Correlation Between Periodontitis and Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis

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While prior research indicates a possible connection between these diseases, the conclusions in the existing literature are highly variable and the findings are inconsistent. Consequently, there is an urgent need for a comprehensive evaluation of this relationship. Methods This study conducted a systematic search of the PubMed, Embase, Scopus, and Web of Science databases, encompassing research published up to June 25, 2025, to assess the association between NAFLD and periodontitis. The review incorporated cross-sectional, case-control, and cohort studies. A meta-analysis was performed utilizing a random effects model, with subgroup and sensitivity analyses conducted to investigate potential sources of heterogeneity. Results Following an extensive screening process of the 628 studies initially retrieved, a total of 12 studies were deemed suitable for inclusion in the analysis, comprising 9 cross-sectional studies and 3 cohort studies. A meta-analysis was performed on the adjusted odds ratios (OR) and 95% confidence intervals (CI) derived from the cross-sectional studies. The results showed that there was a significant association between periodontitis and NAFLD (OR: 1.24, 95% CI: 1.12, 1.38). Subgroup analysis based on diagnostic criteria differences indicated that periodontitis diagnosed by clinical attachment loss and NAFLD had a stronger association (OR: 1.38) and lower heterogeneity ( I 2 : 25%). The results of the cohort studies suggested a bidirectional relationship between periodontitis and NAFLD, but the heterogeneity was too high, so more high-quality prospective studies are needed to confirm this relationship. Conclusion The current research evidence indicates that there is a significant association between periodontitis based on clinical attachment lever definition and NAFLD. Health sciences/Diseases Health sciences/Gastroenterology Health sciences/Health care Health sciences/Medical research Health sciences/Risk factors periodontitis non-alcoholic fatty liver disease meta-analysis clinical attachment loss Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Periodontitis is a chronic inflammatory condition resulting from the dysregulation of the subgingival microbiota. It affects approximately 40–75% of the global adult population and is recognized as the sixth most prevalent disease among humans 1 – 3 . The defining characteristic of this condition is the destruction of the dental supporting structures, encompassing the gums, periodontal ligament, and alveolar bone 4 . In addition to adversely affecting oral health, the dysregulation of the host's immune inflammatory response, as mediated by periodontitis, results in the systemic release of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), as well as bacterial endotoxins like lipopolysaccharides (LPS) 5 . A growing body of evidence suggests a significant association between periodontitis and various systemic diseases, including cardiovascular diseases, diabetes, and respiratory diseases 6 – 8 . Consequently, the consideration of periodontitis as a potential risk factor for overall health has garnered increasing scholarly attention. Liver diseases are another major global health challenge, causing 44,000 deaths in the United States each year and 2 million deaths worldwide annually 9 . Chronic liver diseases are a group of diseases that affect the liver and cause its function to gradually decline over at least 6 months. The most common causes include chronic hepatitis B virus, hepatitis C virus, alcohol-related liver disease, and non-alcoholic fatty liver disease (NAFLD) 9 . The liver, as a front-line immune organ, is easily invaded by pathogenic substances from the intestine and circulating inflammatory factors through the portal vein system 10 . Compensatory hepatocyte proliferation and the gradual replacement of liver components by fibrous tissue are two pathological processes that can lead to end-stage liver diseases, including cirrhosis and hepatocellular carcinoma 11 , 12 . Chronic liver diseases not only cause significant morbidity and mortality but also impose a huge economic burden on the healthcare system 13 . Therefore, understanding the risk factors of liver diseases and potential prevention strategies is crucial for reducing their public health impact. Globally, NAFLD is a common trigger for long-term liver diseases. According to statistics, the prevalence of NAFLD among adults worldwide is as high as 32% 14 . Histologically, NAFLD is defined as the presence of more than 5% of liver cells with fatty degeneration when other causes of chronic liver diseases (excessive alcohol consumption, viral, autoimmune hepatitis, etc.) are excluded. It covers a range of liver diseases, from simple fatty degeneration (non-alcoholic fatty liver) to non-alcoholic steatohepatitis 15 . It is reported that NAFLD is related to lifestyle, and the increase in the prevalence of obesity and type 2 diabetes further exacerbates the disease burden of NAFLD 16 . As previously discussed, the oral microenvironment has the potential to influence the physiological state of other organs. Recent studies have increasingly elucidated a complex bidirectional pathological relationship between the oral cavity and the liver. Some researchers have introduced the concept of the oral-gut-liver axis to explain the potential connection between oral diseases, particularly periodontitis, and liver diseases 17 , 18 . The liver is located in a unique anatomical position and thus has a dual blood supply. At present, two pathways have been proposed to explain the connection between periodontal disease and liver pathology, namely the systemic and intestinal dissemination of hepatotoxic components 19 . One of the pathways connecting the mouth and the liver is considered to be blood circulation diffusion. This is due to the excessive permeability of the pouch-like epithelium and the micro-ulcers in the periodontal inflamed tissues, as well as the inflammatory mediators and microorganisms that are caused by the inflammatory process and are transported through the circulatory system 20 . For instance, in patients with periodontitis, the levels of reactive oxygen species and inflammatory cytokines in the serum increase, suggesting the presence of a mild chronic inflammatory condition throughout the body 21 . Another possible pathway connecting the mouth and the liver is that oral bacteria are transported through the gastrointestinal tract, resulting in abnormal intestinal microbiota 22 . Chronic inflammation and dysbiosis are common features that contribute to the clinical pathology of both periodontitis and NAFLD 17 . Despite progress in understanding the relevant mechanisms, the clinical epidemiological evidence remains fragmented, and the research findings are still contentious, lacking a unified conclusion. In light of this, the present study aims to conduct a meta-analysis of existing literature to systematically evaluate the association between periodontitis and NAFLD, thereby providing a scientific basis for their clinical treatment and early intervention. 2. Methods 2.1 Quality assessment Systematic reviews and meta-analyses are conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, as well as the standards for meta-analysis of observational epidemiological studies. In instances where discrepancies arise between the two reviewers during the processes of study selection, data extraction, or methLodological quality assessment, resolution is achieved through consensus or, if necessary, consultation with a third reviewer. The study protocol has been registered with PROSPERO database (CRD420251102841). 2.2 Database and retrieval strategy We conducted a comprehensive literature search across multiple databases, including PubMed, Scopus, Embase, and the Web of Science, for studies published up to June 2025. Search was done using the following MeSH terms: (Periodontitis OR Periodontal Diseases) AND (Non-alcoholic Fatty Liver Disease OR NAFLD). Detailed search terms are provided in the appendix. 2.3 Eligibility criteria Two independent authors conducted a review of the titles and/or abstracts to identify full-text articles potentially meeting the PECOS criteria (Participants comprised adult humans without hepatic comorbidities; Exposure required clinically verified periodontitis; Controls included matched periodontally healthy subjects; Outcomes necessitated objective NAFLD confirmation; Study designs encompassed observational or interventional approaches with adequate sample sizes). The inclusion criteria were as follows: (1) studies investigating the association between periodontitis and NAFLD; (2) studies that provide diagnostic criteria for NAFLD; (3) studies that clarify and report diagnostic criteria for periodontitis; and (4) studies that include or are suitable for calculating outcome indicators such as risk estimates (odds ratio [OR], relative risk [RR], or hazard ratio [HR]) or secondary outcome measurements like clinical attachment level (CAL) or pocket probing depth (PPD). The exclusion criteria were: (1) inability to quantify outcome indicators; (2) unavailability of full-text articles; (3) documents such as systematic reviews, clinical case reports, letters, commentaries, abstracts, conference proceedings, meta-analyses, animal studies, and other similar publications; and (4) duplicate publications. 