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Association between periodontitis and mortality in participants with metabolic dysfunction-associated steatotic liver disease: results from NHANES

BMC Oral Health volume 25, Article number: 567 (2025) Cite this article

Abstract

Background

It has been reported that periodontitis was a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this study is to investigate the impact of periodontitis on all-cause and cause-specific mortality of MASLD patients.

Methods

We included 11,019 individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) from the National Health and Nutrition Examination Survey. Multivariable Cox proportional hazards models were utilized to analyze the estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality and cause-specific mortality among participants with different periods of periodontitis status. Additionally, we employed restricted cubic splines (RCS) curves to explore the dose-response relationship between clinical attachment level (CAL) and pocket probing depth (PPD) and mortality rates. Finally, a series of sensitivity analyses and stratification analyses were conducted to test the reliability and robustness of the results.

Results

In this study, moderate to severe periodontitis significantly increased the all-cause mortality (HR 1.29, 95% CI 1.08–1.55; P = 0.003) and cardiovascular disease (CVD)-related mortality (HR 1.41, 95% CI 1.10–1.79; P = 0.006) among MASLD participants. However, no significant effects of different periodontal statuses on cancer mortality were observed among MASLD participants.

Conclusions

A nationwide large-sample longitudinal study indicated that MASLD patients with moderate to severe periodontitis experienced significantly higher all-cause and CVD-related mortality rates compared to those with no or mild periodontitis.

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Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly named nonalcoholic fatty liver disease (NAFLD), a metabolic stress liver injury which is characterized by excessive accumulation of triglyceride accumulation in hepatocytes in the absence of alcohol and other specific reasons of liver injury. It is one of the most common causes of liver-related morbidity and mortality [1, 2, 3, 4]. The global prevalence of MASLD is estimated to be 30.2% (95% CI: 28.7–31.7%) [5]. Recently, various models have indicated that MASLD will cause enormous clinical and economic burden, as well as poor prognosis [4, 6, 7].

Over the last decades, it has been shown that the influences of MASLD is not only limited to liver, but growing evidence has indicated that MASLD is multi-system disease, affecting extra-hepatic organs and regulatory pathways. For example, it has been reported that MASLD increases the risk of type 2 diabetes mellitus (T2DM), cardiovascular (CVD) and cardiac diseases, and chronic kidney disease (CKD) [8, 9, 10]. The etiology of MASLD is diverse and the pathological mechanisms are complex. It is currently believed that inflammation, including both extrahepatic and intrahepatic factors, is a key driving force in the development of MASLD [9]. Extrahepatic factors, such as increased carbohydrate and fat intake, progressive adipose tissue dysfunction and insulin resistance could act as pro-inflammatory factors, upregulating liver inflammatory gene expression level and inducing metabolic disturbance and facilitating the development of MASLD [11, 12, 13, 14, 15]. Intrahepatic factors, oxidative stress in hepatocytes and mitochondrial dysfunction could trigger the liver inflammation and injury, and the injury further resulting the infiltration of monocytes and lymphocytes, amplifying the liver inflammation [16, 17, 18].

Periodontitis is a chronic multifactorial inflammatory condition caused by dental plaque biofilm, characterized by localized inflammation due to oral microbial infection, leading to the loss of dental supporting tissues, the formation of periodontal pockets, and bleeding of the gums [19]. Porphyromonas gingivalis (P.g), the key pathogen of periodontitis, can be detected in the liver tissue of about 52.5% MASLD patients, and the number of bacteria is positively correlated with the degree of liver fibrosis [20]. Another study found that P.g can significantly increase the inflammatory response and fibrosis degree in the liver tissue of rats, promoting the progression of MASLD [21]. Therefore, periodontitis is speculated as an important risk factor for the development and prognosis of MASLD [22, 23]. However, the association between periodontal status and mortality in adults with MASLD still remains unclear.

In this study, we aimed to explore the association between periodontitis and all-cause and cause-specific mortality of adults with MASLD.

