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Association of periodontitis and tooth loss with liver cancer: A systematic review
Mohammad Sultan Al-Ak’hali, Sadeq Ali Al-Maweri, Wael Ibraheem Ibraheem, Mohammed Nasser Alhajj, Anas Shamala, Esam Halboub
To cite this version:
Mohammad Sultan Al-Ak’hali, Sadeq Ali Al-Maweri, Wael Ibraheem Ibraheem, Mohammed Nasser Alhajj, Anas Shamala, et al.. Association of periodontitis and tooth loss with liver cancer: A systematic review. Critical Reviews in Oncology/Hematology, Elsevier, 2021, 159, pp.103221.
�10.1016/j.critrevonc.2021.103221�. �hal-03168670�
Title: Association of Periodontitis and tooth loss with liver cancer: a systematic review
Authors: Mohammad Sultan Al-Akhali, Sadeq Al-Maweri, Wael Ibraheem, Mohammed Alhajj, Anas Shamala, Esam Halboub
1
Department of Oral Medicine and Diagnostic Sciences, AlFarabi Colleges of Dentistry and Nursing, Riyadh, Saudi Arabia; Department of Oral Medicine, Faculty of Dentistry, Sana’a University, Yemen.
Email: Sadali05@hotmail.com
2
Department of Preventive Dental Sciences, College of Dentistry, Jazan University, KSA.
Email: sultanperiodontics@gmail.com
3
Department of Preventive Dental Sciences, College of Dentistry, Jazan University, KSA.
Email: dr.wael007@yahoo.com
4
Department of Prosthodontics, Faculty of Dentistry, Thamar University, Dhamar, Yemen
5
Department of Biological and Preventive Sciences, College of Dentistry, University of Sciences and Technology, Sana’a
,Yemen. Email: Anasshamala@gmail.com
6
Department of Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, Jazan University, KSA. Email: mhelboub@gmail.com
Running title: The association between periodontal diseases liver cancer Keywords: Tooth loss; periodontitis; liver cancer; association
Corresponding author:
Dr. Sadeq Ali Al-Maweri, Department of Oral Medicine and Diagnostic Science, Al Farabi Colleges, Riyadh, KSA. Email: sadali05@hotmail.com
Tel: 00966564230889
Abstract:
Background: Some epidemiological studies have reported a positive association between periodontal diseases and orodigestive cancers. The present systematic review aimed to assess the potential association between tooth loss or periodontitis and the risk of liver cancer.
Methods: A comprehensive review of PubMed, Scopus and Web of Science databases was conducted in July 2019 to identify all relevant studies. The inclusion criteria comprised all observational studies that assessed the relationship between tooth loss or periodontitis with liver cancer. Case reports, animal studies, experimental studies, commentaries, and review articles were excluded. Due to great heterogeneity among the included studies, no meta-analysis was conducted.
Results: A total of six studies (four prospective cohorts, one cross-sectional, and one case- control) comprising …… met the inclusion criteria. Three studies found positive association between tooth loss and the risk of liver cancer. One case-control study found some association between liver cancer and loss of 12-23 teeth, but such association was not replicated in patients with greater number of tooth loss. However, two studies found no significant association between tooth loss and/or periodontitis and the incidence of liver cancer.
Conclusion: Within the limitations of the present review, it can be concluded that there might be
a possible link between tooth loss/periodontitis and the risk of liver cancer. More prospective
cohort studies are required to evaluate the potential association between tooth loss/periodontal
disease and liver cancer.
Introduction
Liver cancer is the sixth most common cancer and the fourth leading cause of cancer mortality worldwide, accounting for an estimated 841,000 new cases and 782,000 deaths annually (Bray, Ferlay et al. 2018). The main risk factors for liver cancer include hepatitis B virus, hepatitis C virus, heavy alcohol consumption, tobacco use, aflatoxin exposure, obesity, and diabetes mellitus (Bray, Ferlay et al. 2018). These factors cause chronic liver inflammation, which may progress at the absence of treatment to more severe chronic forms of hepatic inflammation (cirrhosis), and eventually liver cancer (McGlynn, Petrick et al. 2015). Recently, some studies suggested periodontitis or tooth loss as a possible risk factor for orodigstive cancers including liver cancer (Hiraki, Matsuo et al. 2008, Yang, Petrick et al. 2017, Thistle, Yang et al. 2018, Sakai, Yamada et al. 2019).