2.4 Literature screening and data extraction Initially, all studies retrieved from the relevant databases are imported into EndNote X9 software to remove duplicates. Subsequently, an initial screening is performed based on the titles and abstracts. For articles necessitating further review, the full texts are examined, and those meeting the established criteria are selected. Finally, the fundamental characteristics of the qualifying studies are extracted, which include: (1) Research information: the first author's name, publication date, nationality, and study design; (2) Baseline data: sample size, gender, age, and diagnostic criteria for periodontitis; (3) Result data: OR/RR/HR and the corresponding 95% confidence interval (CI). 2.5 Evaluation of literature quality The quality of the literature was assessed using the Newcastle-Ottawa Scale (NOS) 23 and the evaluation criteria recommended by the Agency for Healthcare Research and Quality (AHRQ) 24 . The NOS appraises cohort studies based on three dimensions: the selection of exposed and unexposed cohorts, the comparability of these cohorts, and the outcomes. It employs a 9-point scale, categorizing studies as low-quality (0–4 points), medium-quality (5–6 points), and high-quality (> 7 points). In contrast, the AHRQ criteria for cross-sectional studies encompass 11 items, yielding a total score of 11 points. Studies are classified as low-quality (0–3 points), medium-quality (4–7 points), and high-quality (8–11 points) based on their scores. 2.6 Statistical analysis The relationship between NAFLD and periodontitis was analyzed using RevMan software version 5.3 (Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). The OR/RR/HR values and their 95% CI were calculated as measures of the association between periodontitis and NAFLD. Heterogeneity tests were conducted on the data from the final included studies, and the I 2 statistic was used to analyze the heterogeneity. The heterogeneity of the studies was classified based on the I 2 value. The larger the I 2 value, the greater the heterogeneity. If I 2 was less than 50%, it indicated a lower heterogeneity and the fixed-effect model was applied. In contrast, if I 2 was greater than or equal to 50%, it indicated greater heterogeneity, and the random-effect model was applied. Further sensitivity analysis was conducted, and the publication bias test was evaluated by visual inspection of the funnel plot. 3. Results 3.1 Study Selection We identified 628 documents through the retrieval of 4 databases. After deleting 313 duplicate items, we excluded documents of various types such as reviews, conference abstracts, letters, etc. based on the type of the documents. After reviewing the titles and abstracts, we deleted the documents that did not match the topic. Finally, we read the full texts of 24 studies and included 12 studies in the Meta-analysis, including 9 cross-sectional studies and 3 cohort studies (Fig. 1 ). 3.2 Study Characteristics The general characteristics of the nine cross-sectional studies are presented in Table 1. Collectively, these studies encompassed a total of 663,996 adult participants, with individual study sample sizes ranging from 12,260 to 438,905. All studies included both male and female participants, aged between 18 and 74 years, thus encompassing a broad age spectrum. Several studies did not accurately specify the age range of the participants 25 – 27 . Geographically, these studies were conducted in the United States, South Korea, Japan, and Israel. The majority of the studies diagnosed periodontitis based on the degree and extent of clinical attachment loss (CAL). In contrast, one study relied on participants' self-assessment of periodontal conditions, including symptoms such as gum pain, gum bleeding, or tooth loosening 27 . The other two studies used the probing depth as the diagnostic criterion. 28 , 29 . 3.3 Evaluation of literature quality This study conducted a quality assessment of the nine included cross-sectional studies utilizing the AHRQ scale (Table 2 ), while the three cohort studies were evaluated using the NOS scale (Table 3 ). The evaluation results summarized that the literature selected for this study demonstrated moderate to high quality. Overall, there was no significant difference in the quality of the included studies. There were no obvious biases in the selection of the study population and the measurement of the results. However, none of the multiple studies reported whether there were any missing data and the related handling. Cross-sectional studies generally did not describe the tracking and analysis situations, which may lead to doubts about the reliability of the results and make the source of heterogeneity unclear. Table 2 Agency for healthcare research and quality scores of cross-sectional studies. Study 1 2 3 4 5 6 7 8 9 10 11 Total Alazawi 2017 Y Y Y Y Y U Y Y Y Y U 9 Akinkugbe 2018 Y Y Y Y Y U N Y Y Y U 8 Iwasaki 2018 Y Y Y Y U Y Y Y N Y U 8 Weintraub 2019 Y Y Y Y Y Y Y Y Y Y U 10 Kim 2020 Y Y Y Y Y Y Y Y U Y U 9 Shin 2020 Y Y Y Y Y Y N Y Y Y U 9 Ram 2022 Y Y Y Y U Y N U U Y U 6 Wilensky 2023 Y Y Y Y Y Y Y Y U Y U 9 Liu 2025 Y Y Y Y Y Y Y Y Y Y U 10 Notes: 1: Are the sources clear? 2: Are the inclusion and exclusion criteria for the two groups clear? 3: Is the time to identify patients clear? 4: Are the subjects continuous? 5: Is the evaluator isolated from other objective measures of the patient? 6: Has quality assurance been assessed? 7: Are excluded objects analyzed? 8: Are confounding factors assessed? 9: Is there any processing of the lost data? 10: Is the data complete? 11: Is there follow-up and analysis? Table 3 Quality assessment of cohort studies according to the modified NOS. Study Study population selection Comparability between groups Outcome measurement Total 1 2 3 4 5 6 7 8 Akinkugbe 2017 1 1 1 1 2 1 0 1 8 Shin 2022 1 1 1 1 2 1 1 1 9 Joo 2024 1 1 1 1 2 1 0 1 8 Notes: 1: Representativeness of the exposed group. 2: Selection of non-exposed groups. 3: Identification of exposure factors. 4: No outcome indicators were available before the study began. 5: Comparability of the resulting cohort based on design and analysis. 6: Methods of evaluating outcome events. 7: Whether the follow-up time was sufficient. 8: Integrity of follow-up. 3.4 Meta-analysis In the cross-sectional study (n = 9), the presence of NAFLD was significantly associated with a higher prevalence of periodontitis (OR = 1.24; 95% CI: 1.12, 1.38), however, the estimated values showed moderate heterogeneity ( I 2 = 67%, p < 0.0001) (Fig. 2 ). As previously discussed, the diagnostic criteria for periodontitis and NAFLD may present a fundamental contradiction. We performed a subgroup analysis to explore the impact of differing diagnostic criteria for these two conditions (Table 4 ). In the assessment of periodontitis, six studies utilized CAL as the diagnostic criterion, two studies employed PPD, and one study was based on self-reported data from participants. CAL is defined as the distance from the enamel-dental pulp junction to the base of the periodontal pocket, serving as a direct and critical measure of the irreversible loss of periodontal supporting tissues, including gingival connective tissue and alveolar bone. It is recognized as the most significant indicator of periodontal tissue destruction. In contrast, PPD is measured as the distance from the gingival margin to the base of the periodontal pocket. PPD can be influenced not only by the loss of connective tissue attachment (true periodontal pocket) but also by gingival inflammation and edema (false periodontal pocket). Consequently, CAL is regarded as a more reliable and objective parameter for diagnosing periodontitis, as it is not directly influenced by variations in the position of the gingival margin, whether due to recession or hyperplasia. Therefore, CAL is considered the gold standard for determining the presence and severity of periodontitis. In a subgroup analysis (n = 6) that utilized CAL as the diagnostic criterion for periodontitis, the strongest evidence of association was observed, yielding a combined odds ratio of 1.38, with heterogeneity reduced to 25%. Furthermore, one study 27 diagnosed periodontitis based on patients' self-reported symptoms, such as gum pain, bleeding, and tooth loosening, reporting an OR of 1.10. The self-assessment of periodontal conditions was conducted through a touchscreen-based questionnaire; a professional dental examination was not part of the process. Participants were queried about the presence of symptoms such as painful gums, bleeding gums, or loose teeth, with the option to select multiple symptoms. The self-assessment questionnaire did not effectively serve as a predictive tool for periodontal disease. Therefore, due to the singular nature of this study, it was excluded from the I² statistics. The criteria for detecting NAFLD contribute to the observed heterogeneity among studies. Although liver biopsy is the gold standard for diagnosing NAFLD, ultrasound is more appropriate for large-scale, population-based research. The limited number of pertinent studies has led to considerable variation in the NAFLD detection criteria used across the included studies. However, the heterogeneity associated with diagnosing NAFLD using ICD-9-CM codes and ultrasound was minimal. In contrast, studies that relied on different biochemical markers, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), exhibited