Abstract
Objectives
Phenylketonuria (PKU) is an autosomal recessive inherited disorder of phenylalanine metabolism resulting from a deficiency of phenylalanine hydroxylase. The aim of this study was to evaluate the dental status and periodontal health of PKU patients in Latvia.
Material and Methods
Forty-five PKU patients and age/sex-matched controls were recruited for this cross-sectional study. Their anamnestic data, periodontal health and dental status were assessed by one experienced dentist.
Results
Dental and periodontal clinical evaluation revealed that the median number of filled teeth was significantly smaller among PKU patients compared to the control group (p=0.021). PKU patients had a significantly larger median number of carious teeth than their healthy counterparts (p<0.001). Significant differences between the PKU and control groups were observed for several oral hygiene indices (p<0.001): Silness-Löe plaque index, OR=29.3 (95% CI: 3.7–232.4); CPITN index, OR=35.2 (95% CI: 4.5–278.3); Greene-Vermillion index, OR=10.2 (95% CI: 2.8–38.0); calculus removal necessity, OR=12.3 (95% CI: 3.3–45.4).
Conclusion
Dental status and periodontal health of PKU patients was found to be significantly inferior compared to healthy controls. This is likely due to the regular consumption of PKU formula and the difficulties which mentally and/or physically disabled PKU patients experience with their oral hygiene. To prevent tooth decay and periodontal disease, PKU patients should visit a professional oral hygienist every three to six months. Furthermore, they should adopt the habit of rinsing their mouth with water immediately after consuming PKU formula to counteract the acidity in their oral cavity.
Keywords: Phenylketonuria, Oral Health, Periodontitis
Introduction
Phenylketonuria (PKU) is an autosomal recessive inherited disorder of phenylalanine (Phe) metabolism resulting from a deficiency of phenylalanine hydroxylase (prevalence 1:10,000), (1, 2). Untreated, PKU can lead to intellectual disability, seizures, behavioural problems and mental disorders (3). The treatment of PKU entails following a strict low-protein diet and consumption of Phe-free amino acid formula. For all PKU patients, medical nutrition therapy is the primary form of treatment as it is the only way to avoid ingestion of the amino acid Phe while still meeting their protein intake needs (4). However, although this formula is essential for the wellbeing of PKU patients, it can negatively impact their oral health as it contains a high amount of complex carbohydrates. There are two types of complex carbohydrates – starch and fibre. Salivary and bacterial amylases in human saliva hydrolyse starches into maltose, maltotriose and low-molecular dextrins (5). In high concentrations, these by-products serve as excellent substrates for bacteria that are used in acid production. An increased acidity in oral cavity too often or for prolonged periods of time results in demineralisation of tooth structures. This process is known as dental caries, and all PKU patients are susceptible to higher levels of caries activity due to their dietary needs (5).
Furthermore, patients with mental and/or developmental problems, as seen in PKU patients diagnosed later in life or in cases of poor diet compliance, are likely to find it difficult to sustain adequate dental hygiene (6). Thus, based on their nutritional needs and possible inability to properly brush their teeth, the oral health of PKU patients is likely to be inferior to healthy controls.
Oral health encompasses a range of diseases and conditions. The current study focused on assessment of subjects’ dental status (identification of decayed, missing and filled teeth), oral hygiene habits (frequency of tooth brushing, use of additional oral hygiene tools and fluoride supplements) and evaluation of subjects’ periodontal health by means of clinical examination and oral hygiene indices. Periodontal disease is a multifactorial chronic inflammatory condition of periodontium (the supporting structures of teeth) caused mainly by dysbiosis of oral microflora, in which periodontal pathogens thrive. If left untreated, periodontal disease results in irreversible localised or generalised alveolar bone loss due to constant inflammatory processes in periodontium. Bacteria are the main etiological factor of periodontal disease; however, the severity of periodontal lesions can be influenced by numerous environmental factors and acquired diseases. There can also be a certain degree of genetic predisposition to periodontal disease (7, 8). In most cases, incorrect and/or irregular tooth brushing coupled with a failure to use interdental cleaning products is the direct cause of periodontal disease development since perfect conditions for bacteria to flourish in persistent dental plaque and calculus are thus created (9, 10). Another important factor that influences oral health is salivary flow. Saliva is a very important protective factor in oral cavity. Individuals with a low unstimulated salivary flow rate are more susceptible to dental caries because their saliva contains less of the main salivary buffer bicarbonate, as its concentration in saliva is proportional to flow rate. Lowered salivary production also predisposes individuals to xerostomia (dry mouth syndrome) and ensures that clearance of food from the mouth is delayed (11).
