Introduction

Non-alcoholic fatty liver disease (NAFLD), recently renamed as metabolic dysfunction-associated steatotic liver disease (MASLD), has emerged as a public health threat as it affects up to ~ 38% of the adult population worldwide [1,2,3], with its global prevalence rising in parallel with that of obesity and metabolic syndrome. An estimated ~ 50% of the worldwide adult population is forecasted to have MASLD by 2040 [2]. In 2023, using a multi-society Delphi process that involved 236 panelists from 56 countries, three large pan-national liver associations (i.e., the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Latin American Association for the Study of the Liver) have endorsed the newly proposed change in nomenclature from NAFLD to MASLD [1]. Therefore, for sake of clarity, we have opted to use the term MASLD throughout the manuscript.

Beyond its liver health implications, a rapidly expanding body of evidence indicates that MASLD is a multisystem disease extending its adverse effects beyond the liver [4, 5], and has been associated with an increased risk of develo** extrahepatic cancers (mainly gastrointestinal and gynecological cancers) [6] and cardiometabolic comorbidities, such as type 2 diabetes [7], adverse cardiovascular outcomes [8,9,10] and chronic kidney disease [11].

Among the least investigated extrahepatic complications related to MASLD, an ever-increasing number of observational studies have reported an increased prevalence of urolithiasis in adults with MASLD (as extensively discussed below). Urolithiasis has become one of the most common urinary system diseases worldwide, with an estimated prevalence ranging from ~ 1 to 20% in different regions across the globe [12]. Evidence also suggests that the prevalence of urolithiasis is on the rise globally due to changes in socio-economic conditions, climatic factors and dietary habits, as well as increasing rates of metabolic comorbidities (such as overweight/obesity, metabolic syndrome and type 2 diabetes) [12, 13]. Therefore, the increasing global burden of urolithiasis is expected to have substantial health, economic and social implications in the coming years.

To our knowledge, two previous small meta-analyses (published in 2018) have reported that the risk of urolithiasis in individuals with MASLD appeared to be higher than in those without MASLD [14, 15]. These meta-analyses did not address the question of whether the strength of any association between MASLD and urolithiasis was affected by severity of NAFLD. Notably, after the publication of these two small meta-analyses, it is important to note that new large observational studies have been published on this topic.

We have, therefore, carried out an updated systematic review and meta-analysis of observational studies to quantify the magnitude of the association of urolithiasis in adult individuals with MASLD. We also aimed to examine whether the severity of MASLD was associated with an increased risk of urolithiasis. Clarifying the magnitude of the risk of urolithiasis related to MASLD may favorably impact the development of primary prevention strategies for urolithiasis.

Methods

Registration of review protocol

The protocol of the systematic review was registered on the Open Science Framework (OSF) database (registration DOI: https://doi.org/10.17605/OSF.IO/JVGP2).

Data sources and searches

This systematic review has been performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-analysis Of Observational Studies in Epidemiology (MOSE) guidelines [16, 17]. We systematically searched three large electronic databases (PubMed, Web of Science and Scopus) from database inception to March 31, 2024, to identify relevant observational studies examining the association between MASLD and the risk of urolithiasis. Search free text terms were "urolithiasis" OR "nephrolithiasis" OR "renal stones" OR “urinary calculi” AND “fatty liver” OR “non-alcoholic fatty liver disease” OR “NAFLD” OR “non-alcoholic steatohepatitis” OR “metabolic dysfunction-associated steatotic liver disease” OR “MASLD” OR “metabolic dysfunction-associated steatohepatitis” OR “metabolic dysfunction-associated fatty liver disease” OR “MAFLD”. Searches were restricted to human studies and English language studies. Subjects included in the meta-analysis were of either sex without age, race, or ethnicity restrictions.