significantly greater heterogeneity. ALT and AST are non-specific indicators of hepatocellular injury and do not consistently elevate in cases of NAFLD, potentially introducing bias into the results. Table 4 Subgroup analysis based on NAFLD diagnostic criteria and periodontitis diagnostic criteria Diagnostic criteria NAFLD diagnosis Periodontitis diagnosis ICD-9-CM ultrasonic testing Other markers detection CAL PPD n 2 2 5 6 2 I 2 0% 0% 50% 25% 81% p 0.82 0.51 0.09 0.25 0.02 OR 1.46 1.67 1.12 1.38 1.36 95%CI [1.21,1.75] [1.23,2.23] [1.03,1.21] [1.19,1.60] [0.79,2.32] Due to the substantial methodological differences observed, a sensitivity analysis was performed subsequent to the primary analysis. Upon excluding the three studies 27 – 29 based on probe depth and self-report criteria, the remaining six studies, which employed more consistent diagnostic criteria (primarily CAL), demonstrated that the association between periodontitis and NAFLD remained significantly robust and more stable (OR = 1.38, 95% CI:1.19, 1.60, I² = 25%) (Fig. 3 ). Moreover, research has indicated that gender influences the relationship between the two diseases. Consequently, we performed subgroup analyses based on the gender ratio differences among study participants (Table 5 ). The findings revealed that in studies where the proportion of male participants exceeded 50% (n = 3), the association between periodontitis and NAFLD was stronger and more consistent (OR = 1.51, 95% CI: 1.27, 1.79, I² =0%). In contrast, in studies where the proportion of male participants was less than 50% (n = 4), the association was weaker and exhibited greater heterogeneity (OR = 1.30, 95% CI: 1.00, 1.68, I² =71%). Table 5 Subgroup analysis based on gender ratio Men > 50% Men < 50% n 3 4 I 2 0% 71% p 0.59 0.01 OR 1.51 1.30 95%Cl [1.27,1.79] [1.00,1.68] Among the three cohort studies analyzed in this article, two studies indicated that periodontitis is associated with an increased risk of NAFLD, with RR of 1.6 (95% CI: 1.05, 2.44) 34 and 1.04 (95% CI: 1.01, 1.07) 26 , respectively (Fig. 5 ). Another cohort study investigated the incidence of NAFLD as a consequence of chronic periodontitis development 35 . Due to substantial heterogeneity in study design, definitions of exposure and outcome, and study populations ( I² = 75%), a quantitative synthesis was not performed. The existing cohort evidence tentatively suggests a potential bidirectional relationship; however, further methodologically rigorous and homogeneous prospective studies are urgently required to substantiate these findings. 4. Discussion The present meta-analysis establishes a clinically significant association between periodontitis and NAFLD, with periodontitis patients exhibiting a 24% elevated risk of NAFLD (OR = 1.24, 95% CI: 1.12, 1.38). This relationship is not merely correlative but reflects a bidirectional pathological crosstalk, primarily orchestrated through systemic inflammation and microbial dysbiosis. Periodontitis acts as a persistent source of low-grade systemic inflammation, characterized by sustained release of pro-inflammatory cytokines (IL-6, TNF-α) and bacterial endotoxins (e.g., Porphyromonas gingivalis lipopolysaccharide, Pg-LPS) into the bloodstream 36 , 37 . These mediators directly fuel NAFLD progression by dual hepatic insults: (i) induction of insulin resistance that augments de novo lipogenesis 38 , and (ii) activation of Kupffer cells that amplify lobular inflammation and transition from steatosis to steatohepatitis 39 . The subgroup analysis provides critical validation for this paradigm—studies utilizing CAL, a surrogate for cumulative periodontal tissue destruction, demonstrated a stronger association (OR = 1.38, 95% CI: 1.20, 1.58) with lower heterogeneity, compared to studies using probing depth or self-reported diagnosis. This divergence underscores that irreversible periodontal damage, rather than transient gingival inflammation, constitutes the primary driver of NAFLD risk. Emerging evidence implicates oral pathobionts in directly modulating hepatic pathophysiology. Porphyromonas gingivalis (Pg), a keystone periodontal pathogen, contributes to NAFLD through multisystemic crosstalk 40 . Experimental models reveal that Pg compromises intestinal barrier integrity, enabling translocation of live bacteria and endotoxins into the portal circulation. Subsequent engagement of Toll-like receptors-4 (TLR4) on hepatocytes triggers NF-κB signaling that exacerbates hepatic inflammation and lipotoxicity 41 . Beyond translocation, Pg-derived outer membrane vesicles systemically dysregulate lipid metabolism by upregulating stearoyl-CoA desaturase (SCD-1) while suppressing AMP-activated protein kinase (AMPK) activity 42 , 43 . Furthermore, recent data suggest that Pg-induced Th17/Treg imbalance promotes hepatocyte ferroptosis—an iron-dependent cell death pathway implicated in NASH progression 44 . Intriguingly, NAFLD reciprocally perturbs the oral microbiome through altered lipid metabolism and bile acid circulation, creating a self-perpetuating vicious cycle 45 . The substantial heterogeneity across included studies ( I² =67%) primarily stems from inconsistencies in periodontitis ascertainment. Studies employing CAL-based definitions—which objectively quantify connective tissue destruction—produced robust, homogeneous risk estimates. By contrast, those using surrogate metrics (e.g., probing depth or self-report) yielded nonsignificant associations with marked heterogeneity. This contrast highlights that diagnostic precision fundamentally shapes epidemiological validity. Furthermore, in recent years, epidemiological studies have rarely revealed the causal relationship between the two. This meta-analysis mostly included cross-sectional studies, which can efficiently integrate data from multiple sources and provide preliminary evidence of association. However, they cannot determine the sequence of occurrence between periodontitis and NAFLD. Although many studies have focused on the mechanism of the association between the two diseases, there is still a lack of epidemiological evidence. In the future, causal verification needs to be advanced through prospective studies, mechanism exploration, and standardized methods, ultimately leading to individualized prevention and treatment strategies. And future research should adopt standardized, tissue-destruction-oriented criteria to consistently capture the chronic pathological burden relevant to systemic sequelae. 5. Conclusion 5.1 Implications for Clinical Practice: Robust evidence confirms a significant association between periodontitis and NAFLD. Clinicians should recognize this bidirectional link: periodontal patients (especially with CAL-confirmed disease) may require NAFLD screening, and NAFLD patients should be assessed for periodontitis. Promoting oral hygiene and interdisciplinary collaboration between dental and liver health providers is warranted as part of comprehensive patient care. 5.2 Implications for Research: Future studies must prioritize standardized diagnostics (CAL for periodontitis; ultrasound/ ICD-9-CM for NAFLD) to reduce heterogeneity. High-quality prospective cohorts with rigorous confounder adjustment are essential to establish causality and directionality. Mechanistic research and trials evaluating periodontal therapy’s impact on NAFLD progression are needed. Declarations Author contributions H.L., M.S. and Y.L. contributed to the conception and design of the review and critically revised the manuscript drafts until the final version was approved. R.Y. performed the database searches. H.L. and M.S. conducted assessment of eligibility, data extraction, analysis and interpretation. All authors have made substantive contributions to the article and assume full responsibility for its content. All authors have seen and approved the final version of the manuscript. Funding information This project was supported by the Gansu Province Joint Research Fund (24JRRA949). Conflict of interest statement The authors declare no other conflicts of interest. Data availability statement The study protocol and the data that support the findings of this study are openly available in PROSPERO at https://www.crd.york.ac.uk/PROSPERO/ (reference number PROSPERO: CRD420251102841). ORCID Hanyi Li: https://orcid.org/0009-0001-0873-2922 Mingxuan Shi: https://orcid.org/0000-0001-9161-9906 Ruomeng Yuan: https://orcid.org/0009-0007-2840-1120 Yi Li: https://orcid.org/0009-0001-4299-6796 References Renu K, Gopalakrishnan AV, Madhyastha H. Is periodontitis triggering an inflammatory response in the liver, and does this reaction entail oxidative stress? Odontology. 2025;113(3):889-902. Sanz M, Marco Del Castillo A, Jepsen S, et al. Periodontitis and cardiovascular diseases: Consensus report. J Clin Periodontol. 2020;47(3):268-288. Genco RJ, Borgnakke WS. Diabetes as a potential risk for periodontitis: association studies. Periodontol 2000. 2020;83(1):40-45. Papapanou PN, Sanz M, Buduneli N, et al. 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Prevalence of chronic periodontitis in patients undergoing peritoneal dialysis and its correlation with peritoneal dialysis-related complications. BMC Nephrol. 2023;24(1):71. Demmer RT, Breskin A, Rosenbaum M, et al. The subgingival microbiome, systemic inflammation and insulin resistance: The Oral Infections, Glucose Intolerance and Insulin Resistance Study. J Clin Periodontol. 