Salivary secretion in health and disease.

Saliva is a complex fluid produced by 3 pairs of major salivary glands and by hundreds of minor salivary glands. It comprises a large variety of constituents and physicochemical properties, which are important for the maintenance of oral health. Saliva not only protects the teeth and the oropharyngeal mucosa, it also facilitates articulation of speech, and is imperative for mastication and swallowing. Furthermore, saliva plays an important role in maintaining a balanced microbiota. Thus, the multiple functions provided by saliva are essential for proper protection and functioning of the body as a whole and for the general health. A large number of diseases and medications can affect salivary secretion through different mechanisms, leading to salivary gland dysfunction and associated oral problems, including xerostomia, dental caries and fungal infections. The first part of this review article provides an updated insight into our understanding of salivary gland structure, the neural regulation of salivary gland secretion, the mechanisms underlying the formation of saliva, the various functions of saliva and factors that influence salivary secretion under normal physiological conditions. The second part focuses on how various diseases and medical treatment including commonly prescribed medications and cancer therapies can affect salivary gland structure and function. We also provide a brief insight into how to diagnose salivary gland dysfunction.

[Medicaments and oral healthcare. Systematic review of the -literature assessing the effect of drugs on the salivary glands]. / Serie: Medicamenten en mondzorg.Systematisch literatuuronderzoek naar effect van medicatie op de speekselklieren.

Evidence-based reviews of drugs causing medication-induced salivary gland dysfunction, such as xerostomia (sensation of oral dryness) and subjective sialorrhea are lacking. To compile a list of medicaments that influence salivary gland function, electronic databases were searched for relevant articles published up to June 2013. A total of 269 papers out of 3,867 records located satisfied the inclusion criteria (relevance, quality of methodology, strength of evidence). A total of 56 active substances with a higher level of evidence and 50 active substances with a moderate level of evidence of causing salivary gland dysfunction are described in this article. While xerostomia was a commonly reported outcome, the objective effect on salivary secretion was rarely measured. Xerostomia was, moreover, mostly reported as a negative side effect instead of the intended effect of that drug. A comprehensive list of medications having documented effects on salivary gland function or symptoms was compiled, which may assist practitioners in assessing patients who complain of dry mouth while taking medications.

Filaggrin gene mutations and the distribution of filaggrin in oral mucosa of patients with oral lichen planus and healthy controls.

BACKGROUND: Lichen planus (LP) is a chronic inflammatory disease of unknown aetiology affecting the skin and oral mucosa. Oral lichenoid lesions (OLLs), like oral contact reactions, may resemble oral lichen planus (OLP) both clinically and histopathologically. As OLP and OLL are hyperkeratotic diseases and filaggrin is essential to keratinization, the distribution of filaggrin may be altered in these lesions. OBJECTIVES: To investigate whether patients with OLP/OLL have (i) altered distribution of filaggrin in the oral mucosa; (ii) a higher incidence of mutations in the filaggrin gene (FLG); (iii) active dermatoses, apart from cutaneous LP, than healthy controls; and (iv) patients with OLP/OLL and a defect in the FLG have more widespread oral lesions and report more symptoms than OLP/OLL patients without a concomitant defect in the FLG. METHODS: Forty-nine Caucasian patients (42 women and 7 men, mean age 61.0 ± 10.3 years), with symptomatic OLP, OLL or stomatitis, and 29 matched healthy controls underwent a clinical oral and dermatological examination, oral mucosal biopsy and filaggrin genotyping (testing for R2447X, R501X, 2282del4). Smear tests for Candida spp. were performed in all patients to exclude oral candidiasis. Immunohistochemistry were performed using poly- and monoclonal filaggrin antibodies. RESULTS: The immunoreactivity for filaggrin was significantly more intense in the oral mucosa in the patients with OLP/OLL compared with healthy controls (P = 0.000025). No difference was noted in the incidence of defects in the FLG and active dermatoses between patients and healthy controls. No difference was noted in extension and number of symptoms reported by patients with OLP/OLL with or without a concomitant defect in the FLG. CONCLUSION: OLP/OLL is associated with an altered distribution of filaggrin in the oral mucosa independently of defects in the FLG. Patients with OLP/OLL did not display more active dermatoses other than cutaneous LP when compared to healthy controls.