Study selection

Eligible studies were included in the meta-analysis if they met the following inclusion criteria: (1) observational (cross-sectional, case–control, or longitudinal) studies examining the risk of urolithiasis amongst adult (age ≥ 18 years) individuals with and without MASLD (or NAFLD); (2) studies that reported odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (95% CIs) values for the outcome of interest; (3) the diagnosis of MASLD (or NAFLD) was based on liver biopsy, imaging techniques or blood-based biomarkers/scores, in the absence of significant alcohol consumption (usually defined as < 20 g/day for women and < 30 g/day for men) or other competing causes of hepatic steatosis (e.g., viral hepatitis, iron overload and use of potentially hepatotoxic drugs); and (4) the diagnosis of urolithiasis was based on imaging techniques (ultrasonography or computed tomography) or a self-reported history.

The exclusion criteria of the meta-analysis were as follows: (1) congress abstracts, case reports, reviews, practice guidelines, commentaries or editorials; (2) studies in which the diagnosis of MASLD (or NAFLD) was based exclusively on serum liver enzyme concentrations; (3) studies which did not exclude individuals with significant alcohol consumption or other known causes of chronic liver disease; and 4) studies that included exclusively patient populations with MASLD (or NAFLD) or those with known or suspected urolithiasis.

Data extraction and quality assessment

Data from studies eligible for the aggregate data meta-analysis were independently extracted by two investigators (AM and GT). Any disagreements between investigators about including eligible studies were resolved by consensus and a third investigator if needed (RM).

For each eligible study, we extracted data on publication year, study design, sample size, country, population characteristics, methods used for the diagnosis of MASLD and urolithiasis, outcomes of interest, matching and confounding factors included in multivariable regression analyses, and duration of follow-up (only for longitudinal studies). In the case of multiple publications of the same database, we included the most up-to-date or comprehensive information.

The overall quality of the studies included in the aggregate data meta-analysis was assessed using the Newcastle–Ottawa scale (NOS) by two independent authors (AM and GT). Any disparities in scoring were reviewed, and consensus was obtained following discussion. The NOS scale is a validated scale for non-randomized studies in meta-analyses, which uses a star system to assess the quality of a study in three domains: selection, comparability, and outcome/exposure. The NOS assigns a maximum of four stars for selection (or five stars in the case of cross-sectional studies), two for comparability, and three for outcome/exposure. We judged studies that received a score of at least 8 stars to be at low risk of bias, thus reflecting the highest quality.

Data synthesis and analysis

The primary outcome measure of the meta-analysis was the presence of urolithiasis for cross-sectional studies or the risk of develo** incident urolithiasis for longitudinal studies. The ORs (for cross-sectional studies) or HRs (for longitudinal studies) and their 95% CIs were considered as the effect size for all the eligible studies. When studies reported ORs/HRs with varying degrees of covariate adjustment, we extracted those that reflected the maximum extent of adjustment for potentially confounding variables. The adjusted ORs/HRs of all eligible studies were pooled, and an overall effect-size estimate was calculated using a random-effects model since high heterogeneity was expected for a meta-analysis of observational studies.

The statistical heterogeneity among studies was evaluated by the chi-square test and the I2-statistic, which estimates the percentage of variability across studies due to heterogeneity rather than chance alone. The proportion of heterogeneity accounted for by between-study variability was assessed using the I2-statistic and adjudicated to be significant if the I2 index was > 50% [18]. The possibility of publication bias was examined using the visual inspection of funnel plots and the Egger’s regression asymmetry test [19].

To explore the possible sources of (expected) high heterogeneity among the studies and to test the robustness of the observed associations, we performed subgroup analyses by study country (Asian vs. non-Asian countries), diagnostic methods used for identifying MASLD and urolithiasis (computed tomography vs. ultrasonography vs. survey questionnaires), and degrees of covariate adjustment (minimally vs. fully adjusted studies). We also tested for possible excessive influence of individual studies using a meta-analysis influence test that eliminated each included study at a time. Finally, we performed univariable meta-regression analyses to test the impact of age and sex on the effect size for the association between MASLD and urolithiasis.

All statistical tests were two-sided and used a significance level of p < 0.05. We used R version 4.3.3 (R Core Team 2023, R Foundation for Statistical Computing, Vienna, Austria. < https://www.R-project.org/ >) for all statistical analyses with the following packages: meta (version 7.0–0) and metafor (version 4.4–0).