2017;44(3):255-265. Akinkugbe AA, Avery CL, Barritt AS, et al. Do Genetic Markers of Inflammation Modify the Relationship between Periodontitis and Nonalcoholic Fatty Liver Disease? Findings from the SHIP Study. J Dent Res. 2017;96(12):1392-1399. Yue Y, Liu X, Li Y, Xia B, Yu W. The role of TLR4/MyD88/NF-κB pathway in periodontitis-induced liver inflammation of rats. Oral Dis. 2021;27(4):1012-1021. de Jongh CA, de Vries TJ, Bikker FJ, Gibbs S, Krom BP. Mechanisms of Porphyromonas gingivalis to translocate over the oral mucosa and other tissue barriers. J Oral Microbiol. 2023;15(1):2205291. Cheng P, Wang T, Li W, et al. Baicalin Alleviates Lipopolysaccharide-Induced Liver Inflammation in Chicken by Suppressing TLR4-Mediated NF-κB Pathway. Front Pharmacol. 2017;8:547. Ding C, Shen Z, Xu R, et al. Exosomes derived from periodontitis induce hepatic steatosis through the SCD-1/AMPK signaling pathway. Biochim Biophys Acta Mol Basis Dis. 2024;1870(7):167343. Lv C, Shi K, Guo Y, et al. Emerging Roles of Periodontal Pathogen-Derived Outer Membrane Vesicles in NAFLD. Int Dent J. 2025;75(4):100825. Yao C, Lan D, Li X, Wang Y, Qi S, Liu Y. Porphyromonas gingivalis is a risk factor for the development of nonalcoholic fatty liver disease via ferroptosis. Microbes Infect. 2023;25(1-2):105040. Kuraji R, Sekino S, Kapila Y, Numabe Y. Periodontal disease-related nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: An emerging concept of oral-liver axis. Periodontol 2000. 2021;87(1):204-240. Table 1 Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Appendix.docx Table1.docx Cite Share Download PDF Status: Published Journal Publication published 04 Apr, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 19 Nov, 2025 Reviews received at journal 09 Oct, 2025 Reviews received at journal 06 Oct, 2025 Reviewers agreed at journal 04 Oct, 2025 Reviewers agreed at journal 03 Oct, 2025 Reviewers agreed at journal 01 Oct, 2025 Reviewers invited by journal 16 Sep, 2025 Editor assigned by journal 16 Sep, 2025 Editor invited by journal 05 Sep, 2025 Submission checks completed at journal 02 Sep, 2025 First submitted to journal 02 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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1","display":"","copyAsset":false,"role":"figure","size":282251,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow chart.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7434817/v1/a833b05ff0a3cc9d65bfffd2.png"},{"id":92127090,"identity":"32f47546-8ac9-4785-928e-6fa0d7127df4","added_by":"auto","created_at":"2025-09-25 01:40:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":83904,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMeta-analysis forest plot of the correlation between periodontitis and NAFLD (cross-sectional study)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7434817/v1/0c1525f8f014cf280e147532.png"},{"id":92126283,"identity":"ddc92963-f6fc-4e99-b20a-626da056d5e8","added_by":"auto","created_at":"2025-09-25 01:32:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":30020,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel plot\u003c/strong\u003e \u003cstrong\u003eof the correlation between periodontitis and NAFLD after excluding 3 studies based on probe depth and self-report criteria\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7434817/v1/dc38570dd26bd617220f7756.png"},{"id":92126288,"identity":"8811c54d-0db1-4dd8-a871-65149f42065f","added_by":"auto","created_at":"2025-09-25 01:32:53","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":7706,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure 5:\u003c/strong\u003e \u003cstrong\u003eForest plot of the cohort analysis\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7434817/v1/a236c95dccb5cb4f528d437d.png"},{"id":106343837,"identity":"0c465381-1bfb-4060-ae34-578f66ddeb33","added_by":"auto","created_at":"2026-04-07 16:09:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1371952,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7434817/v1/c893c284-ed0e-47a6-b858-78a808a40425.pdf"},{"id":92126280,"identity":"5b2aca82-8071-44f2-abd6-1520770c56e2","added_by":"auto","created_at":"2025-09-25 01:32:53","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":17368,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-7434817/v1/a1b3450dfde58065d8b9f5c5.docx"},{"id":92127092,"identity":"f4457d8f-20ad-4cb6-9fc3-8aefe9d9503b","added_by":"auto","created_at":"2025-09-25 01:40:53","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":31512,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7434817/v1/d910d4820f799344f7dd1799.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Correlation Between Periodontitis and Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePeriodontitis is a chronic inflammatory condition resulting from the dysregulation of the subgingival microbiota. It affects approximately 40\u0026ndash;75% of the global adult population and is recognized as the sixth most prevalent disease among humans\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. The defining characteristic of this condition is the destruction of the dental supporting structures, encompassing the gums, periodontal ligament, and alveolar bone\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. In addition to adversely affecting oral health, the dysregulation of the host's immune inflammatory response, as mediated by periodontitis, results in the systemic release of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), as well as bacterial endotoxins like lipopolysaccharides (LPS)\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. A growing body of evidence suggests a significant association between periodontitis and various systemic diseases, including cardiovascular diseases, diabetes, and respiratory diseases\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Consequently, the consideration of periodontitis as a potential risk factor for overall health has garnered increasing scholarly attention.\u003c/p\u003e\u003cp\u003eLiver diseases are another major global health challenge, causing 44,000 deaths in the United States each year and 2\u0026nbsp;million deaths worldwide annually\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Chronic liver diseases are a group of diseases that affect the liver and cause its function to gradually decline over at least 6 months. The most common causes include chronic hepatitis B virus, hepatitis C virus, alcohol-related liver disease, and non-alcoholic fatty liver disease (NAFLD)\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The liver, as a front-line immune organ, is easily invaded by pathogenic substances from the intestine and circulating inflammatory factors through the portal vein system\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Compensatory hepatocyte proliferation and the gradual replacement of liver components by fibrous tissue are two pathological processes that can lead to end-stage liver diseases, including cirrhosis and hepatocellular carcinoma\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Chronic liver diseases not only cause significant morbidity and mortality but also impose a huge economic burden on the healthcare system\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Therefore, understanding the risk factors of liver diseases and potential prevention strategies is crucial for reducing their public health impact. Globally, NAFLD is a common trigger for long-term liver diseases. According to statistics, the prevalence of NAFLD among adults worldwide is as high as 32%\u003csup\u003e14\u003c/sup\u003e. Histologically, NAFLD is defined as the presence of more than 5% of liver cells with fatty degeneration when other causes of chronic liver diseases (excessive alcohol consumption, viral, autoimmune hepatitis, etc.) are excluded. It covers a range of liver diseases, from simple fatty degeneration (non-alcoholic fatty liver) to non-alcoholic steatohepatitis\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. It is reported that NAFLD is related to lifestyle, and the increase in the prevalence of obesity and type 2 diabetes further exacerbates the disease burden of NAFLD\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e As previously discussed, the oral microenvironment has the potential to influence the physiological state of other organs. Recent studies have increasingly elucidated a complex bidirectional pathological relationship between the oral cavity and the liver. Some researchers have introduced the concept of the oral-gut-liver axis to explain the potential connection between oral diseases, particularly periodontitis, and liver diseases\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. The liver is located in a unique anatomical position and thus has a dual blood supply. At present, two pathways have been proposed to explain the connection between periodontal disease and liver pathology, namely the systemic and intestinal dissemination of hepatotoxic components\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. One of the pathways connecting the mouth and the liver is considered to be blood circulation diffusion. This is due to the excessive permeability of the pouch-like epithelium and the micro-ulcers in the periodontal inflamed tissues, as well as the inflammatory mediators and microorganisms that are caused by the inflammatory process and are transported through the circulatory system\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. For instance, in patients with periodontitis, the levels of reactive oxygen species and inflammatory cytokines in the serum increase, suggesting the presence of a mild chronic inflammatory condition throughout the body\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Another possible pathway connecting the mouth and the liver is that oral bacteria are transported through the gastrointestinal tract, resulting in abnormal intestinal microbiota\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Chronic inflammation and dysbiosis are common features that contribute to the clinical pathology of both periodontitis and NAFLD\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Despite progress in understanding the relevant mechanisms, the clinical epidemiological evidence remains fragmented, and the research findings are still contentious, lacking a unified conclusion. In light of this, the present study aims to conduct a meta-analysis of existing literature to systematically evaluate the association between periodontitis and NAFLD, thereby providing a scientific basis for their clinical treatment and early intervention.