From liver to limb: Exploring the association between fatty liver disease and peripheral artery disease—A systematic review

Abstract

Introduction

Fatty liver disease, encompassing nonalcoholic fatty liver disease (NAFLD), metabolic dysfunction‐associated fatty liver disease (MAFLD), and the recently redefined metabolic dysfunction‐associated steatotic liver disease (MASLD), is a growing global health concern with significant cardiovascular implications. Peripheral artery disease (PAD), a common manifestation of systemic atherosclerosis, shares key pathophysiological mechanisms with fatty liver disease, including insulin resistance, systemic inflammation and endothelial dysfunction. Although emerging evidence suggests a link between fatty liver disease and PAD, the nature and extent of this association remain unclear. This systematic review synthesizes current research evaluating the relationship between fatty liver disease and PAD.

Methods

A systematic search of PubMed, Embase and Scopus was conducted up to December 19, 2024, following PRISMA 2020 guidelines. Eligible observational studies assessing PAD in MASLD, MAFLD or NAFLD patients were included. Quality assessment was performed independently by two reviewers using the Newcastle‐Ottawa Scale (NOS).

Results

Eleven observational studies, including approximately 848,027 participants, were analysed. Most studies reported a significant association between NAFLD or MAFLD and increased PAD risk, particularly in individuals with type 2 diabetes and metabolic syndrome. Studies using MAFLD criteria demonstrated a stronger association with PAD than those using NAFLD definitions. The presence of hepatic fibrosis was linked to a higher PAD risk in some studies. However, not all studies found a consistent relationship, and a few reported no independent association between fatty liver disease and PAD, highlighting the need for further research. Notably, none of the included studies used MASLD criteria.

Conclusions

Patients with NAFLD or MAFLD, particularly those with metabolic comorbidities, may have an elevated risk of PAD. The severity of liver disease, including fibrosis, appears to contribute to this risk. Future studies should incorporate MASLD definitions and advanced diagnostic methods to clarify this relationship and guide clinical strategies for integrated cardiovascular and liver disease management.

1. INTRODUCTION

Metabolic dysfunction‐associated steatotic liver disease (MASLD), formerly referred to as nonalcoholic fatty liver disease (NAFLD) or metabolic dysfunction‐associated fatty liver disease (MAFLD), is a major global health concern characterized by excessive hepatic fat accumulation in the absence of significant alcohol intake or other specific causes of liver disease. ¹ MASLD affects approximately 38% of the adult population, with prevalence rates rising in parallel with the obesity and type 2 diabetes mellitus pandemics. ² This condition encompasses a spectrum ranging from simple steatosis to more severe forms such as steatohepatitis, liver fibrosis and cirrhosis. ³ The disease is associated with significant morbidity and mortality, not only due to liver‐related complications but also due to its strong association with cardiovascular disease (CVD), underscoring its critical public health relevance.

Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis characterized by narrowing or obstruction of peripheral arteries, most commonly in the lower extremities. ⁴ PAD affects an estimated 113 million people aged ≥40 years globally, with a 1.52% prevalence rate, ⁵ with higher rates in older populations and those with diabetes or other cardiovascular risk factors. ⁶ It is a major cause of morbidity due to reduced quality of life, increased risk of limb loss and elevated cardiovascular mortality. ⁷ Early recognition and management of PAD are critical to mitigating its systemic complications.

Emerging evidence suggests that fatty liver disease may predispose individuals to an increased risk of PAD. ⁸ Possible mechanisms linking these conditions include shared metabolic derangements such as insulin resistance, systemic inflammation and dyslipidemia, which contribute to atherogenesis. Furthermore, fatty liver disease is associated with alterations in endothelial function, increased oxidative stress and enhanced prothrombotic states, all of which can exacerbate the progression of atherosclerotic disease, including PAD. ⁹

Given the overlapping pathophysiological pathways, the association between fatty liver disease and PAD has garnered increasing attention. Studies have proposed that the severity of fatty liver, including higher degrees of hepatic steatosis and fibrosis, may be linked to a greater risk and severity of PAD. ¹⁰ However, the existing evidence is limited and heterogeneous, with variations in study design, population characteristics and outcome definitions contributing to inconsistent findings. This highlights the need for a comprehensive evaluation of the relationship between these conditions.