Since there is only a limited number of reports on the oral health of PKU patients, one of the main objectives of the present study was to investigate the dental status and periodontal health of PKU patients aged 12 years or older in Latvia. An Evaluation of the dental-medical history and the assessment of their permanent teeth and periodontal tissues were carried out.
Material and methods
Ethics
Approval for this study was granted by the Central Medical Ethics Committee and Genome Research Council of Latvia prior to data collection. The study was conducted according to the Helsinki Declaration. All possible risks, objectives, and benefits of involvement in the study were carefully explained to every participant or the parents of minor age participants and mentally disabled patients. Before participation in research, each participant or their representative(s) filled out a questionnaire (Appendix 1).
Study design
Forty-five PKU patients (62.2% females and 37.8% males) of 50 PKU diagnosed in Latvia between the ages 12 and 53 years (median=22) who agreed to participate in this cross-sectional study were recruited. 35 PKU patients were diagnosed with PKU immediately after birth, and 10 participants had delayed diagnoses. The healthy control group consisted of 45 age- and sex-matched individuals.
Salivary sample collection
Upon arrival to the dental office all participants were instructed to have breakfast and brush their teeth in the morning as usual but not later than 2 hours before sample collection time. The questionnaire (Appendix 1) was followed by salivary sample collection to determine basal salivary secretion rate. Participants were provided a graduated plastic tube for sample collection and a quiet, private space. Saliva sample was taken by unstimulated drain method which is easy and safe. No specific procedures were required other than sitting with the head slightly down and spitting saliva spontaneously secreted into the tube. Participants were timed and instructed to keep spitting until 10 ml mark was reached on the tube. Afterwards, the 10 ml were divided by number of minutes required for the participant to provide the sample and to determine whether their salivary flow is within the normal range of 0.3 – 0.4 ml/min. In Table 1, this is displayed as > 60 seconds (it took participants more than 60 seconds to secrete 0.3 – 0.4 ml of saliva, which indicates decreased salivary flow) and < 60 seconds (it took participants less than 60 seconds to secrete 0.3 – 0.4 ml of saliva, which indicates salivary flow within normal range).
Table 1. Oral hygiene habits, professional oral hygiene necessity and basal salivary secretion rate in PKU patients and control group.
| Controls (n=45) | PKU cases (n=45) |
Total
(n=90) |
OR
(95% CI) |
p-value* | ||
|---|---|---|---|---|---|---|
| Frequency of tooth brushing | Do not brush | 0 | 5 | 5 | 14.3 (3.1-66.7) |
<0.001 |
| 0% | 11.1% | 5.6% | ||||
| Once per day | 2 | 13 | 15 | |||
| 4.4% | 28.9% | 16.7% | ||||
| Twice per day | 43 | 27 | 70 | ref | ||
| 95.6% | 60.0% | 77.8% | ||||
| Interdental cleaning products | Do not use | 17 | 34 | 51 | 5.1 (2.05-12.6) |
<0.001 |
| 37.8% | 75.6% | 56.7% | ||||
| Dental floss | 27 | 7 | 34 | ref | ||
| 60.0% | 15.6% | 37.8% | ||||
| Mouthwash | 1 | 4 | 5 | |||
| 2.2% | 8.9% | 5.6% | ||||
| Professional oral hygiene necessity | Not necessary | 21 | 3 | 24 | 12.3 (3.3-45.4) |
<0.001 |
| 46.7% | 6.7% | 26.7% | ||||
| Necessary | 24 | 42 | 66 | |||
| 53.3% | 93.3% | 73.3% | ||||
| Basal salivary secretion rate | <60 seconds | 28 | 18 | 46 | 2.6 (1.1-6.2) |
0.03 |
| 63.6% | 40.0% | 51.7% | ||||
| >60 seconds | 16 | 27 | 43 | |||
| 36.4% | 60.0% | 48.3% | ||||
*Fisher’s exact test
Clinical examination of teeth and periodontal tissues
Salivary sample collection was followed by clinical examination of teeth and periodontal tissues. Clinical examination was carried out by a single dentist under appropriate and uniform lighting conditions. Dental status was assessed by identifying decayed teeth, missing teeth and filled surfaces of teeth (DMFS index) using visuo-tactile dental examination with a sharp dental probe, mirror, 3-1 syringe and dental magnifying loupes worn by the dentist. Several indices were used to assess oral hygiene and gingival health: CPITN index, Silness-Löe plaque index and Greene-Vermilion index. Values for these indices were determined by assessing the presence and abundance of plaque and calculus for specific teeth, measuring the depth of gingival sulci and/or periodontal pockets and evaluating gingival bleeding on probing with a periodontal probe.
