PERIODONTAL CHANGES AND THE NON-ALCOHOLIC FATTY LIVER DISEASE

Abstract

In periodontal medicine, such metabolic disorders are viewed as high risk factors for the onset of periodontal disease, considering their impact on the host immune response. Keywords: periodontal disease, non-alcoholic fatty liver disease, insulin resistance, diabetes mellitus. 1.INTRODUCTION The liver, a crucial organ for the keeping of the general homeostasis and well-being, is the prime location where all the elements and particles that are introduced into the body via food, drink or medicines are being transformed and metabolized. Other studies have concluded that non-alcoholic fatty liver disease increases the risk of ischemic stroke, nonf atal coronary heart disease and cardiovascular death in most type 2 diabetes mellitus [27]. Periodontitis is caused by oral pathogenic bacteria present in the dental subgingival biofilm, inducing chronic inflammation in the supporting structures of the teeth, which can lead to the formation of pockets, clinical attachment loss, and eventually tooth loss [45].

Headnote

Abstract

The characteristics of our modern society put a lot of pressure on the normal function of the liver and its metabolic role, with an increased intake of fatty and sweet foods, abusive alcohol consumption or over-medication. These elements impact the hepatic function and can favor the onset of conditions such as the non-alcoholic fatty liver disease. This disease can be a gateway towards other metabolic conditions like diabetes mellitus and obesity, since important pathophysiological mechanisms, as insulin resistance, can occur. In periodontal medicine, such metabolic disorders are viewed as high risk factors for the onset of periodontal disease, considering their impact on the host immune response. This lead to the official recognition of periodontal disease as the 6th complication of diabetes mellitus. The studies on the relationship between non-alcoholic fatty liver disease and periodontal disease are scarce and their results are so far inconclusive. However, given the important metabolic processes that the liver controls and their impact on periodontal health and pathology, further studies are required on the matter, in order to clarify the characteristics of this connection.

Keywords: periodontal disease, non-alcoholic fatty liver disease, insulin resistance, diabetes mellitus.

1.INTRODUCTION

The liver, a crucial organ for the keeping of the general homeostasis and well-being, is the prime location where all the elements and particles that are introduced into the body via food, drink or medicines are being transformed and metabolized. Some of these elements, such as fatty food, alcohol or excessive use of medicines and drugs can have a long-lasting damaging effect on the normal structure and function of the liver. When fat deposits are begging to be stored inside the hepatic tissue due to the important intake of such molecules, other than alcohol, non-alcoholic fatty liver disease (NAFLD) is triggered [1].

The periodontal structures are the specialized elements that bond the teeth to the alveolar bone. When bacterial plaque begins to grow in the subgingival space and interacts with the host immune system, an inflammatory reaction unveils, beginning from the more superficial structures of the periodontium to the more profound ones like the alveolar bone. This inflammatory reaction which characterizes the periodontal disease causes the destruction of the periodontal tissues, leading to the loosening of the teeth [2].

This narrative review aims to analyze the common pathogenic and pathological connections that exist between the two types of disease by assessing the data in the current scientific literature on the subject and to explore the opportunity of further research on the matter.

2.GENERAL ASPECTS REGARDING NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is characterized by a chronic and progressive liver pathology in which fat accumulates in the liver without a history of drinking or immune system disease and includes simple steatosis and nonalcoholic steatohepatitis (NASH) [1]. NAFLD is an asymptomatic condition in general and it is frequently associated with conditions such as obesity, diabetes mellitus type 2, metabolic syndrome and its individual components. NAFLD presents the following signs and symptoms: fatigue, right upper quadrant pain and hepatomegaly, as well as acanthosis nigricans. The majority of patients with NAFLD are diagnosed by incidental elevated liver enzymes or by imaging studies suggesting hepatic steatosis [1]. The clinical forms of NAFLD are: simple steatosis, nonalcoholic steatohepatitis (NASH), hepatocellular carcinoma (HCC) and liver cirrhosis. Researchers believe that not very far in time, NASH-related cirrhosis and NASHrelated HCC will become the most common indications for liver transplantation [3-5]. Nonalcoholic steatohepatitis is commonly associated with the presence of steatosis, lobular inflammation and hepatocellular ballooning or steatosis adding any stage of fibrosis [6].