The objective of this systematic review was to evaluate the current body of literature regarding the association between MASLD, MAFLD or NAFLD and PAD. Specifically, it aimed to assess the potential influence of hepatic steatosis and the extent of liver fibrosis on the risk and progression of PAD. By synthesizing available evidence, this study seeks to clarify the strength and nature of this association, identify knowledge gaps, and provide a foundation for future research and clinical strategies addressing these interrelated conditions.

2. METHODS

This systematic review was written according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) 2020 checklist. ¹¹

2.1. Data sources and search strategy

To identify potentially eligible observational studies evaluating PAD in MASLD, MAFLD or NAFLD patients, we conducted a systematic search of PubMed, Embase and Scopus from inception until December 19, 2024. The search strategy applied in these three databases is outlined in Appendix S1. Moreover, in order to minimize results bias, we manually searched the reference lists of pertinent articles in order to identify any additional relevant missed publications.

2.2. Study selection and eligibility criteria

All observational studies evaluating the association of PAD in MASLD, MAFLD or NAFLD patients were eligible for inclusion. Original articles were included in the qualitative assessment if they met the following inclusion criteria: (1) observational cohort population‐based/hospital‐based/primary care‐based, case–control studies of prospective or retrospective design; (2) hepatic steatosis confirmed based on one of the following methods: biopsy, imaging techniques such as ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), surrogate or noninvasive biomarkers, liver enzymes or codes such as International Classification of Diseases (ICD); (3) Confirmed diagnosis of PAD according to each study definition; (4) Adult subjects (aged ≥18 years) without restrictions in terms of gender, race or ethnicity; and (5) Studies conducted on humans only.

Exclusion criteria included the following: (1) Significant alcohol consumption or the presence of other secondary causes of hepatic steatosis; (2) Patients with confirmed hepatitis virus of any aetiology; (3) Other known causes of chronic liver disease (CLD); (4) Patients with confirmed cirrhosis of any aetiology; (5) Subjects with end stage liver disease who are awaiting or underwent liver transplantation; (6) Studies published in languages other than English, Romanian, German, French and Russian; (7) Case reports, reviews, practice guidelines, commentaries, opinions, letters, editorials, short surveys, articles in press, conference abstracts, conference papers and abstracts published without a full article.

According to the above‐mentioned eligibility criteria, two investigators (V.C. and J.B.) performed a screening evaluation independently through scrutinising titles and abstracts excluding any apparently irrelevant studies. Subsequently, selected articles fulfilling the above‐mentioned criteria were further evaluated by carefully reviewing the full text. A mutual consensus was reached by discussion with another investigator (A.I.) to resolve any discrepancies regarding study eligibility.

2.3. Data extraction

We extracted the following information from eligible studies: author's name, publication year, study location, study population, the source of cohort, sample size, mean age, the approach to diagnose hepatic steatosis and liver fibrosis, the number of participants, the approach to diagnose PAD, ankle‐brachial index (ABI) category, multivariable‐adjusted odds ratio (OR), relative risk (RR) or hazard ratio (HR), adjusted multivariate regression models, and the main findings of each study. One investigator (V.C) extracted the data through an electronic spreadsheet, and another investigator (J.B.) reviewed the extracted data for accuracy. Discrepancies regarding the results of extracted data were settled by discussion with another investigator (A.I.). Extracted data was then entered into tables, while final data was collated and presented in the text of the manuscript.

2.4. Quality assessment

We evaluated the risk of bias in individual studies using the standardized Newcastle‐Ottawa Scale (NOS) for cross‐sectional studies, which allowed us to assess study quality and internal validity. The NOS criteria considered factors such as sample representativeness, justification of sample size, comparability between respondents and nonrespondents, method of exposure assessment (validated or nonvalidated tools), control for key confounders, outcome assessment approach (independent blinded evaluation, record linkage or self‐report) and the clarity of statistical analysis, including association measures with confidence intervals and p‐values. Two independent reviewers (V.C. and J.B.) performed the assessments, resolving disagreements through discussion to achieve consensus when needed.

