Etiologic Factors of Hyposalivation and Consequences for Oral Health

QUINTESSENCE INTERNATIONAL

Etiologic factors of hyposalivation and consequences for oral health

Peter Tschoppe, Dr Med Dent1/Michael Wolgin, Dr Med Dent2/ Nicole Pischon, Dr Med Dent Habil2/ Andrej M. Kielbassa, Dr Med Dent Habil3

Hyposalivation is represented by a reduced salivary flow rate and can be caused by etiologic factors such as systemic diseases and intake of various medications or by radiotherapy following head and neck cancer. The aim of this review was to compile data about the qualitative and quantitative changes of salivary components during hyposalivation, and to summarize their consequences for oral health. A Medline/PubMed/Scopus search was con- ducted to identify and summarize articles published in English and German that reported on etiology of hyposalivation and changes in the salivary composition due to hyposalivation of different origins. The search revealed 94 articles, 71 of which were original articles. Apart from the reduction of the salivary flow rate, the quality of saliva is strongly altered because of systemic diseases, medications, and radiotherapy, including increased viscosity and pH shift to more acidic values and changes in salivary protein compositions. Furthermore, hypo - salivation may be accompanied by pronounced shifts in specific microbial components, in particular toward a highly acidogenic microflora. Moreover, therapy of hyposalivation is often restricted to palliative treatment (ie, saliva substitutes or gels). To prevent tooth tissue de - mineralization, clinicians should consider saliva substitutes that are supersaturated with calcium and phosphates and contain fluoride. (Quintessence Int 2010;41:321–333)

Key words: caries, drugs, hyposalivation, microflora, periodontitis, radiotherapy, saliva substitutes, Sjögren syndrome, xerostomia

Physiologic amounts of salivary secretion are tion.2 Furthermore, this fluid is implicated in a essential for oral health.1 Saliva influences wide variety of digestive events including various events in the oral cavity such as lubrication of mucosa, bolus formation, and caries protective, digestive, and immunologic enzymatic digestion of food.3 Saliva’s protec- processes. The ability to promote remineral- tive role to the human organism is exhibited ization and to reduce demineralization by delivering antimicrobial peptides and pro- makes saliva a major player in caries protec- teins to the oral epithelium.4 Saliva is predominately secreted from three major paired salivary glands: parotid, sublingual, and submandibular (in all, about 1Assistant Professor, Department of Operative Dentistry and 90% of the total saliva production).3 In addi- Periodontology, CharitéCentrum 3, University School for Dental Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany. tion, hundreds of minor salivary glands (eg,

2Lecturer, Department of Operative Dentistry and Periodon - buccal, labial, palatal), which are spread over tology, CharitéCentrum 3, University School for Dental all parts of the oral mucosa, contribute to Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany. secretion of saliva. Regulation of salivary 3Professor and Head, Department of Operative Dentistry and secretion is reflex controlled by both the sym- Periodontology, CharitéCentrum 3, University School for Dental pathetic and parasympathetic divisions of Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany. the autonomic nervous system.5 The impuls- Correspondence: Dr Michael Wolgin, Abteilung für Zahnerhaltungskunde und Parodontologie, CharitéCentrum 3 es, induced by action of gustation, mastica- für Zahn-, Mund- und Kieferheilkunde, Charité- tion, or smell are forwarded from afferent Universitätsmedizin Berlin, Assmannshauser Strasse 4-6, 14197 receptors to the salivary nuclei (salivation Berlin, Deutschland. Fax: 49 30 450 562 932. Email: michael. 3 [email protected] center) in the medulla oblongata. The