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Quality assessment\u003c/h2\u003e\u003cp\u003e Systematic reviews and meta-analyses are conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, as well as the standards for meta-analysis of observational epidemiological studies. In instances where discrepancies arise between the two reviewers during the processes of study selection, data extraction, or methLodological quality assessment, resolution is achieved through consensus or, if necessary, consultation with a third reviewer. The study protocol has been registered with PROSPERO database (CRD420251102841).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Database and retrieval strategy\u003c/h2\u003e\u003cp\u003eWe conducted a comprehensive literature search across multiple databases, including PubMed, Scopus, Embase, and the Web of Science, for studies published up to June 2025. Search was done using the following MeSH terms: (Periodontitis OR Periodontal Diseases) AND (Non-alcoholic Fatty Liver Disease OR NAFLD). Detailed search terms are provided in the appendix.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Eligibility criteria\u003c/h2\u003e\u003cp\u003eTwo independent authors conducted a review of the titles and/or abstracts to identify full-text articles potentially meeting the PECOS criteria (Participants comprised adult humans without hepatic comorbidities; Exposure required clinically verified periodontitis; Controls included matched periodontally healthy subjects; Outcomes necessitated objective NAFLD confirmation; Study designs encompassed observational or interventional approaches with adequate sample sizes). The inclusion criteria were as follows: (1) studies investigating the association between periodontitis and NAFLD; (2) studies that provide diagnostic criteria for NAFLD; (3) studies that clarify and report diagnostic criteria for periodontitis; and (4) studies that include or are suitable for calculating outcome indicators such as risk estimates (odds ratio [OR], relative risk [RR], or hazard ratio [HR]) or secondary outcome measurements like clinical attachment level (CAL) or pocket probing depth (PPD). The exclusion criteria were: (1) inability to quantify outcome indicators; (2) unavailability of full-text articles; (3) documents such as systematic reviews, clinical case reports, letters, commentaries, abstracts, conference proceedings, meta-analyses, animal studies, and other similar publications; and (4) duplicate publications.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Literature screening and data extraction\u003c/h2\u003e\u003cp\u003eInitially, all studies retrieved from the relevant databases are imported into EndNote X9 software to remove duplicates. Subsequently, an initial screening is performed based on the titles and abstracts. For articles necessitating further review, the full texts are examined, and those meeting the established criteria are selected. Finally, the fundamental characteristics of the qualifying studies are extracted, which include: (1) Research information: the first author's name, publication date, nationality, and study design; (2) Baseline data: sample size, gender, age, and diagnostic criteria for periodontitis; (3) Result data: OR/RR/HR and the corresponding 95% confidence interval (CI).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Evaluation of literature quality\u003c/h2\u003e\u003cp\u003eThe quality of the literature was assessed using the Newcastle-Ottawa Scale (NOS) \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e and the evaluation criteria recommended by the Agency for Healthcare Research and Quality (AHRQ) \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. The NOS appraises cohort studies based on three dimensions: the selection of exposed and unexposed cohorts, the comparability of these cohorts, and the outcomes. It employs a 9-point scale, categorizing studies as low-quality (0\u0026ndash;4 points), medium-quality (5\u0026ndash;6 points), and high-quality (\u0026gt;\u0026thinsp;7 points). In contrast, the AHRQ criteria for cross-sectional studies encompass 11 items, yielding a total score of 11 points. Studies are classified as low-quality (0\u0026ndash;3 points), medium-quality (4\u0026ndash;7 points), and high-quality (8\u0026ndash;11 points) based on their scores.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.6 Statistical analysis\u003c/h2\u003e\u003cp\u003eThe relationship between NAFLD and periodontitis was analyzed using RevMan software version 5.3 (Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). The OR/RR/HR values and their 95% CI were calculated as measures of the association between periodontitis and NAFLD. Heterogeneity tests were conducted on the data from the final included studies, and the \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e statistic was used to analyze the heterogeneity. The heterogeneity of the studies was classified based on the \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e value. The larger the \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e value, the greater the heterogeneity. If \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e was less than 50%, it indicated a lower heterogeneity and the fixed-effect model was applied. In contrast, if \u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e was greater than or equal to 50%, it indicated greater heterogeneity, and the random-effect model was applied. Further sensitivity analysis was conducted, and the publication bias test was evaluated by visual inspection of the funnel plot.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Study Selection\u003c/h2\u003e\n \u003cp\u003eWe identified 628 documents through the retrieval of 4 databases. After deleting 313 duplicate items, we excluded documents of various types such as reviews, conference abstracts, letters, etc. based on the type of the documents. After reviewing the titles and abstracts, we deleted the documents that did not match the topic. Finally, we read the full texts of 24 studies and included 12 studies in the Meta-analysis, including 9 cross-sectional studies and 3 cohort studies (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Study Characteristics\u003c/h2\u003e\n \u003cp\u003eThe general characteristics of the nine cross-sectional studies are presented in Table 1. Collectively, these studies encompassed a total of 663,996 adult participants, with individual study sample sizes ranging from 12,260 to 438,905. All studies included both male and female participants, aged between 18 and 74 years, thus encompassing a broad age spectrum. Several studies did not accurately specify the age range of the participants \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Geographically, these studies were conducted in the United States, South Korea, Japan, and Israel. The majority of the studies diagnosed periodontitis based on the degree and extent of clinical attachment loss (CAL). In contrast, one study relied on participants\u0026apos; self-assessment of periodontal conditions, including symptoms such as gum pain, gum bleeding, or tooth loosening \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. The other two studies used the probing depth as the diagnostic criterion. \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 Evaluation of literature quality\u003c/h2\u003e\n \u003cp\u003eThis study conducted a quality assessment of the nine included cross-sectional studies utilizing the AHRQ scale (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), while the three cohort studies were evaluated using the NOS scale (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The evaluation results summarized that the literature selected for this study demonstrated moderate to high quality. Overall, there was no significant difference in the quality of the included studies. There were no obvious biases in the selection of the study population and the measurement of the results. However, none of the multiple studies reported whether there were any missing data and the related handling. Cross-sectional studies generally did not describe the tracking and analysis situations, which may lead to doubts about the reliability of the results and make the source of heterogeneity unclear.\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAgency for healthcare research and quality scores of cross-sectional studies.