3. RESULTS

3.1. Literature search

The literature search identified records from PubMed (n = 19), Embase (n = 85) and Scopus (n = 62), respectively. Following the removal of 17 duplicates, we obtained a total of 149 records that were carefully reviewed through the assessment of the titles and abstracts, of which a total of 130 records were excluded due to the following reasons: (1) one review article; (2) 118 irrelevant articles; (3) one editorial; (4) one experimental study; (5) nine guidelines and statements. The eligibility of the remaining 19 articles according to the inclusion and exclusion criteria was evaluated through assessing the full text, of which eight records were excluded due to the following: (1) PAD undefined ¹² ; (2) PAD included in CVD group without clear fatty liver group ¹³ , ¹⁴ , ¹⁵ ; (3) PAD as antiplatelet indication in liver or nonliver disease ¹⁶ ; (4) insufficient relevant data, mainly diabetes‐focused, cardiovascular outcomes. ¹⁷ , ¹⁸ , ¹⁹ Hence, a total of 11 records ¹⁰ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ fulfilled our criteria and were included in our systematic review as described in Figure 1.

FIGURE 1.

PRISMA flow diagram for search and selection processes of this systematic review.

3.2. Study characteristics

The main characteristics of included studies are summarized in Table S1. A total of approximately 848,027 subjects were included in this review. The number of NAFLD patients included in the studies varied from 16 to 129,967, while MAFLD patients varied between 246 and 142,915.

Five studies had a cohort study design (retrospective cohort study, ³⁰ , ³¹ prospective cohort study, ³² , ³³ population‐based cohort study, ³⁴ longitudinal cohort study ³⁵ ). Moreover, three studies had a cross‐sectional study design (cross‐sectional study, ³⁶ cross‐sectional case–control study ³⁷ and retrospective, observational, single‐center cross‐sectional study). ²⁶ One study had a community‐based longitudinal study design. ²⁹ One study had an observational study design (multi‐centered, observational study design that was divided in: cross‐sectional study and prospective cohort study), ²⁸ and one study consisted of two longitudinal studies: The UKB study (prospective cohort) and ARIC study (prospective community‐based cohort). ¹⁰

Three studies were conducted in Europe (United Kingdom n = 1, Italy n = 1, Germany n = 1), seven studies in Asia (China n = 7) and one study in Africa (Algeria n = 1).

3.3. Definition of hepatic steatosis

Hepatic steatosis was evaluated using ultrasonography for diagnosing hepatic steatosis in most studies (n = 5), ²⁴ , ²⁵ , ²⁷ , ²⁸ , ²⁹ while the other studies used ICD codes (n = 3), ²⁰ , ²¹ , ²² fatty liver index (FLI) (n = 3) ¹⁰ , ²³ , ²⁶ and Hepatic Steatosis Index (HSI) (n = 1). ²²

Liver fibrosis was evaluated using the NAFLD Fibrosis Score (NFS) ²⁹ and the Fibrosis‐4 Score (FIB‐4). ²³

3.4. Definition of PAD

PAD was primarily diagnosed using the ABI ≤.9 in either leg in most studies (n = 7). ¹⁰ , ²³ , ²⁴ , ²⁵ , ²⁷ , ²⁸ Some studies used additional thresholds, such as ABI of >1.40 as a diagnostic criterion ²⁹ or ABI ≥1.3 as an indicator of vascular calcification. ²⁸ Some studies incorporated ICD codes (n = 3), ¹⁰ , ²¹ , ²² while others utilized a nation‐wide inpatient dataset and primary care dataset, ²⁰ decreased pulsation of the dorsalis pedis artery and intermittent claudication based on the recommendations of the International Working Group on the Diabetic Foot (IWGDF) 2019. ²⁴ Alternative diagnostic methods included self‐reported illness codes, Office of Population Censuses and Surveys Classification of Interventions and Procedures codes. Furthermore, lower extremity vascular computed tomography angiography (CTA) (n = 1) and LLAC score (n = 1) ²⁶ were also employed in one study.