Symptomatic oral lesions may be associated with contact allergy to substances in oral hygiene products.

OBJECTIVE: Dental materials and oral hygiene products may be responsible for oral contact allergic reactions. We aimed to determine the occurrence of allergies in patients with symptomatic oral lichen planus (OLP), oral lichenoid lesions (OLLs) and stomatitis and investigate if patch testing could identify contact allergies to dental materials and oral hygiene products in these patients. METHODS: Forty-nine patients (7 men, 42 women) aged 31 to 77 years (61 ± 10.3 years) with symptomatic OLP, OLL or stomatitis and 29 healthy age- and gender-matched control subjects were included. They underwent an interview, clinical examination, oral mucosal biopsy and epicutan testing to the European baseline series, a toothpaste and dental material series. RESULTS: Nineteen patients had OLP, 19 OLL and 11stomatitis. Oral burning/itching was the most common symptom (83.7%), and 65.3% patients had more than one symptom. Patients visited their dentist more often than the healthy subjects and had statistically higher DMF-T and DMF-S scores. Nineteen patients (38.8%) and 10 healthy control subjects (34.5%) had allergic contact reactions primarily to fragrance ingredients. No differences could be found between OLP, OLL, stomatitis and healthy controls with regard to allergic contact reactions. However, contact allergy to aroma substances differed significantly between the patients and the healthy control subjects (p = 0.02). This type of contact allergy was most common in patients with OLP and OLL (p = 0.01). Avoidance cleared symptoms in all cases. CONCLUSION/CLINICAL RELEVANCE: Allergic reactions to aroma substances in oral hygiene products are common in patients with symptomatic OLP, OLL and stomatitis.

Oral health-related quality of life and complications after treatment with partial removable dental prosthesis.

The aims of this study were to measure and describe the oral health-related quality of life (OHRQoL) and to identify the complications caused by partial removable dental prosthesis (RDPs) in patients 1-5 years after treatment. Complications were identified in 65 patients who were treated with 83 RDPs (48 upper, 35 lower). OHRQoL was measured using the OHIP-49 before treatment and at the baseline (1-2 months after treatment) and follow-up (1-5 years after treatment) examinations. The types and numbers of oral problems that were experienced were described based on OHIP items with a score of 3 and 4. A significant improvement (P < 0·05) in the total OHIP-49 was registered from pre-treatment (mean 42, SD ± 37) to baseline (mean 29, SD ± 27) and from pre-treatment to 1-5 years after treatment (mean 32, SD ± 30). There was no significant difference between the baseline and 1- to 5-year follow-up examinations. Problems with eating and appearance registered at pre-treatment were improved at baseline and after 1-5 years. Problems with dentures that had been registered pre-treatment were improved at baseline but reoccurred after 1-5 years. The two most frequent complications were ill-fitting RDPs and inflammation of the oral mucosa, followed less frequently by fractures of the clasps. Treatment with RDPs improved OHRQoL, but denture-related problems partly remained, and new problems related to RDPs occurred 1-5 years after treatment. The two most frequent complications were ill-fitting RDPs and inflammation of the oral mucosa.

National, clinical cohort study of late effects among survivors of acute lymphoblastic leukaemia: the ALL-STAR study protocol.