Results

Literature search and characteristics of included studies

The PRISMA flow diagram of the meta-analysis is reported in Supplementary Fig. 1. After examining the titles and abstracts of the publications and excluding duplicates, we identified 13 potentially eligible studies from PubMed, Web of Science, and Scopus from the inception to March 31, 2024. We further excluded five studies because of unsatisfactory inclusion criteria (as reported in Supplementary Table 1). Consequently, we identified eight unique observational studies (7 cross-sectional studies and one prospective cohort study) for inclusion in the meta-analysis.

The main characteristics of these eight selected observational studies are reported in Table 1. Regarding the seven cross-sectional studies [20,21,22,23,24,25,26], the diagnoses of MASLD and urolithiasis were based on abdominal ultrasonography (n = 3 studies), non-contrast computed tomography (n = 3 studies), or survey questionnaires (n = 1 study). No studies were available on using liver biopsy to diagnose MASLD. Overall, these cross-sectional studies included 40,385 adult individuals (39.5% men; mean age 47.6 years; ~ 15% had a diagnosis of urolithiasis; ~ 22% had a diagnosis of MASLD). Five studies were conducted in Asia (China, South Korea, Iran, and Israel), one in the USA and one in Colombia. Two of these 7 studies obtained at least 8 stars on the NOS scale, thus reflecting a low risk of bias; two studies obtained 7 stars, and the remaining three studies obtained 6 stars. As shown in Table 1, the single published prospective cohort study was carried out in South Korea and included 208,578 adult individuals undergoing a health checkup examination who were followed for a median period of 6.6 years. The diagnosis of MASLD and urolithiasis was based on ultrasonography [27].

Table 1 Eligible cross-sectional (n = 7) and prospective studies (n = 1) examining the association between MASLD and risk of urolithiasis
Full size table

Cross-sectional studies on the association between MASLD and urolithiasis

The distribution of cross-sectional studies (n = 7 studies involving 40,385 adult individuals from different countries) by estimate of the association between MASLD and the risk of prevalent urolithiasis is plotted in Fig. 1. We found that MASLD was significantly associated with a higher risk of prevalent urolithiasis (pooled random-effects OR 1.87, 95% CI 1.34–2.60; I2 = 91%). In most eligible studies, these results persisted when adjusted for age, sex, obesity, hypertension, type 2 diabetes, and other potential confounding factors (as specified in Table 1).

Fig. 1
figure 1

Forest plot and pooled estimates of the effect of MASLD on the risk of prevalent urolithiasis in the eligible cross-sectional studies

Full size image

Subgroup analyses

We undertook subgroup analyses to explore the possible sources of high heterogeneity across the cross-sectional studies. As shown in Supplementary Fig. 2, the association between MASLD and urolithiasis was stronger in Asian studies (n = 5 studies; pooled random-effects OR 2.38, 95% CI 1.58–3.57; I2 = 83%) than in non-Asian studies (n = 2 studies; random-effects OR 1.29, 95% CI 1.04–1.59; I2 = 51%). Conversely, the association between MASLD and urolithiasis was consistent when the comparison was stratified by different methods used for diagnosing MASLD (or urolithiasis) (Supplementary Fig. 3) or by the degree of covariate adjustment [pooled random-effects OR 2.42, 95% CI 1.15–5.09 for minimally adjusted studies (i.e., adjusted for age and sex), and pooled random-effects OR 1.59, 95% CI 1.12–2.17 for fully adjusted studies (i.e., adjusted for age, sex, obesity and other common metabolic risk factors)] (Supplementary Fig. 4).