Method

Study population

The National Health and Nutrition Examination Survey (NHANES) is a public database of health and nutrition research on U.S. populations. The design incorporates a comprehensive stratification and weighting methodology that ensures the sample is representative of the U.S. population. The study included individuals from the NHANES III (1988–1994), 1999–2004, and 2009–2014 cycles, as data on periodontitis was only available for these cycles [24]. The diagnosis of hepatic steatosis was based on the calculation of the hepatic steatosis index (HSI), which is based on the following formula: HSI = 8 × (alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio) + body mass index (+ 2 for female; +2 for diabetes). Hepatic steatosis was considered to be present when the HSI was > 36 [25, 26]. To ensure uniformity in the criteria, 13,468 participants aged ≥ 30 years with complete data on periodontitis and HSI > 36 were included in the subsequent analysis. Exclusion criteria included heavy alcohol consumption (2,294), hepatitis B (47), hepatitis C (94), and missing data on mortality (14), resulting in the inclusion of 11,019 participants for subsequent analysis (Fig. 1).

Fig. 1
figure 1

Flowchart of participant selection. NHANES, National Health and Nutrition Examination Survey; HSI, Hepatic steatosis index

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Evaluation of periodontitis

In mobile examination centers, data pertaining to the oral health component are recorded directly on computerized data collection forms. The NHANES included periodontal examination records from both the maxillary and mandibular quadrants. However, in order to maintain a consistent diagnosis of periodontitis across cycles, only the proximal buccal and mesiobuccal sites were selected for the subsequent analysis. Mild periodontitis was defined as ≥ 1 interproximal sites with ≥ 3 mm clinical attachment level (CAL), or ≥ 1 interproximal sites with ≥ 4 mm pocket probing depth (PPD). Moderate periodontitis was defined as ≥ 1 interproximal sites with ≥ 4 mm CAL, or ≥ 1 interproximal sites with ≥ 5 mm PPD. Severe periodontitis comprised ≥ 1 interproximal sites with ≥ 5 mm PPD, or ≥ 1 interproximal sites with CAL ≥ 6 mm (on the same site or different sites) [27]. As in previous studies [28, 29], in order to examine the possible effect of a higher prevalence of mild periodontitis on the results, we used no/mild periodontitis as the normal group and moderate/severe periodontitis as the observation group.

Determination of mortality

We combined periodontitis data from NHANES III (1988–1994), 1999–2004, 2009–2014 with mortality data from the National Center for Health Statistics (NCHS) (NCHS Data Linkage-Mortality Data - Public-Use Files (cdc.gov)). Thus, this study on the relationship between periodontitis status and mortality can be considered as a prospective study [30]. Deaths from cardiovascular disease are defined as (ICD-10 codes I00-I09, I11, I13, I20-I51, and I60-I69) and deaths from cancer are defined as (ICD-10 codes C00-C97) [31].

Covariates

The identification of confounding factors was based on clinical experience and included a range of variables, including age, sex, race, socioeconomic status (SES), physical activity, smoking status, alcohol consumption, healthy eating index (HEI), and body mass index (BMI). The analysis of covariates in this study did not include alcohol consumption because the study population comprised individuals with MASLD. Therefore, those who consumed a significant amount of alcohol ( defined as more than 14 drinks/week for men or more than 7 drinks/week for women) were excluded [32]. The race category was divided into four groups: non-Hispanic white, non-Hispanic Black, Hispanic, and others. Poverty income ratio, occupation, education level, and health insurance coverage were used to assess socioeconomic status (SES), which was categorized into low, medium, and high levels [33]. Physical activity was categorized as inactive, insufficient, and recommended [34]. Smoking status was categorized as never smoked, ever smoked, and currently smoked. The HEI-1995 was adapted to the NHANES (1988–1994) cycle, while the HEI-2015 was adapted to the NHANES 1999–2004 and 2009–2014 cycles [29]. BMI was defined as height divided by weight squared(kg/m2). Obesity was defined as BMI ≥ 30 kg/m2 [35]. Furthermore, we considered six additional covariates: estimated glomerular filtration rate (eGFR), diabetes, hypertension, cardiovascular disease, hyperlipidemia, and cancer status, among which hyperlipidemia is characterized by triglyceride levels of ≥ 150 mg/dL, total cholesterol levels of ≥ 200 mg/dL, low-density lipoprotein (LDL) levels of ≥ 130 mg/dL, or high-density lipoprotein (HDL) levels of ≤ 50 mg/dL for women and ≤ 40 mg/dL for men. Moreover, individuals who reported the use of lipid-lowering medications are also classified as having hyperlipidemia [36].

