Metabolic dysfunction-associated steatotic liver disease: an emerging comorbidity in COPD

Abstract

Chronic obstructive pulmonary disease (COPD) and metabolic dysfunction-associated steatotic liver disease (MASLD) are highly prevalent conditions that frequently coexist. MASLD, now the leading cause of chronic liver disease globally, affects up to 25% of the population and is increasingly recognized in COPD patients. Shared cardiometabolic risk factors, chronic inflammation, and lipid-mediated injury underpin their pathophysiological link. This review outlines the epidemiology, shared mechanisms, and clinical impact of MASLD in COPD, as well as diagnostic strategies and current management approaches. Recognizing MASLD as a clinically significant comorbidity in COPD may offer new opportunities for risk stratification, integrated care, and targeted therapeutic interventions, underscoring the need for further research into their mechanistic interplay and bidirectional impact.

Plain language summary

COPD is a chronic lung disease that often comes with other health problems. One common but often overlooked problem in people with COPD is a fatty liver condition now called MASLD (previously known as NAFLD). MASLD happens when too much fat builds up in the liver in people with metabolic issues like obesity or diabetes. Recent research shows many people with COPD also have MASLD. This summary explains how COPD and MASLD are connected and why it matters. Both diseases can be linked by risk factors such as being overweight and inactive, and they share harmful processes like ongoing low-level inflammation in the body. In fact, having MASLD can worsen a COPD patient’s overall health, leading to higher risks of heart problems and possibly more severe lung issues. Doctors should be aware that COPD patients might have this liver condition. Simple blood tests or scans can check for MASLD, and treating it, for example, through weight loss, exercise, and proper medications, might improve patient outcomes. Overall, recognizing and addressing the fatty liver disease in COPD patients is important to provide better, whole-person care. Future research will tell us if treating MASLD also helps people’s COPD and prevents other complications.

Keywords

chronic obstructive inflammation metabolic dysfunction-associated steatotic liver disease metabolic syndrome morbidity non-alcoholic fatty liver disease pulmonary disease

Introduction

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition defined by persistent airflow limitation and chronic respiratory symptoms. It is a leading cause of morbidity and mortality worldwide.^1,2 Comorbidities including cardiovascular (CV) diseases, osteoporosis, and anxiety are frequently observed in COPD patients and are associated with worse outcomes and reduced quality of life.³ In particular, metabolic abnormalities are common in COPD, with up to half of COPD patients exhibiting components of metabolic syndrome or related dysfunction.⁴ A notable metabolic comorbidity gaining attention is fatty liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD),^5,6 is defined as hepatic steatosis affecting more than 5% of hepatocytes in the absence of secondary causes.^6–8 MASLD has become one of the most important liver diseases in the world, accounting for over 75% of chronic liver disease in the United States and representing the most common indication for liver transplantation.⁹ It is recognized as a systemic disorder associated with comorbidities such as chronic kidney disease, CV disease, and, more recently, COPD.¹⁰

Evidence is emerging that MASLD is highly relevant in COPD. Epidemiological studies show a surprisingly high prevalence of NAFLD in COPD patients.^11–13 For example, Viglino et al.¹¹ found that 75% of a COPD cohort had liver abnormalities consistent with NAFLD (41% had steatosis and 37% had nonalcoholic steatohepatitis (NASH) by biomarkers). Another analysis of a large population dataset noted a positive correlation between liver fat content and COPD prevalence.¹³ Conversely, individuals with metabolic syndrome or type 2 diabetes, key risk factors for MASLD, are more likely to have impaired lung function or COPD, suggesting a bidirectional relationship.¹⁴ Both COPD and MASLD are systemic conditions with overlapping risk factors (aging, sedentary lifestyle, poor diet) and pathophysiological processes (chronic inflammation, insulin resistance, oxidative stress).⁴ It is biologically plausible that the two diseases exacerbate each other’s progression.