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amounts of organic nonprotein compounds Table 1 Reference points for unstimulated (UWS) and stimulated (SWS) whole saliva in such as uric, amino, or fatty acids, and glu- adults7,9 cose can be also detected in saliva.7 More than 309 proteins, which include acidic and UWS SWS basic proline-rich proteins, amylase, high- Hypersalivation > 1.0 mL/min > 3.5 mL/min and low-molecular-weight glycoproteins, Normal salivation 0.1–1.0 mL/min 0.5–3.5 mL/min agglutinin, cystatins, histatins and statherin, Hyposalivation < 0.1 mL/min < 0.5 mL/min could be identified in saliva.10 Salivary proteins have a wide range of functional proper- ties. Different groups of saliva proteins take part in immunologic reactions (lysozyme, parasympathetic and sympathetic nerve lactoferrin, lactoperoxidase, immu no globulin, bundles, which separately innervate the sali- defensin),7,11–13 taste perception (carbonic vary glands, form the efferent part of the anhydrase),7 digestion (amylase),7 and many secretory reflex arch by using acetylcholine other processes in the oral cavity. Saliva con- as neurotransmitter.5 tains steroid; nonsteroid; protein; and peptide Saliva contains two major types of protein hormones, such as cortisol, testosterone, secretion: amylase-containing serous and progesterone, estradiol, and aldosterone.7 mucin-containing mucous secretion. The Numerous studies have shown correlations enzyme amylase takes part in initial diges- between serum and saliva levels of different tion, while mucin assists in lubrication and hormones.14–16 The measurement of salivary serves to protect oral surfaces. The physical hormones for diagnostic aims is a widely and chemical characteristics of saliva vary in accepted, noninvasive, and stress-free different salivary glands. The sublingual method compared to plasma and serum col- glands produce mucin-rich viscous saliva; in lection.7,16–18 contrast, the serous parotid glands secrete a The purpose of the present review is to watery, amylase-rich fluid.6 summarize what is known about the qualita- The daily secretion of saliva normally tive and quantitative changes of salivary com- ranges between 1.0 and 1.5 L at a rate of on ponents during hyposalivation and to dis- average 0.5 mL/min (normal salivation; Table cuss the possibilities of their rational therapy. 1).7 The decreased flow of saliva is termed hyposalivation (hypoptyalism), which can be caused by water/metabolite loss, damage of salivary glands and interference with neural DATA SOURCES transmission (see Table 1). Common reasons AND STUDY SELECTION of decreased salivary secretion could be chronic inflammation of the salivary glands, Sjögren A search of Medline/PubMed/Scopus data- syndrome, radiation treatment, dehydration, bases for articles written in English and psychologic factors, and medications.5,8 The German from March to May 2009 was per- increase of saliva is termed hypersalivation formed. The following primary key words/ (see Table 1). Hypersalivation has an phrases were used in the search strategy: unknown origin; however, hypersalivation was hyposalivation / dry mouth / xerostomia / described in patients with herpetic stomatitis, saliva composition / qualitative changes / aphthous stomatitis, ulcerative gingivitis, and quantitative changes / drugs / age / systemic those who wear dentures.9 diseases, disorders / Sjögren syndrome / The various components of saliva are Sicca syndrome / radiation, radiotherapy / organic and inorganic substances, proteins/ cariogenic microflora / periodontopathogen- poly peptides, hormones, and lipid mole- ic microflora / oral health. These terms were cules. Whole saliva is composed mostly of used alone or were combined with each water, which contains ions, such as sodium, other. A few older and/or basic references potassium, magnesium, calcium, chloride, were obtained by hand search and cross-ref- carbonate, and phosphate ions.7 Small erencing from the available literature.

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The authors examined the results returned by the Medline/PubMed/Scopus search to identify potentially relevant ication A ed ge abstracts. Publications that did not report M ? about etiology of hyposalivation or changes in salivary composition due to hyposalivation icho l Ant Deh of different origins were not further consid- a rgic y- t o line drati n th cts on e a c ffe N ered. Finally, 94 full-text articles were select- p ti e eu s m e r m y s o