Patients with CPITN scores of 1 and 2 were labelled as gingivitis patients, while patients with CPITN scores of 3 and 4 were classified as possible risk of periodontal disease.
Statistical analysis
A statistical analysis was conducted using SPSS for Windows. A risk analysis was performed, and the magnitude of the risk was estimated by the odds ratio (OR) and its 95% confidence interval (95% CI). A p-value of <0.05 was considered to be an indicator of a statistically significant result.
Results
In total, 45 PKU patients and 45 healthy controls were examined. Table 1 represents the oral hygiene habits, professional oral hygiene necessity and basal salivary secretion rate for both PKU and control groups. The most striking difference between the two groups was observed in the frequency of tooth brushing; almost all the healthy controls (95.6%) reported brushing their teeth twice a day, whereas there were only 60% of PKU patients (p<0.001). There were also marked differences between the two groups in the use of dental floss and mouthwash. A smaller number of PKU patients reported using dental floss compared with control individuals (15.6% vs. 60.0%); however, a larger number of PKU patients used mouthwash (8.9% vs. 2.2%). Notably, a significantly greater number of PKU patients reported not using any interdental cleaning products (75.6% vs. 37.8%; p<0.001). A significant difference between the two groups was also observed in professional oral hygiene necessity, with more PKU patients requiring this procedure (93.3% vs. 53.3%) (OR=12.3, 95% CI: 3.3–45.4; p<0.001). The control group, on average, had a higher basal salivary secretion rate (63.6% of control group patients had a salivary flow rate within normal range, compared to 40% of PKU patients, p=0.03).
Clinical examination of teeth revealed a significantly smaller median number of filled teeth among PKU patients compared with control individuals (p<0.05) (Table 2). In contrast, PKU patients had a significantly larger median number of carious teeth than their control counterparts (p<0.001) (Table 2).
Table 2. Number or filled, extracted and carious teeth in PKU patients and control group.
|
Controls (n=45) Median number (IQR) |
PKU cases (n=45) Median number (IQR) |
p-value* | |
|---|---|---|---|
| Filled teeth | 6 (6) | 4 (8) | 0.021 |
| Extracted teeth | 0 (1) | 0 (2) | 0.07 |
| Carious teeth | 1 (2) | 4 (6) | <0.001 |
*Mann-Whitney U test; IQR – interquartile range
The values of oral hygiene indices were significantly higher in PKU patients than in control individuals (p<0.001; Appendices 2, 4, 5); Silness-Löe plaque index, OR=29.3 (95% CI: 3.7–232.4); CPITN index, OR=35.2 (95% CI: 4.5–278.3); Greene-Vermillion index, OR=10.2 (95% CI: 2.8–38.0).
Regarding oral health and time of PKU diagnosis, it can be recognized that delayed PKU diagnosis can increase the risk of periodontal disease development. 80% of patients with a delayed diagnosis were determined to already have or to be at risk of developing periodontal disease, compared to only 31.4% of PKU patients diagnosed before the age of two months (OR=8.7, 95% CI: 1.6-48.1; p<0.05) (Appendix 3).