3.NAFLD AND DIABETES

Research over time have established that nonalcoholic fatty liver disease prevalence increases in patients with diabetes (DM) [7,8]. A large number of studies suggest that patients with type 2 diabetes mellitus (T2DM) present a high risk for non-alcoholic steatohepatitis (NASH) and liver fibrosis [9,10]. Studies made over time concluded that NAFLD progression is faster due to preexisting diabetes and will lead to liverrelated mortality and hepatocellular carcinoma [11-13]. Also, patients with NAFLD present a high risk of prediabetes [14] and recent research has concluded that NAFLD predicts the development of type 2 diabetes mellitus [14,15]. T2DM is a multi-factorial disease in which, as a result of chronic hypernutrition and obesity, the body is no longer capable to respond to physiological insulin concentrations [16]. NAFLD and diabetes mellitus (DM) often occur within the same patient, as shown by epidemiological studies. The same studies revealed 18%-33% of NAFLD patients also have T2DM, while a high percentage 66%-83% of patients with NAFLD - have some form of insulin resistance [17-19]. A research revealed that, in all such cases, individuals with NAFLD proved to be insulinresistant after two-step hyperinsulinemic euglycemic clamp analysis [20]. T2DM has an important role in the development of severe liver diseases [18]. A comparison between the subjects affected with NAFLD and T2DM with subjects without this disease, shows that those with T2DM had bigger chances to develop NASH [21]. Obese T2DM patients with NAFLD have a prevalence of NASH that could be significantly higher than individuals without T2DM [22]. Studies have linked T2DM to a fast evolution of liver fibrosis [23] and an increased risk to develop cirrhosis [24]. A comparative study made by Miele, between T2DM patients and controls, showed that the risk to develop hepatocellular carcinoma is threefold bigger in the first group [25]. Some studies concluded that NAFlD individuals have an increased risk of liver-related death increased, due to T2DM [26]. Other studies have concluded that non-alcoholic fatty liver disease increases the risk of ischemic stroke, nonf atal coronary heart disease and cardiovascular death in most type 2 diabetes mellitus [27].

4.NAFLD AND INSULIN RESISTANCE (IR)

An important observation is that liver disease is common in T1DM patients [28]. Risk factors - like obesity, age and poor glycemic control - can be assigned to non-alcoholic disease in patients with type 1 diabetes mellitus (T1DM) [28]. A very important fact that incriminated the evolution of non-alcoholic fatty liver disease was the deregulation in insulin-mediated control over the hepatic production of glucose and lipids [29]. Normally, in healthy people, insulin inhibits gluconeogenesis and stimulates lipogenesis while, in NAFLD cases associated with type 2 diabetes mellitus, an unexpected event is observed, such as the reduced ability to inhibit gluconeogenesis, while lipogenesis continues to be stimulated and enhanced [29]. All the aspects led to the conclusion that IR is partial, reducing the Akt signaling arm, and at the same time allowing SREBP1c activation [30]. Some studies conducted on animals revealed that the levels of triglycerides (TG) are not increased, due to hepatic elimination of the insulin receptor [31]. Alteration produced in Akt signaling has led to elevated gluconeogenesis, while the reduced activation of PKCA. resulted in hypolipidemia and a lower expression of SREBP1c [32]. A study conducted by R.K. Semple on individuals with a rare mutation affecting the insulin receptor and protein kinase Akt2 aimed to assess the model of selective hepatic postreceptor insulin resistance in humans [33]. This research concluded that metabolic dislipidemia did not appear at patients with a mutation that affects the insulin receptor, revealing instead a high metabolic dyslipidemia in patients having Akt2 mutations [34]. In the second category of subjects, very high levels of TG, VLDL/TG/cholesterol, LDL and low HDL cholesterol levels were recorded, as well as increased liver fat and hepatic lipogenesis [34].