Periodontitis, a highly prevalent disease worldwide, is a chronic, destructive, inflammatory disease of the teeth-supporting tissues including gingiva, alveolar bone and periodontal ligament (Meyle and Chapple 2015, Papapanou and Susin 2017). It is characterized by immunological breakdown of the bone and soft tissues in response to the bacterial dental plaque (Meyle and Chapple 2015). If left untreated, periodontitis can progress, leading to destruction of the tooth- supporting structures and ultimately tooth loss (Dhaifullah, Al-Maweri et al. 2015, Meyle and Chapple 2015, Papapanou and Susin 2017). Tooth loss is considered as a marker of periodontal disease (Pihlstrom, Michalowicz et al. 2005), though teeth can be lost due to other reasons such as dental decay and trauma. Hence, tooth loss can be considered as a lifetime accumulative indicator of poor oral health. The current evidence suggests that periodontitis may be associated with several systemic diseases including cardiovascular diseases (Beukers, van der Heijden et al. 2017), reheumatoid arthritis (de Oliveira Ferreira, de Brito Silva et al. 2019), pneumonia (Moghadam, Shirzaiy et al. 2017) and fatty liver disease (Alakhali and Al-Maweri 2018, Helenius-Hietala and Suominen 2019). Moreover, findings from epidemiologic studies suggested an association between periodontitis, tooth loss and the risk of cancers including lung cancer, esophagus cancer, gastric cancer, colorectal cancer and pancreatic cancer (Hiraki, Matsuo et al. 2008, Chen, Nie et al. 2015, Chung, Tsai et al. 2016, Yin, Wang et al. 2016, Zeng, Xia et al. 2016, Maisonneuve, Amar et al. 2017, Corbella, Veronesi et al. 2018, Ma, Dai et al.
2018).
The potential mechanism connecting periodontitis and distant cancers is probably related to the persistent periodontal infection and inflammation that induce systemic chronic inflammation, and ultimately cancer. Additionally, periodontal pathogens especially porphyromonas gingivalis and fusobacterium nucleatum have been isolated from some orodigestive cancer tissues, indicating that these pathogens may play a role in carcinogenesis and tumor multiplicity at distant sites (Ray 2011, Ahn, Segers et al. 2012, Gao, Li et al. 2016).
In this context, a number of epidemiological studies have evaluated the association between periodontitis/tooth loss and the risk of liver cancer (Hiraki, Matsuo et al. 2008, Tamaki, Takaki et al. 2011, Nwizu, Marshall et al. 2017, Yang, Petrick et al. 2017, Thistle, Yang et al. 2018, Sakai, Yamada et al. 2019); the findings were inconsistent, however. For example, a large scale cohort study of Finish male smokers has reported an association between tooth loss and the risk of liver cancer after controlling of potential confounders (Yang, Petrick et al. 2017). Another cohort study conducted among Chinese adults also reported similar results (Thistle, Yang et al.
2018). Additionally, a retrospective cross-sectional study in Japan has reported an association
between liver cancer and periodntititis and tooth loss (Sakai, Yamada et al. 2019). In contrast,
one cohort study by Ansai et al 2013 did not find a significant association between tooth loss and
liver cancer among community-dwelling elderly in Japan (Ansai, Takata et al. 2013). Given the
obvious controversy in the results, the present systematic review sought to summarize the current
available evidence regarding the potential association between periodonotitis, tooth loss and the
risk of liver cancer.
Materials and methods Focused question
This systematic review was conducted following the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA)(Moher, Shamseer et al. 2015). The PECO research question was: Is tooth loss or periodontitis a risk factor for liver cancer?