INTRODUCTION: More than 90% of patients diagnosed with childhood acute lymphoblastic leukaemia (ALL) today will survive. However, half of the survivors are expected to experience therapy-related chronic or late occurring adverse effects, reducing quality of life. Insight into underlying risk trajectories is warranted. The aim of this study is to establish a Nordic, national childhood ALL survivor cohort, to be investigated for the total somatic and psychosocial treatment-related burden as well as associated risk factors, allowing subsequent linkage to nation-wide public health registers. METHODS AND ANALYSIS: This population-based observational cohort study includes clinical follow-up of a retrospective childhood ALL survivor cohort (n=475), treated according to a common Nordic ALL protocol during 2008-2018 in Denmark. The study includes matched controls. Primary endpoints are the cumulative incidence and cumulative burden of 197 health conditions, assessed through self-report and proxy-report questionnaires, medical chart validation, and clinical examinations. Secondary endpoints include organ-specific outcome, including cardiovascular and pulmonary function, physical performance, neuropathy, metabolic disturbances, hepatic and pancreatic function, bone health, oral and dental health, kidney function, puberty and fertility, fatigue, and psychosocial outcome. Therapy exposure, acute toxicities, and host genome variants are explored as risk factors. ETHICS AND DISSEMINATION: The study is approved by the Regional Ethics Committee for the Capital Region in Denmark (H-18035090/H-20006359) and by the Danish Data Protection Agency (VD-2018-519). Results will be published in peer-reviewed journals and are expected to guide interventions that will ameliorate the burden of therapy without compromising the chance of cure.

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life.

PURPOSE: This systematic review aimed to assess the literature for prevalence, severity, and impact on quality of life of salivary gland hypofunction and xerostomia induced by cancer therapies. METHODS: The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. Two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results and conclusions for each article. RESULTS: The inclusion criteria were met by 184 articles covering salivary gland hypofunction and xerostomia induced by conventional, 3D conformal radiotherapy or intensity-modulated radiotherapy in head and neck cancer patients, cancer chemotherapy, total body irradiation/hematopoietic stem cell transplantation, radioactive iodine treatment, and immunotherapy. CONCLUSIONS: Salivary gland hypofunction and xerostomia are induced by radiotherapy in the head and neck region depending on the cumulative radiation dose to the gland tissue. Treatment focus should be on optimized/new approaches to further reduce the dose to the parotids, and particularly submandibular and minor salivary glands, as these glands are major contributors to moistening of oral tissues. Other cancer treatments also induce salivary gland hypofunction, although to a lesser severity, and in the case of chemotherapy and immunotherapy, the adverse effect is temporary. Fields of sparse literature included pediatric cancer populations, cancer chemotherapy, radioactive iodine treatment, total body irradiation/hematopoietic stem cell transplantation, and immunotherapy.

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact.

PURPOSE: This systematic review aimed to assess the literature for management strategies and economic impact of salivary gland hypofunction and xerostomia induced by cancer therapies and to determine the quality of evidence-based management recommendations. METHODS: The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. For each article, two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results, and conclusions. RESULTS: Seventy-two interventional studies met the inclusion criteria. In addition, 49 intensity-modulated radiation therapy (IMRT) studies were included as a management strategy aiming for less salivary gland damage. Management guideline recommendations were drawn up for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. CONCLUSIONS: There is evidence that salivary gland hypofunction and xerostomia induced by cancer therapies can be prevented or symptoms be minimized to some degree, depending on the type of cancer treatment. Management guideline recommendations are provided for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. Fields of sparse literature identified included effects of gustatory and masticatory stimulation, specific oral mucosal lubricant formulas, submandibular gland transfer, acupuncture, hyperbaric oxygen treatment, management strategies in pediatric cancer populations, and the economic consequences of salivary gland hypofunction and xerostomia.

Polymorphic drug metabolizing CYP-enzymes--a pathogenic factor in oral lichen planus?