3.5. NAFLD as a predictor for developing PAD

The relationship between NAFLD and PAD has been explored, with several studies supporting an association, particularly in patients with T2DM and metabolic syndrome. A study conducted by Zou et al. found that patients with T2DM and NAFLD had a higher risk of PAD, compared to diabetic patients without NAFLD, with an adjusted odds ratio of 1.49. ²⁷ This association remained after adjusting for various metabolic risk factors, suggesting that NAFLD may contribute to PAD risk, possibly through mechanisms beyond traditional metabolic factors. Similarly, the authors mentioned that PAD was linked to a 92% increased risk of fibrosis progression in NAFLD patients, highlighting the role of insulin resistance and metabolic dysfunctions in both liver fibrosis and PAD development.

Studies by Taharboucht et al. and Ciardullo et al. also suggest that NAFLD is associated with an elevated risk of PAD. ²³ , ²⁵ Taharboucht found a significant correlation between NAFLD and PAD (ABP < .9) in nondiabetic individuals, with factors like smoking and metabolic syndrome exacerbating the risk. Ciardullo's population‐based study found that PAD was more prevalent in NAFLD patients, especially those over 40, underscoring the need for PAD screening in high‐risk groups such as those with diabetes and metabolic syndrome.

However, not all research has found a consistent relationship. Liu et al.'s longitudinal studies (UKB and ARIC) did not find NAFLD to be independently linked to incident PAD risk, suggesting that other factors may play a more significant role. ¹⁰ Similarly, Labenz et al. found that compared to non‐NAFLD diabetic patients, NAFLD in T2DM patients was linked to a higher risk of renal failure, but not to PAD. ²¹ Mai et al. also observed an inverse correlation between the Fatty Liver Index (FLI) and PAD, implying that NAFLD might not reliably predict PAD in some cases. ²⁶

In summary, while many studies support the hypothesis that NAFLD increases the risk of PAD, especially in the context of metabolic syndrome and liver fibrosis, the relationship remains complex and debated. Further research is needed to clarify the underlying mechanisms and identify which factors are most predictive of PAD in NAFLD patients.

3.6. MAFLD as a predictor for developing PAD

A few studies have highlighted MAFLD as a significant risk factor for developing PAD. Song et al. conducted a prospective study in the Chinese population and found that MAFLD was independently associated with an increased risk of PAD, with a 30% higher risk compared to non‐MAFLD individuals. ²⁸ The risk was particularly higher in those with multiple metabolic comorbidities, but even those with only MAFLD status showed a significant risk for PAD development. Huang et al., involving 889 patients with diabetic foot ulcers, MAFLD was linked to a higher risk of major cardiovascular and cerebrovascular events (MACCEs), including PAD. ²⁴ The study found that individuals with MAFLD had a 2.64‐fold increased risk of MACCEs compared to those without, underlining the added cardiovascular risk in this group.

Liu et al. also examined the relationship between MAFLD or NAFLD and PAD in two large longitudinal studies (UKB and ARIC). They found that MAFLD, particularly in individuals with T2DM, was strongly associated with an increased risk of PAD. Among the four groups studied (nonfatty liver, MAFLD‐only, NAFLD‐only and both MAFLD and NAFLD), the MAFLD‐only group showed the strongest association with PAD risk, while only NAFLD status was not independently linked. These findings underline the importance of PAD screening in individuals with MAFLD, especially those with diabetes or metabolic syndrome.

3.7. NAFLD + MAFLD status as a predictor for developing PAD

The only study conducted by Liu et al. examined the combined NAFLD + MAFLD group that was significantly associated with a higher risk of PAD compared to the nonfatty liver disease (FLD) group. The adjusted HR for this group was 1.51 (95% CI, 1.33–1.72) in the UKB and 1.66 (95% CI, 1.30–2.12) in the ARIC study, even after adjusting for confounders. Kaplan–Meier survival curves confirmed these results, showing a significant difference in PAD incidence between the NAFLD + MAFLD and non‐FLD groups, highlighting the stronger predictive role of combined NAFLD and MAFLD in PAD risk.