Sensitivity analyses and meta-regressions

A sensitivity analysis using the one-study remove (leave-one-out) approach to test the influence of each study on the overall effect size showed that eliminating each of the cross-sectional studies from the pooled primary analysis did not have any significant effect on the association between MASLD and urolithiasis (Supplementary Fig. 5). The results of univariable meta-regression analyses to examine the effect of potential moderator variables showed a significant positive association between age and urolithiasis (p = 0.011) (Supplementary Fig. 6). Conversely, meta-regression analysis did not show any significant effect of sex on the association between MASLD and urolithiasis (in cross-sectional studies) (p = 0.361) (Supplementary Fig. 7). As reported in Table 1, there were insufficient data to perform univariable meta-regression analyses for testing the effects of obesity and diabetes on the presence of urolithiasis.

Cross-sectional studies on the association between more severe MASLD and urolithiasis

The distribution of cross-sectional studies by estimate of the association between the ultrasonographic severity of MASLD and the risk of prevalent urolithiasis is plotted in Fig. 2 [23, 25]. We found that more severe MASLD on ultrasonography was significantly associated with higher odds of urolithiasis (pooled random-effects OR 2.0, 95% CI 1.46–2.74; I2 = 0%). None of the eligible studies examined the association between blood-based biomarkers of liver fibrosis and the likelihood of urolithiasis.

Fig. 2
figure 2

Forest plot and pooled estimates of the effect of ultrasonographic severity of MASLD on the risk of prevalent urolithiasis in the eligible cross-sectional studies

Full size image

Longitudinal studies on the association between MALD and risk of develo** urolithiasis

The distribution of cohort studies by estimate of the association between MASLD and the risk of develo** incident urolithiasis is plotted in Fig. 3. Only one cohort study from South Korea examined the association between MASLD and the risk of develo** urolithiasis amongst 208,578 adult individuals undergoing health checkup examinations [27]. During a median follow-up of 6.6 years, there were 16,442 cases of incident urolithiasis. MASLD assessed by ultrasonography was significantly associated with a higher risk of incident urolithiasis in men (adjusted HR 1.17, 95% CI 1.06–1.30) but not in women (adjusted HR 0.97, 95% CI 0.81–1.16) after adjusting for common metabolic risk factors and other potential confounders. As shown in Fig. 2, when we plotted these two adjusted HRs in a forest plot analysis, MAFLD was not significantly associated with the risk of develo** urolithiasis (pooled random-effects HR 1.08, 95% CI 0.90–1.30; I2 = 69%).

Fig. 3
figure 3

Forest plot and pooled estimates of the effect of MASLD on the risk of develo** incident urolithiasis in the eligible cohort studies

Full size image

Publication bias

As shown in Fig. 4, the visual inspection and the Egger’s regression test (although less than ten studies were included) did not show any statistically significant asymmetry of the funnel plot for the included studies (p = 0.769), thus suggesting that the publication bias was low.

Fig. 4
figure 4

Funnel plot assessing the possibility of publication bias across the eligible studies (n = 8)

Full size image

Discussion

In this comprehensive and updated meta-analysis that included 8 observational studies (seven cross-sectional studies and one longitudinal cohort study) with aggregate data on ~ 250,000 adult individuals from different countries, we found that MASLD was significantly associated with an approximately two-fold higher prevalence of urolithiasis (n = 7 studies; pooled random-effects OR 1.87, 95% CI 1.34–2.60). This association was more robust in studies conducted in Asia than in non-Asian countries but remained unchanged when the comparison was stratified by different modalities for diagnosing MASLD or urolithiasis. Notably, this association remained significant in those studies where statistical analysis was adjusted for age, sex, ethnicity, obesity, type 2 diabetes, and other common metabolic risk factors. Moreover, the ultrasonographic severity of MASLD was significantly associated with higher odds of urolithiasis. Meta-regression analyses also showed a significant positive association between age and MASLD-related urolithiasis, suggesting that this association may be partly mediated by age population in different studies (thus explaining a part of the observed high heterogeneity among studies). Finally, the meta-analysis of data from the single Asian cohort study suggested that MAFLD was not associated with the risk of develo** incident urolithiasis (pooled random-effects HR 1.08, 95% CI 0.90–1.30), although there was a significant interaction between sex and MASLD for the development of nephrolithiasis (MASLD being significantly associated with a higher risk of develo** urolithiasis in men but not in women). Further well-designed prospective studies in Asian and non-Asian populations are needed to better understand whether MASLD may be a risk factor for incident urolithiasis Adequate consideration of sex differences and sex hormones/menopausal status in future clinical investigations will be also needed to fill current gaps and implement precision medicine. Further research is also required to elucidate whether the severity of MASLD (especially higher fibrosis stage, which is the strongest histologic predictor of hepatic and extrahepatic morbidity and mortality in MASLD [4, 28]) may adversely affect the risk of urolithiasis.