Eligibility criteria
The eligibility criteria were as follows: all observational studies (cross-sectional studies, case- control, and cohort studies) that assessed the relationship between tooth loss or periodontitis and the risk liver cancer in humans. Case reports, animal studies, experimental studies, commentaries, review articles, and studies published in a language other than English were excluded.
Outcomes: Incidence of liver cancer
Exposure: periodontal disease or tooth loss.
Literature search
A literature search was conducted through PubMed/Medline, Scopus, and Web of Science (ISI) databases to identify all relevant articles published in English from date of Inception till and including June 2019. We used the following keywords in different combination: ( “tooth loss”
OR “Edentulism” OR “periodontitis” OR “gingivitis” OR “periodontal disease” AND “liver cancer” OR “digestive cancer” OR “hepatocellular carcinoma”). Titles and abstracts of the retrieved articles were screened by two authors (MA and SA) independently, and irrelevant studies were excluded. Full texts of the remaining potential articles were evaluated by two authors independently for inclusion. Moreover, the reference lists of the included articles were manually searched for additional studies.
Assessment of quality
Critical appraisal of the included studies were performed by two independent authors (HA and
WA) according to The Newcastle-Ottawa Scale (NOS) for assessing the Quality of Non-
Randomized Studies (Stang 2010). The NOS is based on three major components: selection of
the study groups (0–4 stars), comparability of cases and controls by controlling for relevant
factors (0–2 stars), and exposure (0–3 stars).
Data extraction
The following data was extracted by two independent authors (MS and WA) using a standard data collection form: authors and year of study; country; study design; number of patients; age and gender of patients; adjusted confounders; exposure parameters such as tooth loss or periodontal diseases; periodontal disease parameters such as clinical attachment loss, gingival bleeding, periodontal pocket, or bone loss; and the main outcomes.
Statistical analysis
Our aim was to carry out meta-analysis but owing to the substantial heterogeneity and inconsistency of data among the included studies, no statistical analysis was performed.
Quality of the included studies:
The results of the NOS-based quality assessment are presented in table 3. Overall, the quality of
the include studies was high, with a total quality score ranging from 6 to 7.
Results:
Search results:
A total of 740 articles were retrieved, of which 275 were duplicates (Figure 1). The titles and abstracts of the remaining 465 articles were screened by two independent reviewers for eligibility. Of these, 430 were irrelevant and were thus excluded. The full text of the remaining 35 potentially relevant studies were obtained and assessed for inclusion. Out of these, 29 articles were excluded for various reasons (Supplementary Table 1), and eventually 6 studies met the inclusion criteria and were further processed for data extraction (Hiraki, Matsuo et al. 2008, Ansai, Takata et al. 2013, Nwizu, Marshall et al. 2017, Yang, Petrick et al. 2017, Thistle, Yang et al. 2018, Sakai, Yamada et al. 2019).
General characteristics of the included studies
Six studies (Hiraki, Matsuo et al. 2008, Ansai, Takata et al. 2013, Nwizu, Marshall et al. 2017, Yang, Petrick et al. 2017, Thistle, Yang et al. 2018, Sakai, Yamada et al. 2019) comprising xxxxxxx were included in this systematic review. With regards to study design, four studies were prospective cohort (Ansai, Takata et al. 2013, Nwizu, Marshall et al. 2017, Yang, Petrick et al. 2017, Thistle, Yang et al. 2018), one case-control (Hiraki, Matsuo et al. 2008), and one retrospective cross-sectional (Sakai, Yamada et al. 2019). Three studies were conducted in Japan (Hiraki, Matsuo et al. 2008, Ansai, Takata et al. 2013, Sakai, Yamada et al. 2019), one in China (Thistle, Yang et al. 2018), one in Finland (Yang, Petrick et al. 2017) and one in the USA (Nwizu, Marshall et al. 2017). Number of participants ranged from 64 to 65, 869 subjects. The age of participants ranged from 18 to 80 years old. All studies reported gender of the subjects;
one study included exclusively male subjects (Yang, Petrick et al. 2017), one study included female subjects (Nwizu, Marshall et al. 2017), while the remaining four studies included both genders (Hiraki, Matsuo et al. 2008, Ansai, Takata et al. 2013, Thistle, Yang et al. 2018, Sakai, Yamada et al. 2019).