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f v s i i l p o l t l t r h e a a e s a s t t g s i i a e y o c ETIOLOGY OF v f

n m p F a d o ib D o a p r lo n r a o b e HYPOSALIVATION Ir re si o r n s o n i h e ch f atio t t v ym Degener c o e a ells ru i rs of gland c t d ib es a Hyposalivation represents a reduced saliva le d R or temporary flow rate, and diagnosis of hyposalivation e can be made by means of saliva flow rate as ise measurements. The saliva flow rate varies ic d stem from person to person and is influenced by a Sy large number of factors, such as degree of hydration, body position, exposure to light, Fig 1 Various possible etiologic factors of hyposalivation. previous stimulation, circadian rhythms, or gland size.10 However, when the conditions during sampling of saliva are uniform, the flow is remarkably stable for every individual. Most investigators have used the measurements of unstimulated whole saliva (UWS) as crease in salivary flow rate of resting whole well as stimulated whole saliva (SWS) as cri- and stimulated parotid and submandibular teria to define hyposalivation or salivary gland saliva was reported,29,30 hyposalivation hypofunction.19 The reference values for seems to be caused secondary to various UWS and SWS secretion rates in adults are diseases or medications.5 depicted in Table 1. A variety of systemic diseases can be asso- Hyposalivation may be caused by different ciated with signs of hyposalivation (Table 2).5 etiologic factors (Fig 1). The developmental Autoimmune diseases such as Sjögren syn- causes of this symptom, such as aplasia or drome, AIDS, lupus erythematosus, rheuma- agenesis of salivary glands, are rare.20 toid arthritis, scleroderma, as well as hormonal Although considerable structural age-related (diabetes mellitus), neurologic (Parkinson dis- changes in salivary glands (loss of secretory ease), and psychogenic diseases (depression) epithelium) may occur,20 there is no strong evi- can irreversibly or temporarily cause a progres- dence that age is a significant cause of hypos- sive destruction of salivary glands.3,5,31 The rela- alivation.21 In contrast, the variety of systemic tionship between hypertension and salivary diseases, drugs, and particularly radiotherapy function is not clearly established. While sever- of malignancies in the head and neck seem to al authors described lower salivary flow rates in be significant factors of importance.22 hypertensive compared to normotensive Based on general clinical experience patients,32,33 other investigators found no signif- reduced salivary flow is common in the eld- icant differences among these groups.34,35 erly compared to the younger age groups.23 More than 400 medications have been However, as already mentioned, the aging reported to cause hyposalivation.36 The process itself does not seem to be the prevalence of hyposalivation is positively primary cause of reduced salivary flow related to the total number of xerogenic and rates.5,8,24–28 Although an age-related de- nonxerogenic drugs in rates of up to 82%.37

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Table 2 Diseases associated with signs In the American population 33% to 51.7% of of hyposalivation or xerostomia older individuals are taking at least one potentially xerogenic medication.38,39 Various Cause Diseases medications such as antidepressants may Chronic inflammatory • Sjögren syndrome cause hyposalivation because of their inter- autoimmune • Systemic lupus erythematosus ferences with transmission at the parasym- • Scleroderma pathetic neuroeffector junction.37,40,41 • Mixed connective tissue disease • Sarcoidosis However, the inhibition of salivation can also • Amyloidosis occur by action of drugs at higher centers of • Crohn disease the autonomic nervous system.5 The mecha- • Ulcerative colitis nism of the xerostomic effect of diuretics can Endocrine • Diabetes mellitus (labile) be explained by dehydration. Diuretics can • Hyper- and hypothyroidism • Cushing syndrome affect the transport of water and electrolytes • Addison disease through the cell membrane of salivary acinar Neurologic • Mental depression cells by causing vasoconstriction in salivary • Narcolepsy glands.5,37,40 In addition, drugs may produce • Parkinson disease mouth dryness without reducing salivary flow • Bell palsy • Alzheimer disease rates. Inhaler medications can cause sensa- • Holmes-Adie syndrome tions of oral dryness by topical effects.37,41 Genetic and congenital • Ectodermal dysplasia Table 3 lists drugs and chemicals with well- • Cystic fibrosis known potential to decrease salivary flow or • Prader-Willi syndrome to cause mouth dryness. Malnutrition • Eating disorders • Anorexia nervosa Salivary gland dysfunction and mouth dry- • Bulimia ness are serious adverse effects of radiother- • Anemia apy of head or neck cancer. Salivary glands, • Atrophic gastritis primarily parotid and to some lesser extent • Dehydration the submandibular, sublingual, and minor • Alcohol abuse Infections • HIV/AIDS glands, are extremely radiosensitive.42 • Epidemic parotitis However, the exact mechanism of hyposali- • Epstein-Barr virus vation development due to radiotherapy • Bacterial sialoadenitis remains to be elucidated. On the one hand, • Tuberculosis the ionization may have an immediate effect Other conditions • Hypertension • Fibromyalgia on the acinar cells of salivary glands42–44; on • Chronic fatigue syndrome the other hand, the radiation damage may be • Burning mouth syndrome caused by impairment and changes in struc- • Compromised masticatory performance ture of blood vessels or by interferences with nerve transmission.5,42 With low-dose ranges, damage seems to be reversible, although the tolerance dose for the parotid gland above which salivary gland function becomes irreversibly reduced is roughly 25 to 40 Gy,44 and with the usual cumulative tumoricidal dose of 60 to 70 Gy, an extensive degenera- tion of acini takes place.44 The occurrence of these etiologic factors leads to quantitative and qualitative changes of salivary components with increased viscosity, reduced buffering capacity, altered salivary electrolyte concentrations, and changed nonimmune and immune antibacterial system.44