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlazawi 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAkinkugbe 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIwasaki 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeintraub 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKim 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShin 2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRam 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWilensky 2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiu 2025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eU\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"13\"\u003eNotes: 1: Are the sources clear? 2: Are the inclusion and exclusion criteria for the two groups clear? 3: Is the time to identify patients clear? 4: Are the subjects continuous? 5: Is the evaluator isolated from other objective measures of the patient? 6: Has quality assurance been assessed? 7: Are excluded objects analyzed? 8: Are confounding factors assessed? 9: Is there any processing of the lost data? 10: Is the data complete? 11: Is there follow-up and analysis?\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eQuality assessment of cohort studies according to the modified NOS.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eStudy\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eStudy population selection\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eComparability between groups\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eOutcome measurement\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAkinkugbe 2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eShin 2022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJoo 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\"\u003eNotes: 1: Representativeness of the exposed group. 2: Selection of non-exposed groups. 3: Identification of exposure factors. 4: No outcome indicators were available before the study began. 5: Comparability of the resulting cohort based on design and analysis. 6: Methods of evaluating outcome events. 7: Whether the follow-up time was sufficient. 8: Integrity of follow-up.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 Meta-analysis\u003c/h2\u003e\n \u003cp\u003eIn the cross-sectional study (n\u0026thinsp;=\u0026thinsp;9), the presence of NAFLD was significantly associated with a higher prevalence of periodontitis (OR\u0026thinsp;=\u0026thinsp;1.24; 95% CI: 1.12, 1.38), however, the estimated values showed moderate heterogeneity (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;67%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eAs previously discussed, the diagnostic criteria for periodontitis and NAFLD may present a fundamental contradiction. We performed a subgroup analysis to explore the impact of differing diagnostic criteria for these two conditions (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). In the assessment of periodontitis, six studies utilized CAL as the diagnostic criterion, two studies employed PPD, and one study was based on self-reported data from participants. CAL is defined as the distance from the enamel-dental pulp junction to the base of the periodontal pocket, serving as a direct and critical measure of the irreversible loss of periodontal supporting tissues, including gingival connective tissue and alveolar bone. It is recognized as the most significant indicator of periodontal tissue destruction. In contrast, PPD is measured as the distance from the gingival margin to the base of the periodontal pocket. PPD can be influenced not only by the loss of connective tissue attachment (true periodontal pocket) but also by gingival inflammation and edema (false periodontal pocket). Consequently, CAL is regarded as a more reliable and objective parameter for diagnosing periodontitis, as it is not directly influenced by variations in the position of the gingival margin, whether due to recession or hyperplasia. Therefore, CAL is considered the gold standard for determining the presence and severity of periodontitis. In a subgroup analysis (n\u0026thinsp;=\u0026thinsp;6) that utilized CAL as the diagnostic criterion for periodontitis, the strongest evidence of association was observed, yielding a combined odds ratio of 1.38, with heterogeneity reduced to 25%. Furthermore, one study \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e diagnosed periodontitis based on patients\u0026apos; self-reported symptoms, such as gum pain, bleeding, and tooth loosening, reporting an OR of 1.10. The self-assessment of periodontal conditions was conducted through a touchscreen-based questionnaire; a professional dental examination was not part of the process. Participants were queried about the presence of symptoms such as painful gums, bleeding gums, or loose teeth, with the option to select multiple symptoms. The self-assessment questionnaire did not effectively serve as a predictive tool for periodontal disease. Therefore, due to the singular nature of this study, it was excluded from the \u003cem\u003eI\u0026sup2;\u003c/em\u003e statistics. The criteria for detecting NAFLD contribute to the observed heterogeneity among studies. Although liver biopsy is the gold standard for diagnosing NAFLD, ultrasound is more appropriate for large-scale, population-based research. The limited number of pertinent studies has led to considerable variation in the NAFLD detection criteria used across the included studies. However, the heterogeneity associated with diagnosing NAFLD using ICD-9-CM codes and ultrasound was minimal. In contrast, studies that relied on different biochemical markers, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), exhibited significantly greater heterogeneity. ALT and AST are non-specific indicators of hepatocellular injury and do not consistently elevate in cases of NAFLD, potentially introducing bias into the results.\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSubgroup analysis based on NAFLD diagnostic criteria and periodontitis diagnostic criteria\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eDiagnostic criteria\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eNAFLD diagnosis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003ePeriodontitis diagnosis\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eICD-9-CM\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eultrasonic testing\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOther markers detection\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCAL\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePPD\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e[1.21,1.75]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e[1.23,2.23]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e[1.03,1.21]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e[1.19,1.60]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e[0.79,2.32]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eDue to the substantial methodological differences observed, a sensitivity analysis was performed subsequent to the primary analysis. Upon excluding the three studies \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e based on probe depth and self-report criteria, the remaining six studies, which employed more consistent diagnostic criteria (primarily CAL), demonstrated that the association between periodontitis and NAFLD remained significantly robust and more stable (OR\u0026thinsp;=\u0026thinsp;1.38, 95% CI:1.19, 1.60, \u003cem\u003eI\u0026sup2;\u003c/em\u003e = 25%) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eMoreover, research has indicated that gender influences the relationship between the two diseases. Consequently, we performed subgroup analyses based on the gender ratio differences among study participants (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). The findings revealed that in studies where the proportion of male participants exceeded 50% (n\u0026thinsp;=\u0026thinsp;3), the association between periodontitis and NAFLD was stronger and more consistent (OR\u0026thinsp;=\u0026thinsp;1.51, 95% CI: 1.27, 1.79, \u003cem\u003eI\u0026sup2;\u003c/em\u003e=0%). In contrast, in studies where the proportion of male participants was less than 50% (n\u0026thinsp;=\u0026thinsp;4), the association was weaker and exhibited greater heterogeneity (OR\u0026thinsp;=\u0026thinsp;1.30, 95% CI: 1.00, 1.68, \u003cem\u003eI\u0026sup2;\u003c/em\u003e=71%).\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSubgroup analysis based on gender ratio\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMen\u0026thinsp;\u0026gt;\u0026thinsp;50%\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMen\u0026thinsp;\u0026lt;\u0026thinsp;50%\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e95%Cl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e[1.27,1.79]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e[1.00,1.68]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eAmong the three cohort studies analyzed in this article, two studies indicated that periodontitis is associated with an increased risk of NAFLD, with RR of 1.6 (95% CI: 1.05, 2.44) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e and 1.04 (95% CI: 1.01, 1.07) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, respectively (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). Another cohort study investigated the incidence of NAFLD as a consequence of chronic periodontitis development \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Due to substantial heterogeneity in study design, definitions of exposure and outcome, and study populations (\u003cem\u003eI\u0026sup2;\u003c/em\u003e = 75%), a quantitative synthesis was not performed. The existing cohort evidence tentatively suggests a potential bidirectional relationship; however, further methodologically rigorous and homogeneous prospective studies are urgently required to substantiate these findings.