Despite these links, MASLD remains an under-recognized comorbidity in pulmonary practice. Many COPD guidelines historically focused on CV and musculoskeletal comorbidities, while fatty liver disease received little attention. The latest GOLD reports (Global Initiative for Chronic Obstructive Lung Disease) have started to emphasize a more comprehensive approach to COPD management, including screening for and managing comorbid metabolic diseases.² Recognizing MASLD in COPD is important because it carries additional clinical implications; for instance, NAFLD in COPD has been associated with worse overall survival and higher rates of CV events.¹² Liver fibrosis, in particular, is associated with a near threefold increase in mortality risk in COPD patients.¹² Moreover, untreated MASLD could potentially contribute to systemic inflammation that aggravates COPD symptoms (e.g., muscle wasting, frequent exacerbations).

In this narrative review, we explore the emerging relationship between MASLD and COPD. We begin by outlining the proposed pathophysiological mechanisms linking both conditions, with a focus on chronic systemic inflammation and altered lipid metabolism. We then discuss the clinical implications of this association, including diagnostic considerations, noninvasive biomarkers, and current therapeutic strategies. Finally, we highlight key gaps in the literature and propose future research directions to better understand the impact of MASLD on COPD outcomes.

Pathophysiological links between MASLD and COPD

Several shared mechanisms underpin the association between COPD and MASLD. Chronic low-grade inflammation, insulin resistance, lipotoxicity, oxidative stress, and gut dysbiosis contribute to both conditions. These processes may act synergistically, forming a bidirectional “liver–lung axis” that amplifies systemic injury across organs (Figure 1).

Figure 1.

Complex pathophysiological links between MASLD and COPD.

Chronic systemic inflammation and immune mediators

Chronic systemic inflammation is a hallmark of both COPD and MASLD and may represent a central mechanistic link between the two conditions.^15–17 Adipose tissue dysfunction in MASLD leads to increased release of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), as well as acute phase reactants like C-reactive protein (CRP).^18–20 COPD, especially in its advanced stages, is also associated with elevated circulating inflammatory markers due to ongoing immune cell activation and oxidative stress from smoking or other irritants.²¹ When a patient has both conditions, these inflammatory signals may be additive or synergistic.

IL-6 is one cytokine of particular interest. IL-6 levels are often elevated in patients with metabolic syndrome and MASLD, correlating with insulin resistance and liver inflammation.^22,23 In COPD, higher IL-6 has been linked to increased.²⁴ Thus, systemic IL-6 driven by MASLD could contribute to the chronic inflammation that exacerbates COPD progression. Similarly, CRP (produced by the liver under IL-6 stimulation) is a well-known marker of systemic inflammation; elevated high-sensitivity CRP is common in both MASLD and COPD and predicts worse outcomes.^15,25–28 Composite markers such as the CRP/albumin ratio have also been shown to reflect inflammatory burden.^17,29 For instance, MASLD patients with coexisting COPD demonstrate significantly higher CRP/albumin ratios than those without COPD.¹⁷

Chemokines play a role in orchestrating the tissue inflammation seen in both MASLD and COPD. In fatty liver disease, adipose tissue and Kupffer cells secrete chemokines such as C-C motif ligand 2 (CCL2, also known as monocyte chemoattractant protein-1 or MCP-1), which recruit monocytes/macrophages to the liver, propagating steatohepatitis.^30,31 Notably, MCP-1 levels are elevated in NASH and correlate with liver fibrosis.³² The same chemokine (MCP-1) is implicated in COPD airway inflammation.^21,33 Lung epithelial cells exposed to cigarette smoke upregulate MCP-1, which attracts circulating monocytes into the lungs.²¹ Patients with COPD have increased MCP-1 expression in bronchial epithelium, contributing to macrophage-rich inflammation in the airways.³⁴ This overlap suggests that MCP-1/CCL2 is a common inflammatory mediator linking liver and lung injury.

