients has garnered attention recently, with the wide global vaccination showing comparable results with the healthy population. Further investigations are required for development of guidelines for management of MAFLD during the COVID-19 pandemic, and assessment of efficacy of vaccination and antiviral therapies in this group of patients.

AN: conceptualization, investigation, writing—original draft, and writing—review & editing. SM: conceptualization, investigation, writing—original draft, writing—review & editing, and visualization. NR: conceptualization, writing—review & editing, and supervision. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.