Statistical analysis

Given the intricate design encompassed by NHANES, all analyses in this study were conducted with the effect of weights taken into account. The student’s t-tests was used for continuous variables and the χ2 test for categorical variables. Data were presented as weighted mean standard error (SE) for continuous variables and weighted percentages SE for categorical variables.

Firstly, a multifactorial Cox proportional risk model was employed to calculate the risk of death Hazard Ratios (HRs) and 95% confidence intervals (CIs) for all-cause and idiosyncratic mortality under different covariates [37]. We chose different models for our analysis. Model 0 was not adjusted for any covariates. Model 1 was adjusted for age, sex, and race. Model 2 was further adjusted for education level, PIR, physical activity, smoking status, HEI, and BMI based on model (1) Model 3 was further adjusted for eGFR, diabetes mellitus, hypertension, cardiovascular disease, hyperlipidemia, and cancer status based on model (2) Secondly, the Weibull accelerated failure time model was employed to evaluate whether moderate to severe periodontitis reduced the expected survival time for all-cause mortality and cardiovascular disease-related mortality among participants with diabetes [38]. At last, a Kaplan-Meier survival curve was used to show all-cause mortality and cardiovascular mortality for different periodontal statuses. In addition, we used restricted cubic splines (RCS) to more intuitively reflect the dose-response relationship between periodontal status (including CAL and PPD) and all-cause and cause-specific mortality.

In order to ascertain the reliability of the results, a series of sensitivity analyses were also performed. At first, a multifactorial Cox proportional risk model analysis was performed after excluding those who died within 2 years of follow-up in order to reduce potential reverse causality bias. Second, we also verified the association between mean CAL and mean PPD with mortality. Finally, we also stratified analyses according to age (< 45 or ≥ 45 years), sex(male or female), race(non-Hispanic white, non-Hispanic Black, Hispanic, and others), education level(< high school or ≥ high school), PIR(< 1, 1 ≤ PIR ≤ 3, ≥ 3), smoking status(never smoker, former smoker, current smoker), HEI (quartiles), obesity(yes or no), hypertension(yes or no), and diabetes(yes or no). The interaction p-values were calculated by examining the corresponding multiplicative interaction term.

Stata 16.0 statistical analysis software (StataCorp, College Station, TX, USA) and R 4.2.1 soft-ware (http://www.R-project.org, The R Foundation, Aus-tria) were used for all analyses. A two-tailed p value < 0.05 indicated a statistically significant result.

Result

Demographic characteristics of participants

Table 1 displays the distribution of periodontitis characteristics in the MASLD population. A total of 11,019 MASLD populations with complete periodontitis as well as mortality data were included in this study, with a mean age of 50.85 years and 53.51% females. Compared to participants with no/mild periodontitis, those with moderate/severe periodontitis were more likely to be older (55.06 vs. 48.71, P < 0.001), male (53.92% vs. 42.72%, P < 0.001), current smokers (18.53% vs. 11.82%, P < 0.001), lower eGFR (87.98 vs. 92.89, P < 0.001), diabetes (27.29% vs. 16.40%, P < 0.001), hypertension (53.09% vs. 45.01%, P < 0.001), cardiovascular disease (9.43% vs. 5.93%, P < 0.001), hyperlipidemia (80.98% vs. 74.21%, P < 0.001), and cancer status ( 10.78% vs. 8.50%, P = 0.005). However, there was no significant difference between the two groups in terms of BMI and HEI.