BACKGROUND: Oral lichen planus (OLP) is a chronic mucosal disease with a characteristic clinical phenotype. Environmental exposures, e.g. drugs have been associated with the pathogenesis. OBJECTIVES: To test the hypothesis that some OLP lesions have a pharmacological pathogenesis related to polymorphisms of the cytochrome P450 enzymes (CYPs) resulting in poor or intermediate CYP metabolism. METHODS: One hundred and twenty patients with OLP and 180 gender-matched controls without OLP were genotyped for CYP2C9, CYP2C19, and CYP2D6 alleles with absent or reduced function. RESULTS: The prevalence of poor or intermediate metabolizers was not higher among the OLPs as compared with the controls; however, there were higher numbers of variant CYP2D6 genotypes among the OLP females (P < 0.05). There were no differences between the groups with regard to intake of drugs metabolized by polymorphic CYPs or drug or herbal products inhibiting CYPs. The prevalence of CYP2D6*4 alleles among the OLPs was higher [28%; 95% confidence interval (CI) 20-36%] than previously reported among Danes (19%; 95% CI 17-22%). Fifty per cent of the OLPs had a CYP2D6*4 genotype as compared with 30% in the background population (P = 0.0001). The CYP2D6*4 protein has sequence homology with human herpes simplex virus type 1 (HSV1) and Candida albicans, which may result in molecular mimicry. CONCLUSION: It was not possible to substantiate a pharmacological pathogenesis of OLP based on poor or intermediate CYP metabolism. However, molecular mimicry between CYP2D6, in particular CYP2D6*4, and common oral pathogens may be involved in the pathogenesis of OLP.

Gingival health status in individuals using different types of toothpaste.

OBJECTIVES: To examine the relationship between the medium term use (>1 year) of a toothpaste containing natural enzymes and proteins (Zendium™) upon gingival index, plaque index and bleeding index compared to medium term use of toothpastes without antimicrobial/antiinflammatory ingredients. METHODS: A total of 305 participants eligible for inclusion were grouped according to their toothpaste use and matched with regard to gender and age (18-30, 31-55 and 56+ years of age). A total of 161 persons were using a toothpaste which contained enzymes and proteins (Zendium™, test group), and 144 persons were using a toothpaste without these ingredients (control group). The amount of dental plaque and the gingival condition were assessed at six sites of each tooth using the modified gingival index (MGI), plaque index (Modified Quigley and Hein plaque index, PI), and bleeding index (BI). Mean values of MGI, PI and BI were compared using analysis of covariance. RESULTS: The test group had significantly less gingival inflammation than the control group (adjusted mean scores (SD); 1.80 (0.65) vs. 2.27 (0.63),p < 0.0001), as well as lower levels of plaque (2.03 (0.33) vs. 2.12 (0.33), p = 0.0168) and gingival bleeding (0.74 (0.45) vs. 1.08 (0.45), p < 0.0001). Females had significantly less gingival inflammation (p < 0.0001), plaque (p = 0.0005) and bleeding (p = 0.0118) than males. Participants aged 18-30 years had significantly higher levels of inflammation and bleeding than the older age groups (p < 0.001), and also higher plaque levels compared to participants aged 31-55 years (p = 0.0069). Potential confounding factors including oral hygiene practices and consistency of dental visits did not differ between groups. CONCLUSIONS: Our findings indicate that medium term use of fluoride toothpaste containing enzymes and proteins (Zendium™) is associated with a better gingival health than the use of other types of fluoride toothpastes without antimicrobial active ingredients. CLINICAL SIGNIFICANCE: Medium term (> 1 year) use of toothpaste containing naturally occurring enzymes and proteins (Zendium™) in an unsupervised home setting is associated with better gingival health compared to the unsupervised use of other commercially available toothpastes without antimicrobial/antiinflammatory active ingredients.

Expression of two drug-metabolizing cytochrome P450-enzymes in human salivary glands.