Discussion
Prior to conducting this study, it was evident to the authors that the subject of oral health in PKU patients requires more in-depth research as very few articles on this subject are available at present, and the past articles are predominantly focused on the oral health of children. Furthermore, the available studies have reported contradictory results. For example, Kilpatrick and colleagues (12), examined 40 children with PKU and found no difference in the amount of dental caries compared with age/sex-matched healthy controls. However, significantly greater number of children with PKU exhibited the signs of tooth wear compared to their healthy counterparts (33% vs. 24%). More recently, in line with our results, Ballikaya et al. (13), reported higher caries prevalence among PKU patients. Nevertheless, it should be noted that their study primarily examined very young patients (1 to 5 years old) and only a small percentage (16.2%) of children was older than 11 years. Again, in accordance with our results, da Costa Silveira et al. (14), found that 75% of PKU patients were at high risk of caries development. They concluded that caries prevention and treatment were of major importance in dental care of these patients. One of the most extensive studies on this subject was conducted by Singh-Hüsgen and colleagues (15). They examined the oral health of 283 children with PKU and found that they experienced higher caries levels than healthy controls, which is a finding similar to the one presented in the current study for adults with PKU.
Our study showed that PKU patients have a decreased salivary secretion rate compared to the control group. Shimazaki et al. (16), examined the association of salivary flow rate with dental caries prevalence and periodontal status among 2,110 Japanese adults and suggested that individuals with lower salivary flow rates have higher risks for both dental caries and periodontal disease. Saliva is an important factor in a plethora of oral functions, such as mastication, swallowing, antimicrobial activity and cleaning action. Saliva also influences oral health both through its non-specific physio-chemical properties, as well as through more specific effects (17).
Significant finding in our study was an increased risk of periodontal disease in PKU patients. This is in line with other studies. For example, Lucas et al. (18), found a significantly greater mean plaque score for 41 PKU patients compared with controls. Ballikaya et al. (13), found moderate plaque accumulation and gingival inflammation in PKU patients, with nearly all of them requiring professional oral hygiene procedures due to excessive plaque and calculus. The scores for several oral hygiene indices were noticeably higher for our PKU patients compared to their controls, thus indicating an increased periodontal disease risk. However, it should be noted that the CPITN index has some limitations as it is based on gradual scoring. It lacks measurement of tooth mobility and attachment loss, which are important clinical symptoms of periodontal disease. The CPITN index should not be the sole approach for diagnosing periodontal disease. It is merely a tool often used in epidemiological studies to determine if a patient is at risk of periodontal problems (19). The main risk factor for periodontal disease development is a constant presence of dental plaque (20). As expected from previous reports, most of our PKU patients struggled with maintaining good oral hygiene habits, brushing their teeth once a day or only a couple of times a week. Consequently, this is likely to lead to plaque accumulation and, over time, to periodontal disease. Oral hygiene and gingival health were significantly worse for the examined PKU patients compared to the control group, indicating that most PKU patients are at risk of periodontal disease.
Interestingly, there is evidence from previous studies that periodontal disease development can also be influenced by diet. The management of PKU involves adherence to a low-protein diet. It is essential to restrict the intake of Phe to only the amount necessary for normal protein synthesis that can ensure growth and development. Additionally, to make up the energy requirements, their diets are often high in carbohydrates, which are usually taken frequently throughout the day (12). This type of diet is highly cariogenic and potentially erosive. Furthermore, PKU patients often reported snacking every two hours throughout the day, which can also be associated with a higher risk of caries development (12). It has been reported that an exceeded amount of carbohydrates can promote chronic inflammatory diseases (21, 22). Moreover, nutritional factors have been implicated in several chronic inflammatory diseases that are associated with periodontitis.
Periodontitis is associated with low micronutrient levels in serum/plasma which may result from dietary and/or lifestyle factors (23). Growing evidence shows that a carbohydrate-rich diet increases the risk of inflammation and gingival bleeding. A diet low in carbohydrates, rich in omega-3 fatty acids, rich in vitamin C and D, and rich in fibre can significantly reduce gingival and periodontal inflammation (24-26). Omega-3 long-chain polyunsaturated fatty acid levels are often reduced for PKU patients, because the primary dietary source of these fatty acids is oily seafood (27, 28). Indeed, Bosdet et al. (28), examined 35 adults with PKU (aged 18–46) and found that plasma docosahexaenoic acid (an omega-3 fatty acid found in cold-water, fatty fish)- levels were significantly lower compared to controls.