Table 1 Baseline characteristics of participants with MASLD according to periodontal status
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Association between periodontitis status with all-cause and specific mortality

In the study, with a median follow-up of 10.58 years, there were 2,293 deaths, including 645 cardiovascular deaths and 526 cancer deaths. In the unadjusted model (model 0), the Cox proportional risk model showed that the HR was significantly higher in the moderate/severe periodontitis population than in participants with no/mild periodontitis (HR 2.19, 95% CI 1.93–2.48; P < 0.001); Adjusted for age, sex, and race in model 1 (HR 1.65, 95% CI 1.45–1.88; P < 0.001); model 2 further adjusted for SES, smoking status, physical activity, BMI, and HEI (HR 1.32, 95% CI 1.15–1.54; P < 0.001), model 3 adjusted in addition to model 2 for ALT, AST, eGFR, diabetes, hypertension, hyperlipidemia, cardiovascular disease, and cancer (HR 1.29, 95% CI 1.08–1.55; P < 0.003). Similar findings were observed for periodontitis status and cardiovascular mortality in both the unadjusted model 0 and the fully adjusted model 3. The moderate/severe periodontitis cohort exhibited a signifiantly elevated cardiovascular mortality rate compared to participants with no/mild periodontitis in model 0 (HR 2.42, 95% CI 1.91–3.06; P < 0.001) and in model 3 (HR 1.41, 95% CI 1.10–1.79; P = 0.006). However, our study identified a significant association between periodontitis status and cancer mortality in models 0, 1, and 2, but this association was not observed in the fully adjusted model 3 (HR 1.15, 95% CI 0.83–1.59; P = 0.399) (Table 2).

Table 2 HR (95% CIs) for all-cause and cause-specific mortality according to periodontitis
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The results of the Weibull accelerated failure time model indicated that moderate to severe periodontitis shortened the expected survival time for all-cause mortality, CVD-related mortality, and cancer-related mortality in participants with MASLD (all-cause: time ratio, 0.90, CI: 0.86–0.95, p < 0.001; CVD-related: time ratio, 0.85, CI: 0.77–0.93, p < 0.001; cancer: time ratio, 0.87, CI:0.77–0.99) (Table 3).

Table 3 Time ratio (95% confidence intervals) for all-cause and cause-specific mortality according to periodontitis by Weibull model
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Furthermore, we conducted a Kaplan-Meier analysis to investigate the relationship between periodontitis status and all-cause (Fig. 2) and cardiovascular mortality (Fig. 3). The results revealed a statistically significant difference in mortality between the two groups, with a log-rank p value < 0.001.

Fig. 2
figure 2

The Kaplan-Meier analysis of periodontitis with all-cause survival

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Fig. 3
figure 3

The Kaplan-Meier analysis of periodontitis with cardiovascular survival

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Association between mean CAL/PPD and mortality

Furthermore, we conducted a separate analysis to investigate the correlation between mean CAL and mean PPD with mortality in the MASLD population. As shown in Table 4, all-cause mortality rate was found to be statistically significant in the fully adjusted model 3 for the second quartile (Q2), the third quartile (Q3), and the forth quartile (Q4) of mean CAL when compared to the first quartile (Q1) (Q2: HR 1.24; 95% CI, 1.09 − 1.50. Q3: HR 1.50; 95% CI, 1.38–1.84. Q4: HR, 1.85; 95% CI, 1.61–2.17. P-trend = 0.010). Similarly, in the fully adjusted model 3, a comparable relationship was observed between PPD quartiles and all-cause mortality, (Q2: HR 1.03; 95% CI, 0.93 − 1.27. Q3: HR 1.24; 95% CI, 1.21–1.59. Q4: HR, 1.31; 95% CI, 1.19–1.62. P-trend < 0.001). In addition, we also observed a significant increasing trend relationship between quartiles of mean CAL and PPD with cardiovascular mortality.