Oxidative stress is a hallmark of COPD, primarily driven by chronic exposure to cigarette smoke, persistent inflammation, and mitochondrial dysfunction.^35,36 Similarly, MASLD is characterized by increased hepatic oxidative stress, resulting from excessive fatty acid oxidation and mitochondrial impairment, which generates reactive oxygen species (ROS).³⁷ In both conditions, oxidative stress exacerbates tissue injury and promotes inflammation through redox-sensitive signaling pathways such as nuclear factor-kappa B (NF-κB).³⁸ For instance, patients with COPD have been found to have significantly lower levels of serum albumin compared to non-COPD controls,³⁹ potentially compromising their antioxidant capacity, as albumin functions as a major extracellular ROS scavenger.⁴⁰

Adipokines, hormones secreted by adipose tissue, further modulate the chronic inflammatory axis linking MASLD and COPD. Adiponectin (APN) is an adipokine secreted by adipose tissue in lean individuals and exerts anti-inflammatory, insulin-sensitizing, and hepatoprotective effects through its receptors AdipoR1 and AdipoR2.^41–45 It suppresses macrophage TNF-α and metalloproteinase activity and promotes anti-inflammatory cytokines like IL-10.^41,42 These receptors are also expressed in the lung epithelium,^46,47 suggesting that APN may modulate pulmonary inflammation. In murine models, APN deficiency induces emphysema-like changes even in the absence of noxious stimuli.⁴⁸ However, clinical data in COPD are inconsistent. A 2020 meta-analysis by Liu et al.⁴⁹ found that APN levels were elevated in COPD patients, especially during acute exacerbations, possibly reflecting a compensatory response to inflammation. Additionally, higher APN was associated with reduced CV risk but increased respiratory mortality.⁴⁹ In MASLD, APN appears to play a protective role. Its levels are lower in MASH compared to MASLD, as shown in meta-analyses by Polyzos et al.⁵⁰ and Tontikidou et al.,⁵¹ suggesting a role in progression rather than disease initiation. However, other prospective studies have identified hypoadiponectinemia as a predictor of MASLD onset.⁵² Leptin, on the other hand, is a pro-inflammatory adipokine elevated in obesity and MASLD; It promotes hepatic inflammation and fibrosis and has been associated with MASH progression.⁵³ Leptin receptors on bronchial epithelial cells modulate both innate and adaptive immunity,^54,55 and leptin has been shown to drive alveolar neutrophilia.⁵⁶ Elevated leptin has been observed in COPD patients with impaired lung function, particularly during acute exacerbations, though population-level associations remain inconsistent.^57–59

Dysregulated lipid metabolism: Free fatty acids and ceramides

Beyond generalized inflammation, altered lipid metabolism and lipotoxicity provide another mechanistic link between MASLD and COPD.⁶⁰ MASLD is characterized by hepatic triglyceride accumulation driven by caloric excess and insulin resistance, leading to elevated circulating free fatty acids (FFAs). Saturated FFAs such as palmitate activate Toll-like receptor 4 (TLR4), inducing pro-inflammatory signaling through NF-κB and promoting cytokine production (e.g., IL-6, TNF-α) in hepatocytes and macrophages.⁶¹ In MASLD, for example, palmitate can activate TLR4 and NF-κB in hepatocytes and macrophages, promoting production of IL-6, TNF-α, and fibrogenic factors.^62,63 This lipotoxic inflammation may therefore extend to the lungs, where FFAs activate TLR4 on pulmonary immune or epithelial cells, aggravating COPD-related inflammation. Moreover, excess FFAs in the liver are shunted into various lipid pathways, leading to the accumulation of toxic lipid intermediates. One group of such intermediates, ceramides (sphingolipid metabolites), has gained attention as a molecular link between metabolic syndrome and chronic diseases.⁶⁰ In patients with MASLD, ceramide levels in the liver and plasma are significantly increased.⁶⁴ Ceramides mediate lipotoxicity by promoting insulin resistance, oxidative stress, and apoptosis.⁶⁵ In fact, ceramides are thought to play a causal role in NAFLD progression: inhibiting ceramide synthesis in obese mice reduces liver steatosis, inflammation, and even atherosclerosis.⁶⁶ Notably, ceramides also have documented pathogenic effects in the lung. Experimental studies demonstrated that ceramide accumulation in pulmonary tissues can induce alveolar cell apoptosis and emphysema-like changes.⁶⁷ Petrache et al.⁶⁷ reported that ceramide is a crucial mediator of alveolar destruction in emphysema: blocking ceramide synthesis prevented lung cell apoptosis and emphysema in cigarette smoke-exposed rodents, and direct instillation of ceramide into mouse lungs reproduced emphysematous damage. Therefore, ceramide overproduction in MASLD may promote lung injury in COPD via systemic lipotoxicity and endothelial dysfunction. This “lipid spillover” may contribute to the worse outcomes observed in COPD patients with metabolic syndrome and represents a potential therapeutic target for both liver and lung disease.