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Table 3 Drugs with potential to cause hyposalivation or dry mouth

Action/medication group Medicaments Action/medication group Medicaments

Sympathomimetic Synergistic mechanism Antidepressants Venlafaxine Opioids, hypnotics Opium Duloxetine Cannabis Reboxetine Tramadol Bupropion Scopolamine Anticholinergic Diazepam Tricyclic antidepressants Amitriptyline Unknown Clomipramine H2 antagonists, proton pump Amoxicillin Amoxapine inhibitors Tetracycline Protriptyline Metronidazole Doxepin Omeprazole Imipramine Cytotoxic drugs Fluorouracil Trimipramine Anti-HIV drugs, protease Didanosine Nortriptyline inhibitors Desipramine Zimelidine Muscarinic receptor antagonists Oxybutynin Alpha-receptor antagonists Tamsulosin Terazosin Antipsychotics Promazine Triflupromazine Mesoridazine Thioridazine Clozapine Olanzapine Azatadine Brompheniramine Chlorpheniramine Cyproheptadine Dexchlopheniramine Hydroxyzine Phenindamine Antihistamines Azatadine Brompheniramine Chlorpheniramine Cyproheptadine Dexchlopheniramine Hydroxyzine Phenindamine Anticholinergic, dehydration Diuretics Furosemide Bumetanide Torsemide Ethacrynic acid Sympathomimetic Antihypertensive agents Metoprolol Monoxidine Rilmenedine Appetite suppressants Sibutramine Fenfluramine Phentermine Decongestants Pseudoephedrine Cetirizine Loratadine Bronchodilators Tiotropium Skeletal muscle relaxants Tizanidine Antimigraine agents Rizatriptain