Table 4 The results of the sensitivity analysis according to quintiles of mean CAL and mean PPD as outcomes of exposure
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RCS curves were employed to illustrate the nonlinear correlation between mean CAL and mean PPD with all-cause and cardiovascular mortality. There was a nonlinear relationship between mean CAL and mean PPD with mortality (P for nonlinear < 0.05) (Fig. 4). The risk of all-cause and cardiovascular mortality showed a tendency to rise with increasing mean CAL and mean PPD values. To examine the link between CAL, PPD levels and mortality in MASLD participants, a Cox proportional hazards model and a two-segment Cox proportional hazards model were employed for analysis. The inflection point values of CAL for all-cause and cardiovascular mortality were both 1.42, as shown in Table 5. When CAL was below 1.42, each 1-unit increase was associated with a 2.29-fold higher risk of all-cause mortality (HR 3.29, 95% CI 2.92–3.71; P < 0.001) and a 2.91-fold higher risk of cardiovascular mortality (HR 3.91, 95% CI 3.09–4.94; P < 0.001). When CAL exceeded 1.42, each 1-unit increase was associated with a 20% higher risk of all-cause mortality (HR 1.20, 95% CI 1.16–1.24; P < 0.001) and a 19% higher risk of cardiovascular mortality (HR 1.19, 95% CI 1.13–1.28; P < 0.001). On the other hand, the inflection point value of PPD for all-cause and cardiovascular mortality risk was 1.35. When PPD was below 1.35, each 1-unit increase was associated with a 94% higher risk of all-cause mortality (HR 1.94, 95% CI 1.61–2.34; P < 0.001) and a 1.82-fold higher risk of cardiovascular mortality (HR 2.82, 95% CI 1.92–4.13; P < 0.001). When PPD exceeded 1.35, each 1-unit increase was associated with an 19% higher risk of all-cause mortality (HR 1.19, 95% CI 1.09–1.29; P < 0.001) and a 22% higher risk of cardiovascular mortality (HR 1.22, 95% CI 1.04–1.42; P < 0.001).

Fig. 4
figure 4

Restricted cubic spline model of the relationship between Mean CAL and PPD with Mortality. (a) Mean CAL and all-cause mortality; (b) Mean CAL and cardiovascular mortality; (c) Mean PPD and all-cause mortality; (d) Mean PPD and cardiovascular mortality

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Table 5 Threshold effect analysis of CAL and PPD on mortality in MASLD participants
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Sensitivity analysis

To verify the accuracy of the results, we conducted the following two sensitivity analyses. First, those participants who died within 2 years were excluded to prevent reverse causation from influencing outcomes. The results indicated that all-cause mortality (HR, 1.27; 95% CI, 1.09–1.48) and cardiovascular mortality (HR, 1.37; 95% CI, 1.18–1.59) remained significantly increased in those with moderate/severe periodontitis compared to those with no/mild periodontitis (Table 6). Second, to ascertain the stability of the results across populations, the analyses were also stratified by age (< 45 or ≥ 45 years), sex (male or female), race (non-Hispanic white, non-Hispanic Black, Hispanic, and others), education level (< high school or ≥ high school), PIR (< 1, 1 ≤ PIR ≤ 3, ≥ 3), smoking status (never smoker, ever smoker, never smoker), HEI (Q1, Q2, Q3, Q4), obesity (yes or no), hypertension (yes or no), and diabetes (yes or no). The interaction p-values were then calculated. The p-values for the interactions were all > 0.05 when stratified by populations except education level in all cause mortality (Fig. 5). This suggests that the relationship between periodontitis status with all cause and cardiovascular mortality was relatively stable.

Table 6 Association of periodontitis with mortality after exclusion of participants who died within first 2 years of follow-up
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Fig. 5
figure 5

Forest plots of stratified analyses of periodontitis status with all-cause and cardivascular mortality

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Discussion

The cohort study is conducted based on NHANES, a public database of health and nutrition research on U.S. populations, showed periodontitis was related to higher all-cause and CVD-related mortality of MASLD patients. This study indicates that moderate or severe periodontitis and higher level of CAL and PPD are related to increased risk of all-cause and CVD-related mortality, and this is the first study that report the association between periodontitis status and mortality of patients with MASLD.