OBJECTIVE: The oral cavity is constantly lubricated by saliva and even small amounts of xenobiotics and / or their metabolites in the saliva may affect the oral mucosa. Our aim was therefore to clarify if xenobiotic metabolizing enzymes CYP1A2 and CYP3A4 are expressed in salivary glands. METHODS: Formalin-fixed paraffin-embedded specimens from parotid (10), submandibular (7) and labial (10) salivary glands were examined immunohistochemically and by in situ hybridization for expression of CYP1A2 and CYP3A4 protein and mRNA. RESULTS: CYP1A2 and CYP3A4 protein and mRNA were detected in ductal and seromucous / serous acinar cells in all gland types although to a varying degree and intensity. Mucous acinar cells were positive to a lesser extent. CONCLUSION: The results indicate a xenobiotic metabolizing capability of salivary glands. This may have implications for development of oral mucosal disease as a result of mucosal exposure to metabolites originating from internal sources (blood) as well as from saliva.

The oral microbiome - an update for oral healthcare professionals.

For millions of years, our resident microbes have coevolved and coexisted with us in a mostly harmonious symbiotic relationship. We are not distinct entities from our microbiome, but together we form a 'superorganism' or holobiont, with the microbiome playing a significant role in our physiology and health. The mouth houses the second most diverse microbial community in the body, harbouring over 700 species of bacteria that colonise the hard surfaces of teeth and the soft tissues of the oral mucosa. Through recent advances in technology, we have started to unravel the complexities of the oral microbiome and gained new insights into its role during both health and disease. Perturbations of the oral microbiome through modern-day lifestyles can have detrimental consequences for our general and oral health. In dysbiosis, the finely-tuned equilibrium of the oral ecosystem is disrupted, allowing disease-promoting bacteria to manifest and cause conditions such as caries, gingivitis and periodontitis. For practitioners and patients alike, promoting a balanced microbiome is therefore important to effectively maintain or restore oral health. This article aims to give an update on our current knowledge of the oral microbiome in health and disease and to discuss implications for modern-day oral healthcare.

The functions of human saliva: A review sponsored by the World Workshop on Oral Medicine VI.

This narrative review of the functions of saliva was conducted in the PubMed, Embase and Web of Science databases. Additional references relevant to the topic were used, as our key words did not generate references which covered all known functions of saliva. These functions include maintaining a moist oral mucosa which is less susceptible to abrasion, and removal of micro-organisms, desquamated epithelial cells, leucocytes and food debris by swallowing. The mucins form a slimy coating on all surfaces in the mouth and act as a lubricant during such processes as mastication, formation of a food bolus, swallowing and speaking. Saliva provides the fluid in which solid tastants may dissolve and distributes tastants around the mouth to the locations of the taste buds. The hypotonic unstimulated saliva facilitates taste recognition. Salivary amylase is involved in digestion of starches. Saliva acts as a buffer to protect oral, pharyngeal and oesophageal mucosae from orally ingested acid or acid regurgitated from the stomach. Saliva protects the teeth against acid by contributing to the acquired enamel pellicle, which forms a renewable lubricant between opposing tooth surfaces, by being supersaturated with respect to tooth mineral, by containing bicarbonate as a buffer and urea and by facilitating clearance of acidic materials from the mouth. Saliva contains many antibacterial, antiviral and antifungal agents which modulate the oral microbial flora in different ways. Saliva also facilitates the healing of oral wounds. Clearly, saliva has many functions which are needed for proper protection and functioning of the human body.

Associations between oral and ocular dryness, labial and whole salivary flow rates, systemic diseases and medications in a sample of older people.