Despite all the aforementioned oral disease risk factors, our questionnaire revealed that PKU patients visit the dentist significantly less frequently than their healthy counterparts. Prevention of dental caries and periodontal disease depends on the patient’s home care measures and regular dental visits. Gingivitis is the only stage of periodontal disease that is reversible, as long as the patient implements and maintains an impeccable oral hygiene routine (29). To avert severe periodontal disease development, it is crucial to implement preventive measures, such as patient information and motivation on how and why to improve their oral hygiene routine (30, 31). Patients who visit their dentists frequently are more likely to maintain a good rapport with them and therefore will be better informed and motivated to take care of their oral health. Periodontal disease should be diagnosed and treated as early as possible with professional oral hygiene procedures and periodontal treatment (32). Ultimately, PKU patients should be reminded and motivated by their geneticist during every routine visit about the importance of proper oral hygiene habits and frequent visits to the dentist and hygienist.
There has been great speculation concerning the possible reasons for high caries incidence in PKU patients. A priority of parents of children with PKU is maintaining an optimal general health and daily functioning of the child rather than focusing on prevention of oral disease. Children with chronic medical conditions and their families have many pressures placed upon them and there is often a delay in seeking dental care as it is simply not a priority (33). Another important variable that determines the overall wellbeing of PKU patients, including their oral health, is the level of education of the parents. It has been reported that the higher the education level of the parents, the greater the understanding of the disease and the greater the support for the affected child (34). As for adults with PKU, it has been proposed that the increased risk of oral health issues may be due to social burdens. The families of children with PKU face several social issues throughout their childhood, as well as difficulties obtaining the recommended amino acid mixture and providing proper nutrition. In the 1990s, the economic situation in Latvia was poor and the availability of various fruits and vegetables was limited, resulting in increased consumption of starchy products and simple carbohydrates. An increased consumption of such staples has long been determined to be one of the main causes of dental caries and periodontal diseases. Patients who are diagnosed with PKU later in life do not practice a healthy lifestyle, which is optimal for their condition. They have not followed a strict Phe-free diet for years and have not taken the prescribed amino acid formula. Consequently, their general health and mental development are affected and it becomes more difficult to take proper care of their oral health. As detailed in the current article, just over a half of the 45 PKU patients reported brushing their teeth twice a day and only a quarter reported using supplementary dental care products. Previous studies have reported that adult patients feel a sense of guilt about this (35).
It is important for geneticists, dentists and general practitioners to be aware of the findings of this study and previous studies regarding PKU patients and their oral health. Although more research is needed on this subject, it is currently evident that oral health is an issue for PKU patients. Therefore, all medical specialists who encounter PKU patients should recommend early oral health care to spare them future dental costs and the discomfort of toothache and periodontal disease.
Conclusions
Overall, PKU patients have a significantly worse dental and periodontal status than healthy controls. PKU patients in the current study had a higher prevalence of carious teeth than controls. The values of oral hygiene indices (Silness-Löe plaque index, CPITN index and Greene-Vermillion index) were significantly higher in PKU patients compared to controls, indicating a worse oral health status and an increased risk of periodontal disease. PKU patients with the highest caries prevalence were those who got a delayed PKU diagnosis. PKU patients with the highest caries prevalence showed the least interest in regular visits to the dentist and oral hygienist, according to their questionnaires. In contrast, individuals who were diagnosed with PKU during neonatal screening and followed a low-protein diet properly were more likely to visit the dentist and dental hygienist regularly. Consequently, they had a better dental/ gingival health status.
Almost all PKU patients who participated in the current study required professional oral hygiene procedure. Additionally, they predominantly had a decreased basal salivary secretion rate. Evidence shows that PKU patients are at an increased risk of periodontal disease, and they should be informed about it. An effective way of increasing their awareness could be regular reminders from their healthcare professionals that regular dental visits are essential for maintaining optimal general and oral health. A timely diagnosis might be an important prerequisite to reduce the risk of periodontal disease development among PKU patients. PKU patients should visit the dentist regularly in order to ensure early diagnosis of caries and periodontal disease, and the dental hygienist every 3 to 6 months to prevent plaque and calculus build-up. Furthermore, they need to be recommended to rinse their mouth with water immediately after consuming PKU formula to counteract the acidity in their oral cavity.
Appendix 1.