Periodontitis, a common chronic inflammatory and infectious disease, is caused by oral biofilm–mediated microbial dysbiosis [39]. The biofilm components also have access to periodontal tissue and host circulation [39]. It not only causes tooth loss, but enter the circulation and exacerbate or be associated with various metabolic disorders, such as dyslipidemia, diabetes, obesity and cardiovascular disease [29, 40, 41, 42, 43]. Recently, growing evidence has suggested that periodontal disease has adverse effects on the pathophysiology of liver disease [44, 45]. In particular, it was reported that periodontal disease can negatively affect MASLD, thus inducing the progression and worsen of MASLD [42]. Whereas, it still remains unclear whether the mortality of MASLD is related to periodontitis. So this study mainly focused on the effect of periodontitis and its severity on the MASLD mortality. In consistent with the above findings, our results showed that MASLD patients with moderate or severe periodontitis did have 28% higher risk of all-cause mortality than those without or with mild periodontitis (Table 2). As is reported that MASLD is considered as the hepatic manifestation of metabolic syndrome because it is closely associated with obesity, insulin resistance, hypertension, and dyslipidemia. For example, the triglyceride glucose (TyG) index has recently emerged as a powerful marker of insulin resistance and metabolic dysfunction, both of which are key factors in the development and progression of MASLD [46, 47]. Moreover, large numbers of researches have confirmed that periodontitis can exacerbate various metabolic disorders, such as diabetes, obesity, dyslipidemia, and chronic kidney disease [48, 49]. Periodontitis-related systemic inflammation may induce to insulin resistance through elevated blood levels of adipocytokines, such as tumor necrosis factor alpha, IL-6, and leptin, which inhibit the insulin receptor and its downstream signaling [50, 51]. Clearly, there is a bidirectional three-way relationship among metabolic syndrome, MASLD, and periodontitis, centering on insulin resistance [42]. Consequently, the mutual influences among these diseases may cause a higher mortality risk in MASLD with peridontitis. Furthermore, the correlation between mean CAL and mean PPD with mortality in the MASLD population was investigated and a comparable relationship was observed between CAL and PPD quartiles and all-cause mortality, implying there may be a potential dose-response effect. These results indicate that periodontitis is strongly linked with the MASLD prognosis, and the severity of periodontitis influence the mortality of MASLD.

Notably, we found the participants with moderate/severe periodontitis were more likely to be older, male, current smokers, lower eGFR, diabetes, hypertension, cardiovascular disease, hyperlipidemia, and cancer status. Then we further analyzed association between periodontitis status with specific mortality induced by cardiovascular diseases or cancer in MASLD patients. Results indicated cancer-related mortality has no significant difference between patients with or without periodontitis. Though increasing evidence that cancer is driven, at least in part, by chronic infection and inflammation [52]. Interestingly, periodontitis, a common chronic oral inflammatory disease driven by exposure to biofilms, has been associated with several forms of malignancy [53]. Nerverthless, due to the diversity of cancer types and the complexity of pathogenesis, the exact association between cancer and periodontits still remains unclear and long term exploration is still needed [54]. However, results showed that CVD-related mortality was 43% higher, suggesting a remarkable mortality association between periodontitis and people with MASLD. Moreover, moderate or severe periodontitis reduces the survival probability and time for all-cause and CVD-related mortality in people with MASLD (Figs. 2 and 3), suggesting that periodontitis may be an important factor for predicting all-cause and CVD-related mortality in adults with MASLD. It has been reported that though MASLD have increased risks of end-stage liver disease, hepatocellular carcinoma, and liver-related mortality, the largest cause of death among patients with MASLD is cardiovascular disease [55]. Also, it has been reported that people with cardiovascular disease may have a higher chance of getting further complications when they have periodontitis and there was a significant association between periodontitis and increased risks cardiovascular mortality [56]. Particularly, recent statistical results show that in Europe CVD is responsible for 3.9 million deaths (45% of deaths). Therefore, people with CVD realated diseases should actively manage all their cardiovascular risk factors. Taking all these into account, MASLD patients with CVD should receive a comprehensive periodontal evaluation, including full mouth probing and bleeding scores. If no periodontitis is diagnosed initially, patients should be recommended a preventive care regime and monitored regularly (at least once a year) for changes in periodontal status. If periodontitis is diagnosed, patients should be informed that they may be at higher risk for subsequent CVD complications, and they should regularly insist on the recommended dental therapeutic, maintenance and preventive regimes. Besides, if the periodontitis is not appropriately controlled, patients should consult his/her physician timely [57].