OBJECTIVE: To investigate the associations between age, gender, systemic diseases, medications, labial and whole salivary flow rates and oral and ocular dryness in older people. METHODS: Symptoms of oral and ocular dryness, systemic diseases, medications (coded according to the Anatomical therapeutic chemical (ATC) classification system), tobacco and alcohol consumption were registered, and unstimulated labial (LS) and unstimulated (UWS) and chewing-stimulated (SWS) whole salivary flow rates were measured in 668 randomly selected community-dwelling elderly aged 65-95. RESULTS: Presence of oral (12%) and ocular (11%) dryness was positively correlated. Oral dryness was associated with low UWS, SWS and LS, and ocular dryness with low UWS and SWS. Oral and ocular dryness was related to female gender, but not to age. Only four persons in the healthy and nonmedicated subgroups reported oral and ocular dryness. The numbers of diseases and medications were higher in the older age groups and associated with oral and ocular dryness, low UWS, SWS and LS. On average, women were slightly older, reported more oral and ocular dryness and had lower UWS, SWS, LS and higher numbers of diseases and medications. High prevalence and odds ratios for oral dryness were associated with metabolic, respiratory and neurological diseases and intake of thyroid hormones, respiratory agents (primarily glucocorticoids), psycholeptics and/or psychoanaleptics, antineoplastics, proton pump inhibitors, antidiabetics, loop diuretics, antispasmodics, quinine and bisphosphonates. Ocular dryness was especially associated with neurological diseases and intake of psycholeptics and/or psychoanaleptics. Intake of magnesium hydroxide, antithrombotics, cardiac agents, thiazides, beta-blockers, calcium channel blockers, ACE inhibitors/angiotensin II antagonists, statins, glucosamine, paracetamol/opioids, ophthalmologicals and certain combination therapies was related to oral and ocular dryness. CONCLUSIONS: In older people, oral and ocular dryness are associated with low salivary flow rates, specific as well as high number of diseases and medications, but neither with age and gender per se nor with tobacco and alcohol consumption. New detailed information concerning associations between medications and oral and ocular dryness has been obtained using the ATC classification system.

The use of acupuncture in controlling the gag reflex in patients requiring an upper alginate impression: an audit.

BACKGROUND: A pronounced gag reflex (GR) can be a problem to both the acceptance and delivery of dental treatment. Despite a range of management strategies, some patients cannot accept even simple dental treatment. The aim of this study was to evaluate the use of acupuncture point CV-24 in controlling a profound gag reflex during dental treatment requiring an upper alginate impression. METHOD: Members of the British Dental Acupuncture Society were invited to take part in an audit of the role of acupuncture point CV-24 in controlling the gag reflex. They were issued with patient inclusion criteria, a standardised procedure instruction sheet and a recording form. All patients fulfilling the inclusion criteria had an upper dental alginate impression taken (or an attempt made at it) before acupuncture, and a second upper alginate impression taken immediately after acupuncture of point CV-24. The GR assessment was undertaken prior to insertion of the acupuncture needle using the Gagging Severity Index (GSI); and after the acupuncture and impression taking using the Gagging Prevention Index (GPI). Both the GSI and GPI were recorded at three stages of the dental impression taking procedure, ie, when the empty impression tray was tried in the mouth, when the loaded tray was inserted into the mouth, and on completion of the impression taking. RESULTS: Twenty-one dentists submitted 64 case reports of which 37 fulfilled the inclusion criteria. Prior to acupuncture all 37 patients (20 females and 17 males with a mean age of 46.8 years) were unable to accept the impression taking. After acupuncture of point CV-24, an improvement of between 51-55% (mean 53%) for the three stages of impression taking was noticed. Thirty patients (81%) were able to accept the impression taking, whereas seven (19%) remained unable to tolerate the procedure. Assessed by the GSI and GPI, there was a significant decrease in GR scores at all three stages of the impression taking procedure (median 3 vs 1; 4 vs 2; 4 vs 2; p < 0.0001). Thus before acupuncture, the patients had moderate to severe GR and after acupuncture the GR had reduced to a level which only complicated dental treatment slightly. CONCLUSION: Our results indicate that acupuncture of point CV-24 is an effective method of controlling severe GR during dental treatment including impression taking. However, the results of the current audit need to be tested in a randomised controlled study in order to substantiate the effectiveness of this method.