Liver cancer parameter:
The reported outcome was the incidence of liver cancer in all included studies.
Tooth loss/periodontal parameters:
The exposure parameters were: number of missing teeth in four studies (Hiraki, Matsuo et al.
2008, Ansai, Takata et al. 2013, Yang, Petrick et al. 2017, Thistle, Yang et al. 2018), periodontitis in one study (Nwizu, Marshall et al. 2017), and both periodontitis and number of missing teeth in one study (Sakai, Yamada et al. 2019). Ascertainment of tooth loss/periodontal status varied greatly across studies; being self-reported in three studies (Hiraki, Matsuo et al.
2008, Nwizu, Marshall et al. 2017, Yang, Petrick et al. 2017); and evaluated by dental examination in three studies (Ansai, Takata et al. 2013, Thistle, Yang et al. 2018, Sakai, Yamada et al. 2019).
Main outcomes:
Three studies found positive association between number of missing teeth and the risk of liver cancer (Yang, Petrick et al. 2017, Thistle, Yang et al. 2018, Sakai, Yamada et al. 2019).
However, three studies found no significant association between tooth loss or periodontitis and the incidence of liver cancer (Hiraki, Matsuo et al. 2008, Ansai, Takata et al. 2013, Nwizu, Marshall et al. 2017).
Yang et al. (Yang, Petrick et al. 2017) assessed the association between tooth loss and liver cancer incidence on a cohort of 29,096 Finnish male smokers. A total of 213 liver cancers were recorded over the follow- up period of 17 years. The authors found a significant association between number of missing teeth and the incidence of liver cancer after adjusting for all confounding factors. Interestingly, the authors observed that the more the number of missing teeth, the higher the risk for liver cancer. The authors concluded that periodontal infection might be a risk factor for liver cancer (Yang, Petrick et al. 2017).
Thistle et al (Thistle, Yang et al. 2018) in their large-scale prospective cohort study on 32, 689
subjects (14,541 males, and 18148 females) assessed the association between tooth loss and liver
cancer incidence. Around 329 liver cancers were diagnosed over the 30 year- follow-up period.
The results showed that subjects in the highest quartile of age-specific tooth loss had an increased risk of liver cancer, with varied results according to gender. Greater tooth loss was positively associated with an increased risk of liver cancer in women (HR = 1.64, 95%CI: 1.04, 2.59), but not in men (HR = 1.08, 95%CI = 0.75, 1.57) (Thistle, Yang et al. 2018).
Another large scale prospective cohort study by Nwizu et al, investigated the association between self-reported periodontitis and the incidence of different types of cancers including liver cancer among American women (n=65,869). During the follow-up period a total of 7,149 cancers including 329 liver cancers were diagnosed. The authors observed a significant association between periodontitis and some types of cancers, but no significant association was observed between periodontitis and liver cancer (Nwizu, Marshall et al. 2017).
Ansai et al. (Ansai, Takata et al. 2013) assessed the association of tooth loss and oro-digestive cancers among a cohort of 80- year old Japanese population. After 12-year follow up period a total of 13 liver cancers were diagnosed. The authors did not find a significant association between periodontitis and liver cancer in this population (Ansai, Takata et al. 2013).
In a large-scale case-control study conducted on 5,240 Japanese cancer patients (of which 167 were liver cancers), and 10,480 age- and gender matched controls, the authors found some association between liver cancer and loss of 12-23 teeth, but such association was not replicated in patients with greater number of tooth loss (Hiraki, Matsuo et al. 2008).
A more recent cross-sectional study, Sakai et al. (Sakai, Yamada et al. 2019) retrospectively
assessed the relationship between dental diseases and the incidence of digestive cancers
including liver cancer. The authors found higher proportion of missing teeth and periodontal
diseases among patients with liver cancer as compared to healthy patients based on the Japanese
2016 national survey. The authors concluded that periodontal diseases and tooth loss might be a
risk factor to digestive cancers including liver cancer (Sakai, Yamada et al. 2019).