There is multiple evidence that periodontitis may be a hazard factor for MASLD. Previous researches showed that the liver of patients with periodontitis is constantly under exposure to pathogenic factors including bacteria and their by-products, reactive oxygen species, inflammatory cytokines that released from oral cavity systemically, and these are involved in MASLD progression [42, 45]. P. gingivalis (P.g), one of the periodontopathic bacteria, is strongly indicated to be involved in MASLD [58]. Yoneda et al. analyzed various periodontopathic bacteria in saliva collected from MASLD patients and found that the detection frequency of P. g was obviously higher in the MASLD patients than in the non-MASLD subjects [59]. In an animal study, rats were infected with P.g and fed with a high fat diet, results showed that infection with P.g aggravated the progression of MASLD, and it is believed that P.g and its endotoxin play a key role in the deterioration of MASLD [21]. Two possible pathways for the link between periodontitis and MASLD were proposed. On one hand, not only bacteria can colonize the liver through blood circulation, but the endotoxin and cytokines produced by bacteria can enter the circulation system, evoking and resulting in liver inflammatory immune reaction and injury [42, 60, 61]. Notabely, several signaling pathways that periodontitis may affect MASLD have been gradually been revealed. Ding indicated that P. gingivalis-derived LPS might contribute to intracellular lipid accumulation and inflammatory reaction of human hepatocellular cells HepG2 via the activation of NF-ĸB and JNK signaling pathways [62]. Moreover, the link between MASLD and T helper 17 (Th17) has also attracted attention in recent years. Th17 cells are a subset of T helper cells defined subsets, which primarily secrete IL-17 A. IL-17 A induces a number of proinflammatory cytokines in both immune and non-immune cells and plays a protective role against infection [63]. Interestingly, it was found that there were a large number of Th17 cells in the liver and peripheral blood of MASLD animal models and the animal studies also showed that the accumulation of Th17 cells in periodontal tissues is dependent on oral bacteria, suggesting that there may be a link among them and it is speculated that Th17 may be a key molecule for explaining the relationship between periodontal disease and NAFLD [64, 65, 66]. Besides, another pathway that periodontitis may influence MASLD is attributed to LPS/TLR4 signaling. It is reported that one of the constituents of periodontal pathogens, LPS, could combine with Toll-like receptor (TLR-2/4) and influence immune system [67]. As Kupper cells in liver express high level of TLR4, they recognize LPS quickly and generate inflammatory cytokines, chemokines and ROS, inducing a cascade of immune responses and further causing liver damage [68]. On the other hand, another mechanism is gut microbiome dysbiosis induced by enteral translocation of periodontopathic bacteria ruptures gut wall barrier and accelerate delivery of hepatotoxins and enterobacteria to the liver through the enterohepatic circulation, further leading to hepatic exposure to bacteria, endotoxin, and bacterial metabolite through the enterohepatic circulation by portal vein system [69, 70, 71]. Consequently, by hematogenous or enteral routes, periodontitis greatly accelerating MASLD progression and may result in higher mortality of MASLD [42].