The questionnaire contained inquiries about:
1. General health medical history.
2. Dental hygiene habits (frequency of tooth brushing, flossing, use of mouthwash and fluoride supplements).
3. Frequency of visits to the dentist and dental hygienist.
4. Overall satisfaction with their oral health.
5. Daily water intake.
6. Nutritional habits (frequency of meals, preferred foods at main mealtimes, snacking habits).
PKU patients additionally were asked about:
7. Their PKU diagnosis (at what age the diagnosis was established).
8. Their adherence to PKU diet (intake of Phe-free medical formula and other low-Phe foods, as well as how successfully patients are avoiding high-Phe foods).
9. Their current and usual plasma Phe concentrations.
Appendix 2. CPITN index of the PKU and healthy control group.
| Control group (n=45) | PKU patients (n=45) | |
|---|---|---|
| 0 (No present disease) | 20 | 1 |
| 44.4% | 2.2% | |
| 1 (Gingival bleeding on probing) | 14 | 12 |
| 31.1% | 26.7% | |
| 2 (Supragingival and/or subgingival calculus) | 9 | 13 |
| 20.0% | 28.9% | |
| 3 (Pathological pocket depth 4-5 mm) | 2 | 12 |
| 4.4% | 26.7% | |
| 4 (Pathological pocket depth >6mm) | 0 | 7 |
| 0.0% | 15.6% | |
| Total | 45 | 45 |
| 100.0% | 100.0% |
Appendix 3. Diagnosis time of PKU patients in association with risk of periodontal disease.
| Diagnosis | Total | |||
|---|---|---|---|---|
| Timely | Delayed | |||
| Risk of Periodontal disease | No | 24 | 2 | 26 |
| 68.6% | 20.0% | 57,8% | ||
| Yes | 11 | 8 | 19 | |
| 31.4% | 80.0% | 42,2% | ||
| Total | 35 | 10 | 45 | |
| 100,0% | 100.0% | 100.0% | ||
Appendix 4. CPITN, Silness & Löe, Greene-Vermillion index of the PKU and healthy control group.
_109-119-g1.jpg)
Appendix 5. Silness & Löe, Greene- Vermillion index of PKU and healthy control group.
| Characteristic | Control, N=451 | PKU, N=451 | p-value2 |
|---|---|---|---|
| Silness Löe index | <0.001 | ||
| 0 | 18 (40%) | 1 (2.2%) | |
| 1 | 17 (38%) | 14 (31%) | |
| 2 | 9 (20%) | 15 (33%) | |
| 3 | 1 (2.2%) | 15 (33%) | |
| Greene-Vermillion index | <0.001 | ||
| 0 | 19 (42%) | 3 (6.7%) | |
| 1 | 16 (36%) | 10 (22%) | |
| 2 | 10 (22%) | 16 (36%) | |
| 3 | 0 (0%) | 16 (36%) |
1n(%) 2Pearson's Chi-squared test
Footnotes
Conflict of interest:
The authors have reported no conflicts of interest.
References
- 1.Shah TJ, Baria D, Brahmbhatt S, Ramavataram DVSS. Management of phenylketonuria: Current and future perspectives. Indian J Forensic Med Toxicol. Published online 2021.