Discussion:
Tooth loss or periodontal diseases have been suggested as potential risk factors for distant cancers including oro-digestive cancers (Javed and Warnakulasuriya 2016, Ren, Luu et al. 2016, Yin, Wang et al. 2016). In this context, some epidemiological studies have explored the potential association between tooth loss and/or periodontal health status and the risk of liver cancer (Nwizu, Marshall et al. 2017, Yang, Petrick et al. 2017, Thistle, Yang et al. 2018, Sakai, Yamada et al. 2019). Hence, the present study sought to systematically review and summarize the available evidence regarding the possible association of tooth loss or periodontitis with the risk of liver cancer. Overall, the findings were inconsistent; three studies (two cohorts and one cross- sectional) (Yang, Petrick et al. 2017, Thistle, Yang et al. 2018, Sakai, Yamada et al. 2019) showed a significant positive association between tooth loss or periodontal disease and the risk of liver cancer; two cohorts studies failed to replicate such results (Ansai, Takata et al. 2013, Nwizu, Marshall et al. 2017); whereas one case-control study found some association between liver cancer and loss of 12-23 teeth, but no association in patients with greater number of tooth loss (Hiraki, Matsuo et al. 2008). Of note, it is pertinent to mention that the two cohort studies that reported lack of association comprised very small sample sizes with a limited number of liver cancers, being 19 cases in one study (Nwizu, Marshall et al. 2017) and only 13 cases in the other (Ansai, Takata et al. 2013). By contrast, among the three studies that reported positive associations, two were prospective cohorts studies (Yang, Petrick et al. 2017, Thistle, Yang et al.
2018) with very large sample sizes (n=32,689 and n= 29,096, respectively ) and relatively adequate number of liver cancer cases (n=329 and n= 213, respectively). By and large, the findings of this review are inconclusive and should be interpreted with caution given the heterogeneity and other limitations discussed in the subsequent sections.
Previous studies have linked periodontal disease/ tooth loss with various cancers including gastric cancer, esophagus cancer, colorectal cancer, pancreatic cancer, oral cancer, and lung cancer (Hiraki, Matsuo et al. 2008, Chen, Nie et al. 2015, Yin, Wang et al. 2016, Zeng, Xia et al.
2016, Maisonneuve, Amar et al. 2017, Corbella, Veronesi et al. 2018, Ma, Dai et al. 2018). To
the best of our knowledge, this is the first study that investigated the potential association
between liver cancer and oral health parameters. Tooth loss is a fatal sequel of bacterial
infections, mainly periodontitis (Meyle and Chapple 2015, Papapanou and Susin 2017). The exact mechanism underlying the potential association between periodontal disease/tooth with distant cancers is not fully understood. However, a number of pathways have been suggested.
First, persistent periodontitis can induce systemic inflammation through activating inflammatory mediators such as histamine, prostaglandin, cytokines and proteinases (Coussens and Werb 2002, Mantovani, Savino et al. 2010). Another possible mechanism is related to the role of oral pathogens (Ahn, Chen et al. 2012, Gao, Li et al. 2016, Stashenko, Yost et al. 2019, Zhang, Niu et al. 2019). There is a growing body of evidence implicating oral microbiome in initiation and progression of oro-digestive cancers (Ahn, Chen et al. 2012, Javed and Warnakulasuriya 2016).
Oral pathogens especially periodontal pathogens are believed to contribute to carcinogenesis through producing carcinogenic metabolic byproducts, with subsequent oncogenic and antiapoptotic effects (Ray 2011, Kostic, Chun et al. 2013, Gao, Li et al. 2016, Zhang, Niu et al.
2019). Specifically, certain periodontal pathogens namely p. gingivalis and Fusobacterium nucleatum have been implicated in cancer progression and were isolated from various orodigestive cancers (Ray 2011, Castellarin, Warren et al. 2012, Kostic, Chun et al. 2013, Gao, Li et al. 2016).
