Periodontal health status in cirrhotic patients: a systematic review and meta-analysis

Liver cirrhosis is a disease with widespread prevalence and high mortality, alcohol misuse, hepatitis virus infection, and nonalcoholic fatty liver disease (NAFLD) are the main causes; the global estimated age-standardized death rate (ASDR) of alcohol-associated cirrhosis was 4.5 per 100,000 [1]. Cirrhosis is a diffuse pathophysiological state of the liver manifested by hepatocyte degeneration and necrosis, hepatic parenchymal fibrosis, regenerative nodules, and finally loss of liver function [2]. Cirrhotic patients often have an imbalance of the coagulation system because of defects in both prothrombotic and antithrombotic components, which can increase gingival bleeding risk [3]. Periodontal pathogenic bacteria, such as Porphyromonas gingivalis, Peurella intermediate, Peurella melanobacterium, and other melanin-producing pathogens are based on hemoglobin, heme as nutrients, bleeding periodontal pocket and provide a better growth environment for related microorganisms [4, 5]. Besides, a reduced immune reaction to bacterial infections owing to immune dysfunction would further drive periodontal infection [6]. Furthermore, defects in Kupffer cells and neutrophil function can turn exaggerated inflammatory responses to systemic inflammation, promoting periodontal disease, impairing periodontal health [7].

Regarding periodontal health status, we must pay attention to the health of periodontal support tissues such as cementum, periodontal ligament and alveolar bone. Clinically, the corresponding indicators are generally used to reflect: probing depth (PD), clinical attachment loss (CAL), alveolar bone loss (ABL), etc. If these periodontal-related clinical indicators are abnormal, the patient may have periodontitis [8]. Periodontitis is a chronic, devastating inflammatory disease caused by bacteria. Severe periodontitis is reported to be the sixth most prevalent medical condition worldwide, placing a huge socio-economic burden on patients [9]. A dysbiosis of the dental plaque biofilm triggers periodontitis, then interacts with the immune defenses of the host, causing destructive inflammatory disorders [10]. Periodontitis not only destroys periodontal health, but also is a significant risk factor for several systemic diseases such as diabetes [11], cardiovascular diseases [12], rheumatoid arthritis [13], and some types of cancers [14]. Periodontitis may regulate the immune and inflammatory response of the body through periodontal pathogens and inflammatory mediators, affecting overall health [15]. Moreover, these systemic diseases may influence the pathogenesis of periodontitis: alter the composition of oral microbiota, increase those species harmful to the balance of microbe-host interaction, and cause a higher inflammatory response, resulting in accelerated periodontal destruction [16, 17].

A recent study showed poor periodontal health in cirrhotic patients, which was significantly associated with three months of hospitalization [18]. Some epidemiological studies revealed that cirrhotic patients presented a significantly higher risk of periodontitis than controls [19, 20]. A recent clinical study also found liver cirrhosis as an independent risk factor for patients with severe periodontitis [21]. The current evidence suggests that liver cirrhosis can likely interfere with the balance of periodontal health, so we conduct a systematic review and meta-analysis about the periodontal health status in cirrhotic patients, providing new evidence for the influence of systemic diseases on periodontal health.

In clinical diagnosis and treatment, we often find poorer periodontal health in cirrhotic patients, and most of them have symptoms such as bleeding gums, redness, and oral odor. Although the exact mechanism of the link between periodontal inflammation and liver cirrhosis is unclear, some possible hypotheses have been reported: hepatitis virus infections, increased inflammatory response, microbiota dysbiosis, and local microcirculation disorders. First, chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections are the main causes of liver cirrhosis [36]. Paraschiv et al. found that there was a strong association between chronic HBV, HCV, and periodontitis [37]. HCV-infected patients ranging between 25–44 years old have a poor periodontal condition, manifested increased BOP and PD [38]. Besides, the liver regulates many aspects of the immune system’s physiology and impaired hepatic function can promote a systemic inflammatory state. The levels of serum cytokines were higher in cirrhotic patients, particularly IL-1β, IL-6, IL-8, and TNF-α [39]. These cytokines are also important in the destructive process of periodontal tissues [40]. Therefore, we could speculate that an altered immune response and elevated serum cytokines in cirrhotic patients may precipitate periodontitis. In addition, Jensen et al. analyzed the subgingival microbiome in cirrhotic patients with periodontitis, found that bacteria usually considered as periodontal pathogens: Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, three bacteria known as the red complex, showed low abundance. Subgingival microbiota was composed of a unique microbiota not normally associated with periodontitis, suggesting that periodontitis in cirrhotic patients was a consequence of dysbiosis due to a compromised immune system, which might render commensal bacteria to become pathogenic [41]. However, another study reported that cirrhotic patients were at increased risk of developing red complex bacteria [42]. Contrary results make this issue controversial, maybe a high incidence of periodontitis in cirrhotic patients is related to changes in the oral microbial community. Moreover, in recent years a new concept has been proposed–the oral-intestinal-liver axis. This axis triggers hepatic inflammation and exacerbates the systemic inflammatory load through bacterial metabolites, toxins, and multiple inflammatory factors [43]. Furthermore, Funatsu et al. found that the number of capillaries in the periodontium and oral mucosa in cirrhotic patients was lower than those in the controls. This change can cause microcirculatory disturbances, diminish self-defense mechanism of the periodontium and promote periodontal inflammation [44]. Finally, patients with advanced liver disease may have depression [45]. A depressed psychological state of cirrhotic patients can affect oral health care, cause bad oral hygiene, and subsequently precipitate periodontal condition [46]. Depression also leads to dysregulation of neurobiological and neurobehavioral factors, periodontal immune imbalance and microbiome disorders, promoting periodontal inflammation [47].