This study is the first representative study on the association between periodontitis and all-cause and CVD-related mortality in patients with MASLD. However, there are some limitations in our study should be noticed. First, data on periodontitis and MASLD was obtained at baseline the same time, which may not previously reflect the causal and mediating effects between the conditions. Second, the covariates acquired at baseline may have changed over time, which may have weakened the true association between periodontitis and mortality in people with MASLD. Third, in this study, the severity of periodontitis was classified by CAL and PPD based on quartiles of the study population, so the results are not comparable to other studies using different sorting scheme.

Conclusions

In a nationally representative sample of US adults with MASLD, we found that moderate or severe periodontitis and high levels of mean CAL and PPD are associated with an elevated risk of all-cause and CVD-related mortality among adults with MASLD in the US. Periodontitis has prognostic utility in explaining residual risk of MASLD. Further researches are needed to affirm our findings and establish causal inference.

Data availability

The publicly available data used in this study can be downloaded for free on NHANES website: https://wwwn.cdc.gov/nchs/nhanes/.

Abbreviations

MASLD:

Metabolic dysfunction associated steatotic liver disease

HRs:

Hazard Ratios

CIs:

Confidence Intervals

RCS:

Restricted cubic Splines

CAL:

Clinical Attachment Level

PPD:

Pocket Probing Depth

CVD:

Cardiovascular Disease

T2DM:

Type 2 Diabetes Mellitus

NHANES:

National Health and Nutrition Examination Survey

HSI:

Hepatic Steatosis Index

NCHS:

National Center for Health Statistics

ALT:

Alanine Aminotransferase

AST:

Aspartate Aminotransferase

SES:

Socioeconomic Status

HEI:

Healthy Eating Index

BMI:

Body Mass Index

eGFR:

Estimated glomerular filtration rate

SE:

Standard error

TyG:

Triglyceride Glucose

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Acknowledgements

This study was analyzed using the data provided by the National Health and Nutrition Examination Survey III (1988–1994), 1999–2004, and 2009–2014. We gratefully acknowledge all contributors to the NHANES.

Funding

This work is supported by grants from the fellowship of GuangDong Basic and Applied Basic Research Foundation, Grant/Award number: 2021A1515110267 and 2022A1515110388; National Natural Science Foundation of China, Grant/Award number: 82303794 and Shenzhen Science and Technology Program, Grant/Award number: JCYJ20240813150220026.

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Author notes

  1. Zhaofu Zhang and Qiuyun Zheng are co-first authors.

Authors and Affiliations

  1. Department of Infectious Diseases, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, PR China

    Zhaofu Zhang

  2. Department of Obstetrics and Gynecology, Zigui County People’s Hospital, Zigui, 443200, PR China

    Qiuyun Zheng

  3. School of Medicine, Sun Yat-sen University, Shenzhen, 518107, PR China

    Yiheng Liu

  4. Department of Stomatology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, PR China

    Guanhui Chen & Yiming Li

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  4. Guanhui Chen
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Contributions

Zhaofu Zhang: Writing– original draft, Conceptualization, Methodology, Formal analysis. Qiuyun Zheng: Methodology, Conceptualization. Yiheng Liu: Validation, Data curation. Guanhui Chen: Writing– review & editing, Conceptualization. Yiming Li: Writing– review & editing, Conceptualization, Supervision.

Corresponding authors

Correspondence to Guanhui Chen or Yiming Li.

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Ethics approval and consent to participate

The parts of this study that involved human participants, human materials, or human data were conducted in compliance with the Declaration of Helsinkiand were approved by the National Center for Health Statistics (NCHS) Ethics Review Board. The patients/participants provided written informed consent to participate in this study. Ethical address as the follow: https://www.cdc.gov/nchs/nhanes/irba98.htm.

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The authors declare no competing interests.

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Zhang, Z., Zheng, Q., Liu, Y. et al. Association between periodontitis and mortality in participants with metabolic dysfunction-associated steatotic liver disease: results from NHANES. BMC Oral Health 25, 567 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12903-025-05959-7

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BMC Oral Health

ISSN: 1472-6831

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