The Lasting Effects of COVID-19 on the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Abstract

It is estimated that around 30% of the population living in Western countries has metabolic dysfunction-associated steatotic liver disease (MASLD), a spectrum of pathology (not attributed to alcohol/substance intake) initiated by steatosis and progression toward inflammation and irreversible fibrosis metabolic dysfunction-associated steatohepatitis (MASH). With inflammation being a key component of the transition to MASH, it raises the question of whether the ongoing COVID-19 pandemic, which has notoriously induced hyperinflammatory states, may influence the progression of MASLD. Specifically, it remains unclear if the potential chronic sequelae of COVID-19 in patients who recovered from it may increase the predisposition for MASH. Since MASH maintains a high risk for hepatocellular carcinoma, liver failure, and the need for a liver transplant, the potential additive effects of COVID-19 could prove critical to study. Thus, the objective of this study was to conduct a literature review to examine if COVID-19 could have chronic sequelae that affect the progression of MASLD pathogenesis. It was hypothesized that severe cases of COVID-19 could induce systemic inflammation, metabolic changes, and lasting gut microbiome alterations that lead to inflammatory and fibrotic changes in the liver, similar to those seen in MASH. A scoping review of the literature was conducted utilizing the PubMed database. Studies that examined hepatobiliary pathology, gut microbiome, systemic inflammation, metabolic changes, drug-induced liver injury (DILI), and hypoxia seen in COVID-19 were included. Human studies of adult cohorts, animal models, and in vitro experiments were included. Genetic components of MASLD were not examined. Exclusion criteria also encompassed any studies not referencing the hepatobiliary, gastrointestinal tract, portal system, or systemic circulation. Findings indicated a frequent trend of elevated liver enzymes, mild steatosis, Kupffer cell hyperplasia, and hepatobiliary congestion. It was found that direct cytopathic effects on hepatocytes were unlikely, but the direct viral insult of cholangiocytes was a potential complication. High serum levels of IL-1, TNF-a, and MCP-1, in COVID-19 were found as potential risk factors for MASH development. Hypoxia, altered lipid metabolism, and iatrogenic DILI were also proposed as potential precipitators of MASH development. Notably, lasting changes in gut microbiome were also frequently observed and correlated closely with those seen in MASH.

Keywords: covid-19; covid-19 + dili; covid-19 + gut microbiota; hepatobiliary congestion; mash; masld; nafld; nafld pathogenesis; nash; non-alcoholic fatty liver disease.

Figure 1. Visually summarized demonstration of the stages of progression of metabolic dysfunction-associated steatotic liver disease. Yellow bidirectional arrows indicate reversible progression, whereas red unidirectional arrows indicate irreversible change.

The figure was designed and produced by the authors. Acronyms: * = Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD); ** = Ethanol (EtOH); *** = Metabolic Dysfunction-Associated Steatohepatitis (MASH).

Figure 2. PRISMA 2020 flow diagram of the literature search process in this study. The initial search used the terms mentioned in the methods and materials section for the years 2020-2022 and produced 1,638 results. No automation tools were used for exclusion, but manual exclusion of resources that were books, documents, not full texts, and not free access removed 1,117 results. The resulting 521 articles were screened, and non-pertinent articles were excluded, to eventually yield 29 articles used to meet the objective of this study. The figure was created by the authors, based on the PRISMA 2020 template for literature reviews.

Figure 3. Diagram of the multifactorial pathophysiology of metabolic dysfunction-associated steatotic liver disease. The central circles of steatosis, inflammation, and fibrosis represent the central components of MASLD progression.

Note that genetic and epigenetic components have not been represented in this diagram. The figure was designed and produced by the authors. Acronyms: IL-1 = interleukin 1; TNF-a = tumor necrosis factor-alpha; NF-kB = nuclear factor kappa beta; M1 & M2= M1 and M2 Kupffer cell phenotypes; TGF-B = transforming growth factor beta; LPS = lipopolysaccharides; EtOH = ethanol.

Figure 4. Diagram of the multifactorial pathophysiology of metabolic dysfunction-associated steatotic liver disease with the addition of COVID-19 pathophysiology.

Pertinent COVID-19 pathophysiology is demonstrated by red boxes and arrows, to illustrate its effects on MASLD progression. The central circles of steatosis, inflammation, and fibrosis represent the central components of MASLD progression. Note that iatrogenic, pharmacologic, and pathophysiologic factors are not illustrated. The figure was designed and produced by author Sean Backer-Meurke. Acronyms: IL-1 = interleukin 1; TNF-a = tumor necrosis factor alpha; MCP-1 = monocyte chemoattractant protein 1; NF-kB = nuclear factor kappa beta; M1 & M2= M1 and M2 Kupffer cell phenotypes; TGF-B = transforming growth factor beta; LPS = lipopolysaccharides; EtOH = ethanol; GIT = gastrointestinal tract; SIRS = systemic inflammatory response syndrome; ROS = reactive oxygen species; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.