In this report, we found that the destruction of periodontal support tissue in cirrhotic patients is more serious, the clinical parameters like CAL, PD, and ABL can intuitively reflect these damages, and the prevalence of periodontitis is significantly increased in cirrhotic patients compared to controls. Our conclusions are consistent with a previous systematic review by Grønkjær L et al., they concluded that cirrhotic patients have poor oral hygiene and a high prevalence of periodontitis, periodontitis is related to liver cirrhosis, but since there are not enough articles included, the author only did a qualitative analysis [48]. Therefore, to the authors' knowledge, this article may be the first meta-analysis to quantitatively assess the periodontal status in cirrhotic patients.

Clinical parameters PD, CAL, PBI, BOP, and ABL that are often used to evaluate periodontal health status were chosen to conduct this meta-analysis. PD, ABL, and CAL are the gold standard measures of periodontitis [49]. In this meta-analysis, there was no statistical difference in mean PBI and BOP while the difference in mean PD, CAL, and ABL in cases was significantly higher than in control. In the PD analysis, sensitivity analysis showed that the exclusion of Costa et al. had the greatest impact on the results [19]. We believe the main reason is that the study was relatively new and adopted the 2018 classification of periodontal disease, which only included patients with moderate, severe, and advanced periodontitis [stage II, III, and IV] i.e. The inclusion criteria for PD would be higher than in other studies. PD exhibited high heterogeneity in this meta-analysis, which is undoubtedly related to the inconsistency of the visiting tools used by physicians, whether the visiting tooth position is indexed or full-mouth, the standard of periodontitis, etc. Therefore, future research requires the unification of standards to obtain more valuable data and results. For CAL analysis, the meta-analysis showed that cirrhotic patients presented a greater mean of CAL than without. Statistically significant high heterogeneity was observed, no significant reduction in heterogeneity in sensitivity analysis. However, when the Costa et al. study was ignored, the WMD did not change much, suggesting that the data is valuable for the overall estimate, reflected the periodontal status in cirrhotic patients. The results also showed that cirrhotic patients recorded statistically significant higher mean ABL than controls, no statistically significant high heterogeneity was observed. Gingival bleeding is one of the most common chronic bleeding manifestations in the decompensated stage of liver cirrhosis [50]. Nevertheless, there was no difference in mean BOP, not only because not enough articles, but chronic bleeding from liver cirrhosis affects the measurement of BOP. However, in clinical work we found that when cirrhotic patients with poor periodontal condition receive systematic periodontal basic treatment, the condition of bleeding gums can be improved to a certain extent.

While our results are limited by the small number of studies that meet the criteria for meta-analysis, it is worth noting that cirrhotic patients have poor periodontal health. However, current meta-analysis has limitations, the results should be interpreted with caution: First, the overall quality of the evidence was comparatively low because they were performed in hospitals, which inevitably results in less representation to public. But this limitation is justified, the degree of periodontal inflammation and liver cirrhosis can only be diagnosed in hospitals through specialist examination by physician. Second, studies define and diagnose periodontitis differently, not all studies have chosen consistent techniques to measure periodontitis-related parameters, diagnosing periodontal conditions requires combination of several clinical parameters to be accurate. Using PD, CAL, and ABL to definite periodontitis is widely accepted by periodontists worldwide, according to the recommendations of the European Federation of Periodontology [51]. The absence of recognized criteria to define periodontitis might influence the results, combining using clinical and radiological approaches to define periodontitis are of high quality and safety so that the heterogeneity of studies is reduced and provides more reliable data. Third, the confounding factors, such as age, gender, smoking/drinking history, or systemic status, may have an impact on both cirrhosis and periodontal health. Thus, future well-designed prospective studies to provide strong evidence are necessary. Fourth, our search results were primarily limited to articles published in English. Finally, most studies were cross-sectional or case–control studies, therefore, we cannot draw any causal conclusions from this study. Based on these limitations, we need more longitudinal studies to conduct more comprehensive analyses.

This article reveals the effect of liver cirrhosis on periodontal health status. Cirrhotic patients tend to have higher CAL, PD, and ABL, the prevalence of periodontitis also increases. However, given the paucity of data and significant limitations, we must interpret the results carefully. Considering our findings, we suggest cirrhotic patients carefully monitor periodontal health and conduct routine periodontal examinations. Dentists and physicians collaborate can improve patients' quality of life and prognosis of liver cirrhosis, and reduce mortality.