- 2.de Baulny HO, Abadie V, Feillet F, De Parscau L. Management of phenylketonuria and hyperphenylalaninemia. J Nutr. 2007. June;137(6) Suppl 1:1561S–3S, discussion 1573S–5S. 10.1093/jn/137.6.1561S [DOI] [PubMed] [Google Scholar]
- 3.ten Hoedt AE, De Sonneville LMJ, Francois B. High phenylalanine levels directly affect mood and sustained attention in adults with phenylketonuria: A randomised, double-blind, placebo-controlled, crossover trial. J Inherit Metab Dis. 2011. February;34(1):165–71. 10.1007/s10545-010-9253-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Hansen J, Hollander S, Drilias N, Van Calcar S, Rohr F, Bernstein L. Simplified diet for nutrition management of phenylketonuria: A survey of u.s. metabolic dietitians. JIMD Rep. 2020. April 8;53(1):83–9. 10.1002/jmd2.12106 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lingström P, Van Houte J, Kashket S. Food starches and dental caries. Crit Rev Oral Biol Med. 2000;11(3):366–80. 10.1177/10454411000110030601 [DOI] [PubMed] [Google Scholar]
- 6.Chapple ILC, Bouchard P, Cagetti MG. Interaction of lifestyle, behaviour or systemic diseases with dental caries and periodontal diseases: consensus report of group 2 of the joint EFP/ORCA workshop on the boundaries between caries and periodontal diseases. J Clin Periodontol. 2017. March;44 Suppl 18:S39–51. 10.1111/jcpe.12685 [DOI] [PubMed] [Google Scholar]
- 7.Quappe L, Jara L, López NJ. Association of Interleukin-1 Polymorphisms With Aggressive Periodontitis. J Periodontol. 2004. November;75(11):1509–15. 10.1902/jop.2004.75.11.1509 [DOI] [PubMed] [Google Scholar]
- 8.Chatzopoulos GS, Doufexi AE, Zarenti S, Anastasopoulos M, Kouvatsi A. Interleukin-6 and interleukin-10 gene polymorphisms in patients with chronic periodontitis and response to treatment after 3 years. Acta Stomatol Croat. 2020. September;54(3):238–49. 10.15644/asc54/3/2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Ericsson JS, Abrahamsson KH, Östberg AL, Hellström MK, Jönsson K, Wennström JL. Periodontal health status in Swedish adolescents: An epidemiological, cross-sectional study. Swed Dent J. 2009;33(3):131–9. [PubMed] [Google Scholar]
- 10.Musić L, Par M, Peručić J, Badovinac A, Plančak D, Puhar I. Relationship between halitosis and periodontitis: A pilot study. Acta Stomatol Croat. 2021. June;55(2):198–206. 10.15644/asc55/2/9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Dawes C, Wong DTW. Role of Saliva and Salivary Diagnostics in the Advancement of Oral Health. J Dent Res. Published online 2019. 10.1177/0022034518816961 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kilpatrick NM, Awang H, Wilcken B, Christodoulou J. The implications of Phenylketonuria on oral health. Pediatr Dent. 1999. November-December;21(7):433–7. [PubMed] [Google Scholar]
- 13.Ballikaya E, Yildiz Y, Sivri HS. Oral health status of children with phenylketonuria. J Pediatr Endocrinol Metab. J Pediatr Endocrinol Metab. 2020. March 26;33(3):361–5. 10.1515/jpem-2019-0439 [DOI] [PubMed] [Google Scholar]
- 14.da Costa Silveira A, Prado LC, Do Socorro Corrêa Dos Santos Pires E. Evaluation of oral health status in children with phenylketonuria. J Pediatr Endocrinol Metab. 2020. March 26;33(3):361–5. 10.1515/jpem-2019-0439 [DOI] [PubMed] [Google Scholar]
- 15.Singh-Hüsgen P, Meissner T, Bizhang M, Henrich B, Raab WHM. Investigation of the oral status and microorganisms in children with phenylketonuria and type 1 diabetes. Clin Oral Investig. 2016. May;20(4):841–7. 10.1007/s00784-015-1564-7 [DOI] [PubMed] [Google Scholar]
- 16.Shimazaki Y, Fu B, Yonemoto K. Stimulated salivary flow rate and oral health status. J Oral Sci. 2017. March 31;59(1):55–62. 10.2334/josnusd.16-0372 [DOI] [PubMed] [Google Scholar]
- 17.Dodds MWJ, Johnson DA, Yeh CK. Health benefits of saliva: A review. J Dent. 2005. March;33(3):223–33. 10.1016/j.jdent.2004.10.009 [DOI] [PubMed] [Google Scholar]
- 18.Lucas VS, Contreras A, Loukissa M, Roberts GJ. Dental disease indices and caries related oral microflora in children with phenylketonuria. ASDC J Dent Child. Jul-Aug 2001;68(4):263-7, 229. [PubMed]