Hypoxia

Chronic hypoxemia is a well-recognized complication in patients with COPD, particularly in those with advanced airflow limitation or frequent exacerbations. This state of reduced oxygen availability is not merely a byproduct of disease severity but plays an active role in COPD pathogenesis and progression.⁶⁰ Hypoxia-inducible factors (HIFs), a family of oxygen-sensitive heterodimeric transcription factors composed of α and β subunits, are key mediators of the cellular response to hypoxia.⁶⁸ In lung tissue from COPD patients, HIF-1α expression has been shown to be significantly upregulated.^69,70 Fu et al.⁶⁹ demonstrated that elevated levels of HIF-1α in COPD lungs are associated with progressive loss of lung function. Moreover, Shukla et al.⁷⁰ found that increased HIF-1α expression facilitates bacterial colonization in the airways, contributing to frequent exacerbations. Beyond its effects on the lungs, hypoxia contributes to extrapulmonary manifestations of COPD, including liver involvement. Through activation of HIF signaling, hypoxia promotes several mechanisms implicated in the pathogenesis of MASLD.^71–73 In a murine study, HIF-2α was found to be upregulated in hepatocytes under hypoxic conditions, leading to suppression of β-oxidation and stimulation of lipogenesis via PPARα inhibition, thereby promoting hepatic steatosis.⁷¹ Silencing of HIF-2α in this model reversed steatotic changes, underscoring its central role. HIF-1α has also been implicated in the fibrotic progression of MASLD in multiple studies.^72,73 In addition, hypoxia-induced HIF signaling exacerbates oxidative stress, mitochondrial dysfunction, and gut permeability, all of which are key contributors to MASLD development and progression.⁷⁴

Dysbiosis

Emerging evidence highlights a complex bidirectional relationship between the gut microbiome, lungs, and liver, collectively referred to as the gut–lung–liver axis. This crosstalk is mediated by shared mechanisms, including systemic inflammation, microbial translocation, and microbiota-derived metabolites that influence distant organs.

In COPD, gut dysbiosis may arise from cigarette smoking, chronic inflammation, sedentary lifestyle, and frequent exposure to antibiotics or corticosteroids, particularly macrolides used for both maintenance and exacerbation management.⁷⁵ Li et al.⁷⁶ showed a distinct gut microbial signature in COPD patients, characterized by a shift toward a Prevotella-dominant enterotype and reduced abundance of short-chain fatty acid (SCFA)-producing bacteria such as Faecalibacterium and Ruminococcaceae. Bowerman et al.⁷⁷ similarly identified an increase in Streptococcus, Romboutsia, Intestinibacter, and Escherichia, alongside reductions in beneficial taxa like Lachnospira and Bacteroides. These microbial patterns closely mirror those observed in MASLD, supporting a shared dysbiotic profile across both conditions.⁷⁸ Importantly, dysbiosis may not be merely a consequence of disease but a contributing factor, with mechanistic links to inflammation and tissue dysfunction increasingly recognized. SCFAs, such as butyrate and propionate, are key anti-inflammatory metabolites that maintain gut epithelial integrity, promote T-regulatory cell differentiation, and suppress systemic cytokine release (e.g., TNF-α, IL-1β).^75,79–84 In COPD, depletion of SCFA-producing microbes correlates with disease severity and increased inflammation.⁷⁶ Li et al.⁷⁶ further demonstrated in a murine model that fecal microbiota transplantation (FMT) from COPD patients led to increased bronchial wall thickening, airway remodeling, mucus production, and inflammatory infiltration, features consistent with COPD pathology, compared to FMT from healthy donors.