3.8. Quality assessment

As outlined in Table S2, the Newcastle‐Ottawa Scale (NOS) for cross‐sectional studies was applied to assess the methodological quality of 11 studies, focusing on the selection, comparability and outcome domains. Overall, the studies adhered well to the NOS criteria, with many employing validated tools for outcome assessment and adjusting for key confounders such as age, sex and BMI. Some studies scored slightly lower in the exposure assessment due to reliance on nonvalidated methods, like ICD codes, and in the selection assessment because sample sizes were not justified. Despite these limitations, the overall methodological quality of the studies was high, with scores ranging from 9/10 to 10/10, supporting their suitability for further investigation into the relationship between PAD and FLD.

4. DISCUSSION

Fatty liver disease and PAD represent critical global health challenges, each linked to significant morbidity and mortality. Understanding the interplay between these conditions is essential, given their shared pathophysiological mechanisms, including metabolic derangements, systemic inflammation and atherogenesis. ³⁸ To the best of our current knowledge, this is the first systematic review to include diverse observational studies to evaluate the association between NAFLD, MAFLD or MASLD, and the progression of PAD. We analysed 11 studies involving a total of approximately 848,027 participants from Europe, Asia and Africa. Our findings indicate a complex but consistent relationship, with NAFLD and PAD, ¹⁰ , ²³ , ²⁷ as well as MAFLD severity, particularly hepatic fibrosis and steatosis, correlating with an elevated risk of PAD. ¹⁰ These results underscore the importance of integrating PAD screening and management strategies into clinical care pathways for patients with fatty liver disease, particularly those with metabolic comorbidities.

One important observation is that the recent shift from NAFLD to MAFLD and currently to MASLD was accompanied by updated diagnostic criteria. ³⁹ However, these terms should not be used interchangeably. Recently, several studies demonstrated that MAFLD is more effective in identifying patients with hepatic steatosis who are at higher risk of disease progression and associated CV risk. ⁴⁰ Notably, our systematic review mostly includes studies that utilized NAFLD criteria, with only three adopting the MAFLD definition ¹⁰ , ²⁴ , ²⁸ ; however, it is important to highlight that two of these MAFLD studies ¹⁰ , ²⁴ account for approximately 480,000 participants, nearly half of the total sample size, thereby representing a comparable proportion in terms of population despite the smaller number of studies. However, no included studies used the MASLD criteria, meaning our findings are specifically relevant to NAFLD and MAFLD.

Secondly, the methods for diagnosing hepatic steatosis varied across studies. While liver biopsy remains the gold standard, ⁴¹ many studies used ultrasonography, which, despite lower sensitivity for mild steatosis, is a widely accessible and specific tool for screening. ⁴² Other noninvasive tools, such as the FLI and HSI scores, were also employed, though they are less precise than more advanced imaging techniques like MRI. ⁴³ Liver fibrosis was commonly assessed using the NFS and the FIB‐4. On the other hand, PAD was primarily diagnosed using ABI, a noninvasive and cost‐effective test. However, ABI values alone may not fully capture the extent of PAD, particularly in the early stages. ⁴⁴ One study in our review incorporated lower extremity vascular computed tomography angiography (CTA) for a more accurate diagnosis. ²⁶ Nevertheless, the LLAC score, which quantifies calcified plaques, may miss soft plaques and fail to fully capture plaque burden, further complicating PAD diagnosis.

Thirdly, our systematic review supports the hypothesis that fatty liver disease increases the risk of PAD, particularly in individuals with metabolic syndrome and diabetes. ²⁴ , ²⁸ Notably, the severity of liver disease, including hepatic steatosis and fibrosis, is associated with a higher PAD risk. ¹⁰ , ²² , ²³ Insulin resistance, systemic inflammation, and a prothrombotic state, common features of metabolic dysregulation in fatty liver disease, are likely key mechanisms linking these conditions to PAD. ²⁴ , ²⁹ However, conflicting results from some studies, such as those by Liu et al. and Mai et al., highlight the complexity of this relationship, suggesting that other factors may contribute to PAD risk beyond liver dysfunction.