- 19.Benigeri M, Brodeur JM, Payette M, Charbonneau A, Ismaïl AI. Community Periodontal Index of Treatment Needs and prevalence of periodontal conditions. J Clin Periodontol. 2000;••• 10.1034/j.1600-051x.2000.027005308.x [DOI] [PubMed] [Google Scholar]
- 20.Yu N, Van Dyke TE. Periodontitis: a Host-Mediated Disruption of Microbial Homeostasis. Curr Oral Health Rep. 2020. March;7(1):3–11. 10.1007/s40496-020-00256-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Bosma-den Boer MM, Van Wetten ML, Pruimboom L. Chronic inflammatory diseases are stimulated by current lifestyle: How diet, stress levels and medication prevent our body from recovering. Nutr Metab (Lond). 2012;••• 10.1186/1743-7075-9-32 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Kim HS, Park JW, Yeo S. Il, Choi BJ, Suh JY. Effects of high glucose on cellular activity of periodontal ligament cells in vitro. Odontology. 2017. January;105(1):76–83. 10.1007/s10266-016-0235-8 [DOI] [PubMed] [Google Scholar]
- 23.Van der Velden U, Kuzmanova D, Chapple ILC. Micronutritional approaches to periodontal therapy. J Clin Periodontol. 2011. March;38 Suppl 11:142–58. 10.1111/j.1600-051X.2010.01663.x [DOI] [PubMed] [Google Scholar]
- 24.Woelber JP, Bremer K, Vach K. An oral health optimized diet can reduce gingival and periodontal inflammation in humans - a randomized controlled pilot study. BMC Oral Health. 2016. July 26;17(1):28. 10.1186/s12903-016-0257-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Amaliya, Timmerman MF, Abbas F. Java project on periodontal diseases: The relationship between vitamin C and the severity of periodontitis. J Clin Periodontol. 2007. April;34(4):299–304. 10.1111/j.1600-051X.2007.01053.x [DOI] [PubMed] [Google Scholar]
- 26.Amaliya A, Laine ML, Loos BG, Van Der Velden U. Java project on periodontal diseases: Effect of vitamin C/calcium threonate/citrus flavonoids supplementation on periodontal pathogens, CRP and HbA1c. J Clin Periodontol. 2015. December;42(12):1097–104. 10.1111/jcpe.12478 [DOI] [PubMed] [Google Scholar]
- 27.Koletzko B, Beblo S, Demmelmair H, Hanebutt FL. Omega-3 LC-PUFA supply and neurological outcomes in children with phenylketonuria (PKU). J Pediatr Gastroenterol Nutr. 2009. March;48 Suppl 1:S2–7. 10.1097/MPG.0b013e3181977399 [DOI] [PubMed] [Google Scholar]
- 28.Bosdet T, Branov J, Selvage C, Yousefi M, Sirrs S. Diet history is a reliable predictor of suboptimal docosahexaenoic acid levels in adult patients with phenylketonuria. JIMD Rep. 2015;21:97–102. 10.1007/8904_2014_399 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Color Atlas of Dental Hygiene : Periodontology; 2014.
- 30.Petersen PE, Ogawa H. The global burden of periodontal disease: Towards integration with chronic disease prevention and control. Periodontol 2000. 2012. October;60(1):15–39. 10.1111/j.1600-0757.2011.00425.x [DOI] [PubMed] [Google Scholar]
- 31.Forbes-Haley C, Jones SB, Davies M, West NX. Establishing the effect of brushing and a day’s diet on tooth tissue loss in vitro. Dent J (Basel). 2016. August 9;4(3):25. 10.3390/dj4030025 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Bendoraitienė E, Zūbienė J, Vasiliauskienė I. Periodontal status in 18-year-old Lithuanian adolescents: An epidemiological study. Medicina (Kaunas). 2017;53(4):253–8. 10.1016/j.medici.2017.06.002 [DOI] [PubMed] [Google Scholar]
- 33.Moursi AM, Fernandez JB, Daronch M, Zee L, Jones CL. Nutrition and oral health considerations in children with special health care needs: Implications for oral health care providers. Pediatr Dent. 2010. July-August;32(4):333–42. [PubMed] [Google Scholar]
- 34.Castro IPS, Borges JM, Chagas HA, Tibúrcio J, Starling ALP, De Aguiar MJB. Relationships between phenylalanine levels, intelligence and socioeconomic status of patients with phenylketonuria. J Pediatr (Rio J). 2012. July;88(4):353–6. 10.2223/JPED.2175 [DOI] [PubMed] [Google Scholar]
- 35.Cazzorla C, Bensi G, Biasucci G. Living with phenylketonuria in adulthood: The PKU ATTITUDE study. Mol Genet Metab Rep. 2018. July 11;16:39–45. 10.1016/j.ymgmr.2018.06.007 [DOI] [PMC free article] [PubMed] [Google Scholar]