A parallel gut–liver axis dysfunction underlies MASLD pathogenesis. A meta-analysis by Li et al.⁷⁸ encompassing 15 studies and over 1200 individuals revealed that MASLD patients exhibited enrichment of Escherichia, Prevotella, and Streptococcus, and depletion of Coprococcus, Faecalibacterium, and Ruminococcus, a pattern strikingly similar to that of COPD. These alterations compromise gut barrier integrity, promoting intestinal permeability (“leaky gut”) and allowing translocation of endotoxins such as lipopolysaccharide and microbial metabolites like ethanol into the portal circulation.^85,86 This contributes to hepatic inflammation, steatosis, and fibrogenesis. Moreover, both diseases share SCFA depletion as a key mechanistic link. In MASLD, reduced SCFA levels foster a pro-inflammatory hepatic milieu,⁸⁷ analogous to their role in promoting systemic and pulmonary inflammation in COPD. Additional mechanisms in MASLD include endotoxin hypersensitivity,⁸⁸ disrupted gut–liver hormonal signaling, and altered bile acid metabolism,⁸⁹ all of which may amplify hepatic injury. Interestingly, microbiome signatures are now being evaluated as biomarkers for MASLD progression, including the development of cirrhosis.⁹⁰

Obesity/visceral fat deposits

Central (abdominal) obesity is a common and clinically relevant feature shared by both MASLD and COPD, contributing to systemic inflammation, insulin resistance, and broader metabolic dysregulation implicated in both conditions. While body mass index (BMI) provides a general measure of obesity, visceral fat distribution appears to be more closely linked to pulmonary and hepatic outcomes. Epidemiological data suggest that abdominal obesity and waist circumference, rather than BMI alone, are more strongly associated with impaired lung function and increased COPD risk.^91,92 Leone et al.⁹¹ found that abdominal adiposity correlated with reduced pulmonary function, and Behrens et al.⁹² demonstrated that waist circumference predicted COPD development even in never-smokers, supporting a role for adiposity beyond tobacco exposure. Similarly, systemic inflammation, reflected by elevated levels of TNF-α, IL-6, leptin, and CRP, is more pronounced in obese COPD patients.^93,94 The ECLIPSE study further highlighted this link, showing that COPD patients with systemic inflammation had significantly higher BMIs.⁹⁵ Visceral adiposity, assessed via waist circumference or imaging-based measures such as visceral fat area (VFA), has also been associated with COPD severity.^96–100 Furutate et al.⁹⁷ observed that even non-obese individuals with advanced COPD exhibited increased VFA, indicating that visceral fat burden may influence disease phenotype independent of BMI. Comparable trends are seen in MASLD, where visceral adiposity is a well-established contributor to disease development and progression.^101–104 Yu et al.¹⁰² demonstrated that VFA not only correlates with MASLD presence but is also higher in patients with more advanced histological findings such as MASH and liver fibrosis. Epicardial fat thickness (EFT), another marker of visceral adiposity, has been linked to both COPD and MASLD, though findings remain mixed in COPD,^105–108 and more consistent in MASLD, where EFT correlates with disease severity and CV risk.¹⁰⁹

The overlap between these conditions extends to the broader context of metabolic syndrome, a cluster of abnormalities, including central obesity, insulin resistance, dyslipidemia, and hypertension, that increases susceptibility to both MASLD and COPD. Metabolic syndrome affects over 30% of COPD patients,¹¹⁰ particularly those with milder disease,¹¹¹ and is associated with higher BMI, elevated inflammatory markers (CRP, IL-6), and female sex.^110–112 These characteristics align with a “comorbidity-predominant” COPD phenotype,^113,114 within which MASLD may be underdiagnosed. Shared pathophysiologic mechanisms, such as oxidative stress, chronic inflammation, and glucose metabolism disturbances, may contribute to hepatic steatosis in COPD patients.⁴ Central to this overlap is insulin resistance, which is independently associated with lung function impairment in COPD,^115–118 increased prevalence of type 2 diabetes,¹¹⁹ and greater all-cause mortality.¹²⁰ In MASLD, insulin resistance is both a driver and a consequence of disease progression. MASLD is present in over 55% of patients with type 2 diabetes,¹²¹ and diabetes significantly increases the risk of fibrosis, cirrhosis, and liver-related outcomes.^122,123 These patients also carry a greater risk of CV disease, chronic kidney disease, and mortality,¹²⁴ further compounding the cardiometabolic burden that is frequently observed in COPD.