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe present meta-analysis establishes a clinically significant association between periodontitis and NAFLD, with periodontitis patients exhibiting a 24% elevated risk of NAFLD (OR\u0026thinsp;=\u0026thinsp;1.24, 95% CI: 1.12, 1.38). This relationship is not merely correlative but reflects a bidirectional pathological crosstalk, primarily orchestrated through systemic inflammation and microbial dysbiosis.\u003c/p\u003e\u003cp\u003ePeriodontitis acts as a persistent source of low-grade systemic inflammation, characterized by sustained release of pro-inflammatory cytokines (IL-6, TNF-α) and bacterial endotoxins (e.g., Porphyromonas gingivalis lipopolysaccharide, Pg-LPS) into the bloodstream \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. These mediators directly fuel NAFLD progression by dual hepatic insults: (i) induction of insulin resistance that augments \u003cem\u003ede novo\u003c/em\u003e lipogenesis \u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, and (ii) activation of Kupffer cells that amplify lobular inflammation and transition from steatosis to steatohepatitis \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. The subgroup analysis provides critical validation for this paradigm\u0026mdash;studies utilizing CAL, a surrogate for cumulative periodontal tissue destruction, demonstrated a stronger association (OR\u0026thinsp;=\u0026thinsp;1.38, 95% CI: 1.20, 1.58) with lower heterogeneity, compared to studies using probing depth or self-reported diagnosis. This divergence underscores that irreversible periodontal damage, rather than transient gingival inflammation, constitutes the primary driver of NAFLD risk.\u003c/p\u003e\u003cp\u003eEmerging evidence implicates oral pathobionts in directly modulating hepatic pathophysiology. \u003cem\u003ePorphyromonas gingivalis\u003c/em\u003e (Pg), a keystone periodontal pathogen, contributes to NAFLD through multisystemic crosstalk \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. Experimental models reveal that Pg compromises intestinal barrier integrity, enabling translocation of live bacteria and endotoxins into the portal circulation. Subsequent engagement of Toll-like receptors-4 (TLR4) on hepatocytes triggers NF-κB signaling that exacerbates hepatic inflammation and lipotoxicity \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. Beyond translocation, Pg-derived outer membrane vesicles systemically dysregulate lipid metabolism by upregulating stearoyl-CoA desaturase (SCD-1) while suppressing AMP-activated protein kinase (AMPK) activity \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. Furthermore, recent data suggest that Pg-induced Th17/Treg imbalance promotes hepatocyte ferroptosis\u0026mdash;an iron-dependent cell death pathway implicated in NASH progression \u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Intriguingly, NAFLD reciprocally perturbs the oral microbiome through altered lipid metabolism and bile acid circulation, creating a self-perpetuating vicious cycle \u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe substantial heterogeneity across included studies (\u003cem\u003eI\u0026sup2;\u003c/em\u003e=67%) primarily stems from inconsistencies in periodontitis ascertainment. Studies employing CAL-based definitions\u0026mdash;which objectively quantify connective tissue destruction\u0026mdash;produced robust, homogeneous risk estimates. By contrast, those using surrogate metrics (e.g., probing depth or self-report) yielded nonsignificant associations with marked heterogeneity. This contrast highlights that diagnostic precision fundamentally shapes epidemiological validity. Furthermore, in recent years, epidemiological studies have rarely revealed the causal relationship between the two. This meta-analysis mostly included cross-sectional studies, which can efficiently integrate data from multiple sources and provide preliminary evidence of association. However, they cannot determine the sequence of occurrence between periodontitis and NAFLD. Although many studies have focused on the mechanism of the association between the two diseases, there is still a lack of epidemiological evidence. In the future, causal verification needs to be advanced through prospective studies, mechanism exploration, and standardized methods, ultimately leading to individualized prevention and treatment strategies. And future research should adopt standardized, tissue-destruction-oriented criteria to consistently capture the chronic pathological burden relevant to systemic sequelae.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e5.1 Implications for Clinical Practice:\u003c/h2\u003e\u003cp\u003eRobust evidence confirms a significant association between periodontitis and NAFLD. Clinicians should recognize this bidirectional link: periodontal patients (especially with CAL-confirmed disease) may require NAFLD screening, and NAFLD patients should be assessed for periodontitis. Promoting oral hygiene and interdisciplinary collaboration between dental and liver health providers is warranted as part of comprehensive patient care.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e5.2 Implications for Research:\u003c/h2\u003e\u003cp\u003eFuture studies must prioritize standardized diagnostics (CAL for periodontitis; ultrasound/ ICD-9-CM for NAFLD) to reduce heterogeneity. High-quality prospective cohorts with rigorous confounder adjustment are essential to establish causality and directionality. Mechanistic research and trials evaluating periodontal therapy\u0026rsquo;s impact on NAFLD progression are needed.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH.L., M.S. and Y.L. contributed to the conception and design of the review and critically revised the manuscript drafts until the final version was approved. R.Y. performed the database searches. H.L. and M.S. conducted assessment of eligibility, data extraction, analysis and interpretation. All authors have made substantive contributions to the article and assume full responsibility for its content. All authors have seen and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project was supported by the Gansu Province Joint Research Fund (24JRRA949).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no other conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol and the data that support the findings of this study are openly available in PROSPERO at https://www.crd.york.ac.uk/PROSPERO/ (reference number PROSPERO: CRD420251102841).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eORCID\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHanyi Li: https://orcid.org/0009-0001-0873-2922\u003c/p\u003e\n\u003cp\u003eMingxuan Shi: https://orcid.org/0000-0001-9161-9906\u003c/p\u003e\n\u003cp\u003eRuomeng Yuan: https://orcid.org/0009-0007-2840-1120\u003c/p\u003e\n\u003cp\u003eYi Li: https://orcid.org/0009-0001-4299-6796\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRenu K, Gopalakrishnan AV, Madhyastha H. 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The gut-liver axis in liver disease: Pathophysiological basis for therapy. \u003cem\u003eJ Hepatol. \u003c/em\u003e2020;72(3):558-577.\u003c/li\u003e\n\u003cli\u003eKuraji R, Shiba T, Dong TS, Numabe Y, Kapila YL. Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis. \u003cem\u003eWorld J Gastroenterol. \u003c/em\u003e2023;29(6):967-996.\u003c/li\u003e\n\u003cli\u003eHujoel PP, White BA, Garc\u0026iacute;a RI, Listgarten MA. The dentogingival epithelial surface area revisited. \u003cem\u003eJ Periodontal Res. \u003c/em\u003e2001;36(1):48-55.\u003c/li\u003e\n\u003cli\u003eGon\u0026ccedil;alves TED, Zimmermann GS, Figueiredo LC, et al. Local and serum levels of adipokines in patients with obesity after periodontal therapy: one-year follow-up. \u003cem\u003eJ Clin Periodontol. \u003c/em\u003e2015;42(5):431-439.\u003c/li\u003e\n\u003cli\u003eZhu L, Baker SS, Gill C, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. \u003cem\u003eHepatology. \u003c/em\u003e2013;57(2):601-609.\u003c/li\u003e\n\u003cli\u003eStang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. \u003cem\u003eEur J Epidemiol. \u003c/em\u003e2010;25(9):603-605.\u003c/li\u003e\n\u003cli\u003eCatsambas TT, Kelley E, Legros S, Massoud R, Bouchet B. The evaluation of quality assurance: developing and testing practical methods for managers. \u003cem\u003eInt J Qual Health Care. \u003c/em\u003e2002;14 Suppl 1:75-81.\u003c/li\u003e\n\u003cli\u003eKim JY, Lee GN, Song HC, et al. Association between Fatty Liver Index and Periodontitis: the Korea National Health and Nutrition Examination Survey. \u003cem\u003eScientific reports. \u003c/em\u003e2020;10(1):3805.\u003c/li\u003e\n\u003cli\u003eShin H-S. Association between periodontal status and non-alcoholic fatty liver disease in a Korean adult population: A nationwide cross-sectional study. \u003cem\u003eJournal of periodontology. \u003c/em\u003e2020;91(4):524-532.