5.NAFLD AND OBESITY

A factor playing an important role in the progression of NAFLD cases associated with T2DM is obesity [35]. Obesity induces chronic systemic inflammation due to visceral adipose tissue [35]. Hypernutrition leads to hypertophic adipocytes, their access to proper oxygenation being reduced [36], physically restricted by the stromal matrix [37]. Hypertrophic adipocytes, activate the local immune system, having a weak inflammatory response in the adipose tissue [38]. With the aggravation of obesity, the adipose tissue inflammation grows, releasing proinflammatory cytokines [38-40]. IR causes a high level of free fatty acids (FFAs) in circulation [41]. These aspects help lipid accumulation and liver inflammation, finally leading to NAFLD [41].

6.PERIODONTAL DISEASE - GENERAL ASPECTS

Periodontitis is a common public health problem worldwide [42], appearing as a highly prevalent, chronic inflammatory disease that negatively influences everyday life [43]. Periodontal disease occurs when the ecological balance of the oral cavity is disrupted and periodontal bacterial pathogens start triggering an inflammatory reaction [44]. Periodontitis is caused by oral pathogenic bacteria present in the dental subgingival biofilm, inducing chronic inflammation in the supporting structures of the teeth, which can lead to the formation of pockets, clinical attachment loss, and eventually tooth loss [45].

Periodontal disease is one of the most common diseases [46], its classification being based on the clinical features, age, systemic and local risk factors and progression rate [46]. Periodontal diseases include gingivitis (reversible, the inflammation of the gingiva) and periodontitis (the inflammation evolves resulting in tissue destruction and alveolar bone resorption) [47]. The periodontal pockets between the gingiva and the tooth result from the destruction of the collagen fibers present in the periodontal ligament. Periodontal probing is essential to assess the periodontal pockets [48]. The tissue destruction that occurs in periodontitis is irreversible, even if the disease is a slowly progressing one [48]. In its early stages, periodontitis may be asymptomatic; not very painful, so that most of the patients are unaware of it, until the disease has sufficiently evolved, leading to tooth mobility [48]. Destruction of fibers of the periodontal ligament and associated resorption of the alveolar bone are accompanied by a progressing attachment loss, leading to deeper pockets [48]. Advanced periodontitis presents itself with gingival erythema, edema, gingival bleeding and recession, suppuration in the periodontal pockets, tooth mobility and, in the end, tooth loss [48]. More common is moderate periodontitis, a form affecting 40-60% of adults [49]. A major risk factor is smoking, as it significantly increases the risk of installation and the severity of the condition [50, 51]. The main cause for periodontal tissues inflammation is the presence of subgingival biofilm for long period of time [52]. Analysis of the inflammatory response revealed changes in the secretion of host-derived mediators of inflammation and tissue breakdown [52]. The host-derived mediators encountered are IL-1ß, IL-6, chemokines, prostaglandin E2, TNF-a, T cell regulatory cytokines like IL-12, IL-18, receptor activator of nuclear factor kB ligand, and the matrix metalloproteinases such as MMP-8, MMP-9 and MMP-13 [52].

7. INTERACTIONS BETWEEN PERIODONTAL DISEASE AND OBESITY

Obesity is one of the lifestyle factors that may increases the risk for periodontitis [53]. Studies on the effect of obesity on periodontitis were first conducted on rats and concluded that obese rats having periodontitis had a higher rate of alveolar bone loss than non-obese rats [53]. Numerous studies came to assess the association between obesity and periodontitis [54]. Analysis of NHANES III data showed that patients having a body mass index (BMI) >30 kg/ m2 faced a high risk to develop periodontitis than those with a body mass index between 18.5-24.9 kg/ m2 [55]. This association is probably related to insulin resistance [56]. The subjects having a BMI >27 kg/ m2, situated in the highest quartile for insulin resistance showed a higher risk of severe periodontitis than those from the lowest quartile [56]. The relationship between obesity and periodontitis was revealed by a recent metaanalysis: OR 1.35; 95%, CI 1.23, 1.47, meaning an increased prevalence of periodontitis for obese adults [57]. Even if interesting, these studies - generally cross-sectional/observational [58] - are limited, because they do not clearly state whether obesity precedes periodontitis.