Sarcopenia

Sarcopenia, the progressive loss of muscle mass and function, is frequently observed in patients with COPD, especially in advanced stages.^{92,97,125,126} Behrens et al.⁹² demonstrated that low muscularity, inferred indirectly by low BMI after adjustment for waist circumference, was positively associated with COPD. Conversely, greater gluteal muscularity, approximated by hip circumference, was found to be protective.⁹² This muscle loss is a key component of the “obesity paradox,” whereby lower BMI is paradoxically associated with worse outcomes in severe COPD. Several studies attribute this paradox to the preferential loss of fat-free mass in advanced COPD,^97,125 with fat-free mass index emerging as a strong predictor of mortality irrespective of BMI or total fat mass.¹²⁷ One mechanistic explanation is a metabolic shift in advanced COPD, where energy production favors amino acid and FFA utilization over TCA cycle activity, leading to progressive muscle wasting.¹²⁸

Sarcopenia is also increasingly recognized as a comorbidity in MASLD. In a large population-based study of 15,132 individuals from KNHANES, Lee et al.¹²⁹ showed that sarcopenia, measured by skeletal muscle index, was independently associated with MASLD, even after adjusting for obesity and insulin resistance. Several studies have further linked sarcopenia to liver fibrosis severity in MASLD,^130–132 with underlying chronic inflammation proposed as a common driver. Elevated levels of proinflammatory cytokines such as NF-κB, IL-6, and TNF-α have been implicated in both sarcopenia and fibrogenesis.¹³⁰

Although limited, emerging data suggest a pathophysiological overlap between sarcopenia, COPD, and MASLD. In a study of 850 COPD patients, Hong et al.¹³³ found that 14.6% had coexisting MASLD. These patients were more likely to have metabolic risk factors, including higher BMI, waist circumference, hypertension, and diabetes, and importantly, sarcopenia was significantly associated with both MASLD and liver fibrosis within this cohort.¹³³

Smoking

Cigarette smoking remains the leading modifiable risk factor for COPD, accounting for approximately 15% of cases among active smokers.¹³⁴ Beyond its well-established pulmonary consequences, smoking is increasingly recognized as a contributor to MASLD. A meta-analysis by Akhavan Rezayat et al.,¹³⁵ including over 20,000 patients across 12 studies, demonstrated a significant association between smoking and MASLD. Similarly, Kim et al.¹³⁶ identified smoking as an independent risk factor for MASLD after adjusting for confounders, with risk notably elevated among individuals with more than 10 pack-years of exposure.¹³⁶ The mechanisms linking smoking to both COPD and MASLD are multifactorial and overlapping. Smoking induces systemic inflammation via upregulation of cytokines such as TNF-α, IL-1, and IL-6, contributing to both lung injury and hepatic steatosis. It also impairs endothelial function, promotes insulin resistance, and exacerbates features of metabolic syndrome, central elements in the pathogenesis of both diseases.¹³⁷ Furthermore, cigarette smoke has been implicated in the development of sarcopenia,¹³⁸ and gut dysbiosis,¹³⁹ all of which contribute to MASLD progression and may amplify COPD severity. Experimental studies reinforce the hepatotoxic potential of cigarette smoke. In rodent models, smoking increases hepatic lipogenesis, impairs cholesterol clearance,^140–142 and worsens diet-induced steatosis.¹⁴³ Smoke exposure also exacerbates preexisting MASLD through enhanced hepatocyte apoptosis and oxidative injury.^144,145

Clinical and research implications

Impact on patient outcomes

The coexistence of MASLD can significantly influence the clinical course of COPD. As noted, MASLD is common among COPD patients, particularly those with obesity or features of metabolic syndrome. This overlap is not benign. Studies indicate that COPD patients with MASLD tend to have worse overall health status and higher comorbidity burden than those without fatty liver.^11,12 One of the most critical implications is the increased CV risk. Viglino et al.¹² demonstrated that COPD patients with evidence of liver fibrosis had nearly three times the hazard of experiencing a major CV event or death over 5 years compared to those without fibrosis. Notably, in that study, simple steatosis or even NASH (without fibrosis) did not significantly affect outcomes, whereas fibrosis did, underscoring the importance of identifying advanced fibrotic NAFLD in COPD. This finding suggests that fibrosis in MASLD could be a key prognostic marker in COPD, likely because it reflects a longer-standing, more severe metabolic insult that also drives systemic vascular damage.