Emerging evidence points to MAFLD as a stronger predictor of PAD than NAFLD, especially when considering its broader metabolic implications. For instance, Song et al. demonstrated a 30% increased risk of PAD in individuals with MAFLD, particularly those with multiple comorbidities. Liu et al.'s findings further suggest that the combination of NAFLD and MAFLD significantly elevates PAD risk, indicating that both liver dysfunction and metabolic abnormalities must be considered in PAD risk assessment.

Several metabolic mechanisms may underlie the observed association between fatty liver disease and PAD. Insulin resistance, a hallmark of both NAFLD and MAFLD, contributes to endothelial dysfunction and accelerates atherosclerosis. ⁴⁵ Chronic low‐grade inflammation and increased oxidative stress, commonly present in hepatic steatosis, can promote vascular injury and impair arterial compliance. ⁴⁶ Moreover, dyslipidemia, characterized by elevated triglycerides, small dense LDL particles and low HDL cholesterol, is frequently observed in these patients and is a known contributor to peripheral atherogenesis. ⁴⁷ Hepatokines such as fetuin‐A and fibroblast growth factor 21 (FGF21), released from steatotic liver tissue, may also play a role in modulating vascular inflammation and metabolic homeostasis. ⁴⁸ These overlapping metabolic pathways provide a plausible biological framework linking liver and vascular disease.

Despite these insights, several limitations should be acknowledged. The studies included in our review presented considerable heterogeneity in their design, diagnostic methods and participant characteristics. As previously discussed, the reliance on ABI as the primary diagnostic tool for PAD may also have led to an underestimation of PAD prevalence. Additionally, the observational design of the included studies means residual confounding could influence the outcomes, and causality cannot be confirmed.

Nevertheless, this review offers several strengths. First, it highlights the clinical relevance of fatty liver disease, given its rising prevalence and the associated morbidity of PAD. By distinguishing between NAFLD and MAFLD, we provide a more nuanced understanding of their roles in PAD risk. We also emphasize the critical role of metabolic and cardiovascular comorbidities in this association. Our inclusion of studies from diverse ethnic and geographic backgrounds enhances the generalizability of our findings and provides insight into potential regional variations in the relationship between these conditions. Another notable strength of this review is the large, combined sample size of over 800,000 participants, with several of the largest studies demonstrating significant associations between fatty liver disease and PAD; importantly, some of these studies also adjusted for a wide range of potential confounders, thereby enhancing the robustness and credibility of the findings. These findings are crucial for clinicians managing patients with both liver and vascular disease. Moving forward, future research should aim to incorporate the updated MASLD criteria to further clarify the relationship between MASLD and PAD.

5. CONCLUSIONS

Fatty liver disease patients present an increased PAD risk, particularly in individuals with metabolic syndrome and diabetes. While MAFLD may be a stronger predictor of PAD than NAFLD, the evidence is still limited. Data regarding MASLD and PAD lack in the current literature. The review not only highlights the importance of metabolic factors in this association but also points out the need for more advanced diagnostic methods and further research to clarify this relationship.

AUTHOR CONTRIBUTIONS

V.C. and A.I. had the idea of the manuscript. V.C., J.B. and A.I. independently applied the search strategy, performed the study selection and data extraction. V.C., J.B. and A.I. performed the risk of bias assessment. V.C. drafted the manuscript. A.I., J.B., S.L.P., T.S.B. and D.L.D. contributed to the writing of the manuscript. A.I. and D.L.D. made substantial contributions to the conception and critically revised the manuscript for important intellectual content. All authors revised the final manuscript and approved the final version.

FUNDING INFORMATION

The authors did not receive any financial support for the research, authorship and/or publication of this article.

CONFLICT OF INTEREST STATEMENT

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.

Supporting information

Appendix S1.

Table S1.

Table S2.

Ciornolutchii V, Ismaiel A, Bogdan J, Popa S‐L, Surdea‐Blaga T, Dumitrascu DL. From liver to limb: Exploring the association between fatty liver disease and peripheral artery disease—A systematic review. Eur J Clin Invest. 2025;55:e70075. doi: 10.1111/eci.70075

DATA AVAILABILITY STATEMENT

The analysed data was extracted from the cited original articles as outlined in Table S1.