To our knowledge, this is the most updated and comprehensive meta-analysis assessing the association between MASLD and the risk of having or develo** urolithiasis. Our findings corroborate and further expand the results of two previous meta-analyses published in 2018 [14, 15]. Unlike these two smaller meta-analyses, we included three large observational studies (published in 2020 and 2022) and performed separate analyses for cross-sectional and longitudinal studies (although only one Asian prospective cohort study was available so far), thus examining the possible distinct effects of MASLD on the prevalence and incidence of urolithiasis. Furthermore, our subgroup analyses and meta-regressions confirmed the robustness of the observed associations. Contrary to these previous meta-analyses [14, 15], we did not include “grey” literature, as we excluded unpublished studies and studies published outside widely available journals. Therefore, we did not include two cross-sectional studies from Colombia and Israel of very low quality that were published only as poster communications (as specified in our Supplementary material).

The findings of our meta-analysis may have some important clinical implications; more specifically, adult patients with MASLD may be screened for urolithiasis (especially in Asian people with MASLD) as these patients are at higher risk of urolithiasis. A recent Mendelian randomization study revealed no genetic evidence for a causal relationship between genetically predicted MASLD and the risk of urolithiasis [

Data availability

All supporting data of the meta-analysis are available within the article and in the online-only Supplementary Material.

Abbreviations

NAFLD:

Non-alcoholic fatty liver disease

MASLD:

Metabolic dysfunction-associated steatotic liver disease

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

NOS:

Newcastle–Ottawa Quality Assessment Scale

OR:

Odds ratio

HR:

Hazard ratio

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Funding

Open access funding provided by Università degli Studi di Verona within the CRUI-CARE Agreement. There was no funding source for this study.

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Authors and Affiliations

  1. Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy

    Alessandro Mantovani, Riccardo Morandin, Veronica Fiorio & Maria Giovanna Lando

  2. Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy

    Salvatore Petta

  3. Section of Nephrology, Department of Medicine, University of Verona, Verona, Italy

    Pietro Manuel Ferraro

  4. Department of Medicine, University of Verona, Verona, Italy

    Giovanni Targher

  5. Metabolic Diseases Research Unit, IRCCS Sacro Cuore, Don Calabria Hospital, Viale Luigi Rizzardi, 4, 37024, Negrar di Valpolicella (VR), Italy

    Giovanni Targher

Authors
  1. Alessandro Mantovani
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  4. Maria Giovanna Lando
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  5. Salvatore Petta
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  6. Pietro Manuel Ferraro
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  7. Giovanni Targher
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Contributions

AM and GT were involved in the conception of the study and the analysis and interpretation of the results. GT wrote the first draft of the manuscript. RM, VF, and MGL were involved in the conduct of the study and searched the published articles. SP and PMF was involved in the interpretation of the results and contributed to the discussion. All authors edited, reviewed, and approved the final version of the manuscript.

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Correspondence to Giovanni Targher.

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Human and animal rights statement and Informed consent

This study involves human participants but was not approved by an Ethics Committee. Approval from an Ethics Committee is not necessary as this is a meta-analysis of published observational studies that had already obtained both informed consent from participants and ethical approval by their local Ethics committees.

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Mantovani, A., Morandin, R., Fiorio, V. et al. Association between metabolic dysfunction-associated steatotic liver disease and risk of urolithiasis: an updated systematic review and meta-analysis. Intern Emerg Med (2024). https://doi.org/10.1007/s11739-024-03705-5

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