Diagnostic considerations: Identifying MASLD in COPD

Given the clinical importance of MASLD, a key question is how to screen and diagnose this condition in COPD patients. MASLD is often a “silent” disease, many patients have normal or only mildly elevated liver enzymes (alanine aminotransferase (ALT) and aspartate aminotransferase) despite significant steatosis or fibrosis. Thus, relying solely on liver enzymes can miss many cases. However, certain clinical clues should raise suspicion in a COPD patient: the presence of obesity (especially central adiposity), type 2 diabetes, or hypertriglyceridemia, all components of metabolic syndrome, strongly predispose to MASLD. If a COPD patient has metabolic syndrome features or unexplained mild elevations in ALT or gamma-glutamyl transferase, further evaluation for fatty liver is warranted.

Management strategies: An integrated approach

Based on this review, we propose considering MASLD disease spectrum as an important COPD comorbidity when evaluating for multimorbidity based on GOLD guidelines. We also call for more awareness on MASLD burden by providers treating COPD patients, including primary care practice and respiratory medicine. The evaluation should include screening patients with risk factors including metabolic syndrome, obesity, or sarcopenia. One opportunity for MASLD screening in COPD patients is to use low-dose lung cancer CT screening to identify hepatic steatosis on imaging, a process that can be automated. Diagnosing MASLD in COPD patients should trigger a specialist evaluation and more strict CV risk factors mitigation. The expansion of the treatment options of MASLD, including GLP1 agonists, may allow better quality of life and outcomes in patients with COPD, especially with the proven CV benefits of these drugs, knowing that CV disease is a major driver of morbidity and mortality in these patients. On the other hand, patients diagnosed with MASLD should be counseled on smoking cessation, the increased risk of lung function loss, and should be promptly referred for evaluation of COPD when symptoms exist. Increased awareness about the coexistence of both diseases is an important first step to open doors for further research with subsequent therapeutic implications and further advancements.

Further basic science and clinical research should clarify the exact interaction between these two prevalent and morbid diseases to clarify if the association is a simple comorbidity or if a causal relationship exists. Future research should focus on: (1) determining whether treating MASLD improves respiratory outcomes such as exacerbation frequency, lung function decline, or quality of life in COPD patients; (2) identifying whether specific COPD phenotypes, such as frequent exacerbators, emphysema-dominant, or eosinophilic subtypes, are more susceptible to hepatic steatosis or fibrosis; (3) clarifying whether distinct MASLD subtypes, such as MASH or fibrosis stage, are independently associated with COPD severity or progression; and (4) evaluating the diagnostic yield and cost-effectiveness of implementing routine MASLD screening in patients with COPD, and vice versa. Longitudinal prospective studies and interventional trials are needed to elucidate the bidirectional clinical impact and therapeutic opportunities at this intersection.

Accumulating evidence suggests that MASLD is emerging as an important COPD comorbidity with potential effect on disease progression. MASLD and COPD share common risk factors and comorbid predisposing conditions, including obesity, metabolic syndrome, insulin resistance, and sarcopenia in addition to common pathophysiological pathways related to low-grade inflammation, intermittent hypoxia, adipokines, oxidative stress, and dysbiosis. We recommend increasing awareness in the medical community on this association and screening for MASLD in high-risk COPD patients. We also recommend counseling MASLD patients about the risk of COPD and on smoking cessation. Further research is still needed to further shed more light on the links between the two conditions.

Footnotes

Acknowledgements

We thank Ms Reem Kheireddine for her valuable assistance in designing the diagram for this review paper. Her expertise and effort significantly improved the quality of this work. (Acknowledgments of technical help).

Declarations

ORCID iDs

Toufic Chaaban

Rajaa Chatila

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