\u003c/li\u003e\n\u003cli\u003eLiu B, Jia Y, Gu Z, Li Y, Zhou Y, Cao Y. Periodontal diseases, potential mediators and development of liver fat content: a community-based large cohort. \u003cem\u003eFrontiers in medicine. \u003c/em\u003e2025;12:1563459-1563459.\u003c/li\u003e\n\u003cli\u003eIwasaki T, Hirose A, Azuma T, et al. Correlation between ultrasound-diagnosed non-alcoholic fatty liver and periodontal condition in a cross-sectional study in Japan. \u003cem\u003eScientific Reports. \u003c/em\u003e2018;8.\u003c/li\u003e\n\u003cli\u003eAlazawi W, Bernabe E, Tai D, et al. Periodontitis is associated with significant hepatic fibrosis in patients with non-alcoholic fatty liver disease. \u003cem\u003ePloS one. \u003c/em\u003e2017;12(12):e0185902.\u003c/li\u003e\n\u003cli\u003eWeintraub JA, Lopez Mitnik G, Dye BA. Oral Diseases Associated with Nonalcoholic Fatty Liver Disease in the United States. \u003cem\u003eJournal of dental research. \u003c/em\u003e2019;98(11):1219-1226.\u003c/li\u003e\n\u003cli\u003eAkinkugbe AA, Barritt AS, Cai J, et al. Periodontitis and prevalence of elevated aminotransferases in the Hispanic Community Health Study/Study of Latinos. \u003cem\u003eJournal of Periodontology. \u003c/em\u003e2018;89(8):949-958.\u003c/li\u003e\n\u003cli\u003eWilensky A, Frank N, Mizraji G, Tzur D, Goldstein C, Almoznino G. Periodontitis and Metabolic Syndrome: Statistical and Machine Learning Analytics of a Nationwide Study. \u003cem\u003eBioengineering (Basel, Switzerland). \u003c/em\u003e2023;10(12).\u003c/li\u003e\n\u003cli\u003eRam D, Wilensky A, Zur D, Almoznino G. The Triangle of Nonalcoholic Fatty Liver Disease, Metabolic Dysfunction, and Periodontitis: Analysis of the Dental, Oral, Medical and Epidemiological (DOME) Records-Based Nationwide Research. \u003cem\u003eMetabolites. \u003c/em\u003e2022;12(12).\u003c/li\u003e\n\u003cli\u003eAkinkugbe AA, Slade GD, Barritt AS, et al. Periodontitis and Non-alcoholic Fatty Liver Disease, a population-based cohort investigation in the Study of Health in Pomerania. \u003cem\u003eJournal of Clinical Periodontology. \u003c/em\u003e2017;44(11):1077-1087.\u003c/li\u003e\n\u003cli\u003eJoo K, Kang YW, Moon SY, Baek YH, Son M. Association between nonalcoholic fatty liver disease scores and chronic periodontitis: A retrospective cohort study. \u003cem\u003eJournal of periodontology. \u003c/em\u003e2024.\u003c/li\u003e\n\u003cli\u003eChen Z, Deng H, Sun K, et al. Prevalence of chronic periodontitis in patients undergoing peritoneal dialysis and its correlation with peritoneal dialysis-related complications. \u003cem\u003eBMC Nephrol. \u003c/em\u003e2023;24(1):71.\u003c/li\u003e\n\u003cli\u003eDemmer RT, Breskin A, Rosenbaum M, et al. The subgingival microbiome, systemic inflammation and insulin resistance: The Oral Infections, Glucose Intolerance and Insulin Resistance Study. \u003cem\u003eJ Clin Periodontol. \u003c/em\u003e2017;44(3):255-265.\u003c/li\u003e\n\u003cli\u003eAkinkugbe AA, Avery CL, Barritt AS, et al. Do Genetic Markers of Inflammation Modify the Relationship between Periodontitis and Nonalcoholic Fatty Liver Disease? Findings from the SHIP Study. \u003cem\u003eJ Dent Res. \u003c/em\u003e2017;96(12):1392-1399.\u003c/li\u003e\n\u003cli\u003eYue Y, Liu X, Li Y, Xia B, Yu W. The role of TLR4/MyD88/NF-\u0026kappa;B pathway in periodontitis-induced liver inflammation of rats. \u003cem\u003eOral Dis. \u003c/em\u003e2021;27(4):1012-1021.\u003c/li\u003e\n\u003cli\u003ede Jongh CA, de Vries TJ, Bikker FJ, Gibbs S, Krom BP. Mechanisms of Porphyromonas gingivalis to translocate over the oral mucosa and other tissue barriers. \u003cem\u003eJ Oral Microbiol. \u003c/em\u003e2023;15(1):2205291.\u003c/li\u003e\n\u003cli\u003eCheng P, Wang T, Li W, et al. Baicalin Alleviates Lipopolysaccharide-Induced Liver Inflammation in Chicken by Suppressing TLR4-Mediated NF-\u0026kappa;B Pathway. \u003cem\u003eFront Pharmacol. \u003c/em\u003e2017;8:547.\u003c/li\u003e\n\u003cli\u003eDing C, Shen Z, Xu R, et al. Exosomes derived from periodontitis induce hepatic steatosis through the SCD-1/AMPK signaling pathway. \u003cem\u003eBiochim Biophys Acta Mol Basis Dis. \u003c/em\u003e2024;1870(7):167343.\u003c/li\u003e\n\u003cli\u003eLv C, Shi K, Guo Y, et al. Emerging Roles of Periodontal Pathogen-Derived Outer Membrane Vesicles in NAFLD. \u003cem\u003eInt Dent J. \u003c/em\u003e2025;75(4):100825.\u003c/li\u003e\n\u003cli\u003eYao C, Lan D, Li X, Wang Y, Qi S, Liu Y. Porphyromonas gingivalis is a risk factor for the development of nonalcoholic fatty liver disease via ferroptosis. \u003cem\u003eMicrobes Infect. \u003c/em\u003e2023;25(1-2):105040.\u003c/li\u003e\n\u003cli\u003eKuraji R, Sekino S, Kapila Y, Numabe Y. Periodontal disease-related nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: An emerging concept of oral-liver axis. \u003cem\u003ePeriodontol 2000. \u003c/em\u003e2021;87(1):204-240.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"periodontitis, non-alcoholic fatty liver disease, meta-analysis, clinical attachment loss","lastPublishedDoi":"10.21203/rs.3.rs-7434817/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7434817/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u0026amp; Aims\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBoth non-alcoholic fatty liver disease (NAFLD) and periodontitis are prevalent chronic conditions. While prior research indicates a possible connection between these diseases, the conclusions in the existing literature are highly variable and the findings are inconsistent. Consequently, there is an urgent need for a comprehensive evaluation of this relationship.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study conducted a systematic search of the PubMed, Embase, Scopus, and Web of Science databases, encompassing research published up to June 25, 2025, to assess the association between NAFLD and periodontitis. The review incorporated cross-sectional, case-control, and cohort studies. A meta-analysis was performed utilizing a random effects model, with subgroup and sensitivity analyses conducted to investigate potential sources of heterogeneity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing an extensive screening process of the 628 studies initially retrieved, a total of 12 studies were deemed suitable for inclusion in the analysis, comprising 9 cross-sectional studies and 3 cohort studies. A meta-analysis was performed on the adjusted odds ratios (OR) and 95% confidence intervals (CI) derived from the cross-sectional studies. The results showed that there was a significant association between periodontitis and NAFLD (OR: 1.24, 95% CI: 1.12, 1.38). Subgroup analysis based on diagnostic criteria differences indicated that periodontitis diagnosed by clinical attachment loss and NAFLD had a stronger association (OR: 1.38) and lower heterogeneity (\u003cem\u003eI\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e: 25%). The results of the cohort studies suggested a bidirectional relationship between periodontitis and NAFLD, but the heterogeneity was too high, so more high-quality prospective studies are needed to confirm this relationship.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe current research evidence indicates that there is a significant association between periodontitis based on clinical attachment lever definition and NAFLD.\u003c/p\u003e","manuscriptTitle":"Correlation Between Periodontitis and Non-Alcoholic Fatty Liver Disease: Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-25 01:32:48","doi":"10.21203/rs.3.rs-7434817/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-19T05:40:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-09T07:36:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-06T10:24:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"243656680855733269471000760380935600539","date":"2025-10-04T10:20:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"104322355249940553331179039997542954374","date":"2025-10-03T09:53:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"285160405903381999663148184702071868427","date":"2025-10-01T20:53:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-16T09:00:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-16T08:34:22+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-05T04:27:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-02T13:42:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-09-02T13:36:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6a6b84c6-d65d-4952-be65-a3a8a1514126","owner":[],"postedDate":"September 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":54827625,"name":"Health sciences/Diseases"},{"id":54827626,"name":"Health sciences/Gastroenterology"},{"id":54827627,"name":"Health sciences/Health care"},{"id":54827628,"name":"Health sciences/Medical research"},{"id":54827629,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2026-04-07T16:05:53+00:00","versionOfRecord":{"articleIdentity":"rs-7434817","link":"https://doi.org/10.1038/s41598-026-42308-2","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-04-04 15:59:22","publishedOnDateReadable":"April 4th, 2026"},"versionCreatedAt":"2025-09-25 01:32:48","video":"","vorDoi":"10.1038/s41598-026-42308-2","vorDoiUrl":"https://doi.org/10.1038/s41598-026-42308-2","workflowStages":[]},"version":"v1","identity":"rs-7434817","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7434817","identity":"rs-7434817","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}