In the same context, periodontal infection has been implicated in chronic liver inflammation including cirrhosis and none-alcoholic fatty liver disease, both of which are precursor of liver cancer (Alazawi and Bernabe 2017, Costa, Lages et al. 2019, Helenius-Hietala and Suominen 2019, Weintraub, Lopez Mitnik et al. 2019). A recent systematic review of clinical and microbial studies reported a strong association between periodontal diseases and non-alcoholic fatty liver disease (Alakhali and Al-Maweri 2018). Additionally, multiple studies conducted on humans found a strong positive association between periodontal pathogens especially p. gingivalis and non-alcoholic fatty liver disease development and progression (Yoneda, Naka et al. 2012, Omura, Kitamoto et al. 2016, Alakhali and Al-Maweri 2018, Nakahara, Hyogo et al. 2018).
Moreover, some animal studies found that oral administration of P. gingivalis caused impaired gut barrier function, increased serum endotoxin levels, and dissemination of enterobacteria to the liver which could be hepatocarcinogenic
Whereas the findings of the present review are based on limited number of published studies,
they are supported by some other studies that showed higher mortality of oro-digestive cancers
including hepatic cancers in patients with periodontitis and those with seropositive to periodontal pathogens namely p gingivalis (Ahn, Segers et al. 2012). Furthermore, Hirarki et al. (Hiraki, Matsuo et al. 2008) in their study on liver cancer patients found that liver cancer patients with chronic periodontitis had higher serum bilirubin levels, higher levels of reactive oxygen species than those with healthy periodontum. The authors also found significant association between progression of liver cancer and severity of periodontitis (Hiraki, Matsuo et al. 2008). The findings of the present review are in line with previous literature that suggested potential association between tooth loss/periodontitis and other oro-digestive cancers (Javed and Warnakulasuriya 2016, Yin, Wang et al. 2016, Maisonneuve, Amar et al. 2017, Ma, Dai et al.
2018).
It is well recognized that the level of evidence is dependent on many factors, one of which is the quality of the included studies. We have critically appraised the included studies using NOS, a widely used quality assessment tool for the observational studies. The results of the quality assessment revealed some methodological flaws that might have caused some bias. Particularly one important shortcoming is related to methods of recording the exposures (tooth loss and periodontal disease), in which half of the included studies relied on self-reported data rather than on clinical examination. Self-reported data is potentially prone to recall errors, and thus might have biased the results.
The present systematic review has indicated some association between tooth loss/periodontal disease and liver cancer. However, there are several limitations that should be acknowledged.
The main limitation is related to the relatively limited number of the included studies as well as
the small sample size of liver cancers in some of these studies. Another key limitation is related
to the mixed study designs across the reviewed studies (4 cohort studies, one case control study
and one retrospective cross-sectional study), and thus no robust conclusion can be drawn. In
addition to the variability of the study designs, the included studies showed a substantial
heterogeneity with respect to the gender and age of the subjects, exposure parameters, methods
of exposure measurements, ethnicity, and geographical differences. Such heterogeneity
prevented us from performing statistical analysis to quantify the magnitude of the association.
Another important drawback is the fact that information about tooth loss/periodontitis was self- reported in half of the included studies, and thus is prone to recall bias. Finally, although most of the included studies adjusted for gender, age, smoking and alcohol consumption, other important confounders such as obesity, metabolic diseases, serum hepatitis B and C infection status, and socioeconomic status were not controlled in most of the included studies and thus might have biased the results. Nevertheless, despite the potential methodological shortcomings, the present review has some strength worth mentioning. First, this is the first systematic review to summarize the current literature and provide an insight on the possible association between tooth loss/periodontal disease and the risk of liver cancer. Second, four out of the six included studies were prospective cohort studies with a relatively long follow-up period as well as large sample sizes in most of these studies.
In summary, within the limitations of the present review, we can conclude that there is some
evidence that periodontitis, tooth loss may be associated with liver cancer. More prospective
cohort studies with long follow-up periods, large sample sizes and sound methodologies are
required to further explore the potential association between tooth loss and the risk of liver
cancer.
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Figure1: Flow-chart of methodology according to PRISMA guidelines