8. ASSOCIATION BETWEEN PERIODONTAL DISEASE AND DIABETES MELLITUS (DM)

Diabetes has been incriminated as an important risk factor for periodontitis [59-61]. Diabetic individuals present a threefold higher risk for periodontitis than the non-diabetic ones [62]. DM is associated with high levels of systemic markers of inflammation [63]. High serum levels of IL-6 and TNF-a were observed in diabetes and obesity [63]. Serum levels of IL-6, also C-reactive protein (CRP) are considered to reveal the development, in time, of DMT2 [64]. TNF-a, IL-6 and CRP have shown a potentially role leading to insulin resistance [65, 66]. In patients with periodontitis, the serum levels of IL-6 and CRP are higher than the normal values, being correlated with the extent of disease [67, 68]. Diabetes increases inflammation in the periodontal tissues, in type 1 diabetic patients with gingivitis or periodontitis [69].

The gingival crevicular fluid (GCF) levels of prostaglandin E2 (PGE2) and IL-1ß are higher when compared to non-diabetic individuals with the same level of periodontal disease [69]. Gingival crevicular fluid is a serum exudate found in the gingival sulcus and in the periodontal pockets, carrying mediators of local tissue destruction and byproducts of tissue metabolism. This oral fluid is used for detection and monitoring of certain immunomarkers concentrations [70].

Studies conducted on DMT2 subjects showed that those with HbA1c >8% had an elevated GCF IL-1ß level, compared to those having HbA1c <8% [71]. Equally, some changes were evidenced in the activity of polymorphonuclear leucocyte (PMN) in cases of diabetes, such as microbicidal functions, decrease of chemotaxis and phagocytosis [72]. As known, diabetic patients with severe periodontitis have depressed PMN chemotaxis and defective PMN apoptosis, compared to diabetic individuals with mild periodontitis [73,74], which could cause increased retention of PMNs in the periodontal tissue.

Diabetes has shown a prolonged inflammatory response to Porphyromonas gingivalis, with increased production of TNF-a [75]. A study evidenced important histological alterations of the gingival epithelium in patients with DM and periodontitis, and an inflammatory diabetic polymorph infiltrate with plasmocyte predominant in patients with aggressive periodontitis [76]. PMN levels were higher at patients with periodontal abscesses [76].

9.NAFLD AND PERIODONTAL DISEASE

Studies conducted in recent years revealed the existence of an inter-relationship between different systemic diseases and periodontal disease [77,78].

As known, chronic periodontitis is associated with several systemic disorders like diabetes mellitus, obesity, atherosclerosis, heart disease [79-87].

In a recent review, [88] the conclusions of multiple studies on the association between NAFLD and periodontal disease were emphasized. Thus, studies conducted in Japan lead to identifying the relationship between NAFLD and periodontitis. In a study conducted on university students in Japan, it was observed that men students having an elevated level of serum ALT develop a different form of periodontal disease than those with a low level of serum ALT [89]. In the case of women, the high level of serum ALT could not be associated with an increased risk of periodontitis. [90]. Another cross-sectional study, also conducted in Japan, evidenced elevated levels of ALT and GGT in patients with periodontal pockets, more than >4 mm, compared to healthy patients. Multiple tests with GGT or ALT were performed, their conclusion evidencing an important relation between periodontal pockets and GGT. Also observed were elevated serum levels of y-glutamyl transferase (GGT) in patients with severe periodontitis, yet without drinking habits [91].

10.CONCLUSIONS

The associations between periodontitis and NAFLD have previously been investigated and certain pathological features are showed to be shared by the two conditions, however further studies are needed for a better understanding of the topic.

Aknowledgment

All authors contributed equally as the first author.

References

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