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CHANGES OF SALIVARY kallikrein, cystatin, and albumin were report- COMPOSITION AS CONSE- ed to be higher in patients with Sjögren syn- QUENCE OF HYPOSALIVA- drome than in healthy subjects.12,50 TION CAUSED BY DIFFER- Furthermore, oral lactobacilli and yeast ENT ETIOLOGIC FACTORS counts seem to be significantly higher among patients with rheumatic diseases and The decrease of salivary secretion leads to Sjögren syndrome.51 Decreased saliva flow changes in composition of saliva. These rates may be favorable for multiplication of changes could promote plaque accumula- acidogenic microorganisms and yeasts.52,53 tion and increase the risk for caries, mucosal However, data are controversial since some and gingival infection, and inflammation.44 studies reported no difference in concentrations of acidogenic microorganisms and Changes of salivary composition yeasts in Sjögren syndrome compared to caused by systemic diseases healthy conditions.52–54 Sjögren syndrome is a chronic inflammatory Next to hyposalivation in rheumatic dis- autoimmune disorder that, next to xerosto- eases, diabetes mellitus is another example mia, is characterized by keratoconjunctivitis affecting saliva flow rates and composi- sicca. Sjögren syndrome is known to occur tions.55–57 Nevertheless, data about salivary with a variety of autoimmune diseases, such flow rates and compositions are controversial as rheumatoid arthritis, systemic lupus ery- and seem to depend on the type of saliva as thematosus, and primary biliary cirrhosis.45 well as the type of diabetes mellitus (insulin- The recently published European classifica- dependent or non-insulin-dependent).55–57 tion suggests that at least four out of six cri- Further more, decreased salivary flow rates teria (subjective oral and ocular symptoms, and pH values as well as impaired salivary keratoconjunctivitis sicca, focal sialadenitis gland function were reported in type 1 as well on biopsy, instrumental evidence of salivary as in type 2 diabetes. Elevated levels of glu- gland involvement, and presence of autoanti- cose have been found in saliva57; moreover, bodies) are needed to define patients with higher potassium, calcium, and total protein primary Sjögren syndrome. Secondary concentrations were detected in patients with Sjögren syndrome is characterized by the diabetes.55,56 These findings might be due to presence of one of the two subjective symp- hyperaldosteronism or to impaired sodium- toms with at least two objective items of glan- potassium pump (Na+-K+-ATPase [adenosine dular dysfunction.46 triphosphatase]) activity leading to altered In patients with rheumatic diseases, transport of potassium in the salivary decreased secretion of saliva is often associ- glands.55 However, a former investigation ated with focal sialadenitis. An increased showed reduced salivary potassium concen- leukocyte infiltration of salivary glands can be trations in diabetic patients compared to observed in primary Sjögren syndrome47 with healthy age-matched controls as well as lymphocyte activation and autoantibody pro- decreased concentration of magnesium and duction (ie, antinuclear antibodies).48 In spite zinc,56 while the salivary concentrations of of normal potassium and phosphate con- innate antimicrobial defense factors, such as centrations of the saliva of patients with lysozyme, lactoferrin, and peroxidase obvi- Sjögren syndrome, the concentration of sodi- ously were not affected.57 In contrast, the sali- um and chloride was reported to be higher, vary concentrations of IgG and IgA were and the concentration of bicarbonate and, as found to be elevated in whole saliva of dia- a consequence, pH and buffer capacity betic patients.57 decreased compared to healthy subjects.49 In addition, it is widely accepted that high Also, an increased salivary concentration of salivary glucose levels in diabetic patients calcium and proteins is found with Sjögren favor oral yeast growth. The accumulation of syndrome.12,49 Proteins such as immunoglob- glycosylation products on the epithelial sur- ulin (Ig) A and IgG, lactoferrin, lysozyme, face may favor the adhesion of pathogens. It matrix metalloproteinase, ␤2-microglobulin, is likely that the decrease in salivary flow

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rates following diabetes in addition to Diuretics such as furosemide and ben- impaired immune response may enhance droflumethiazide demonstrate during chron- candidal colonization.58 In contrast, peri- ic treatment a pronounced effect on saliva odontal bacteria have not been shown to be composition, especially on sodium and elevated in the saliva among patients with chloride concentration in stimulated and diabetes.58 unstimulated saliva.63 Another group of anti- Several systemic diseases that primarily hypertensive drugs, angiotensin-converting do not impair the salivary flow rate can enzyme (ACE) inhibitors and calcium chan- indeed affect the composition of saliva and nel antagonists, seem to generate no incite oral pathologic processes. One exam- alterations in the salivary composition.64 In ple is celiac disease, where no changes in contrast, the concentrations of calcium, salivary secretion rates were evident but sig- phosphate, chloride, and magnesium were nificant elevation of total protein concentra- reported to be altered in saliva during active tion, such as albumin, IgG, IgA, as well as treatment periods with ␣-adrenoreceptor peroxidase, were found in saliva.59 antagonists (atenolol and propranolol).65 These results suggested that the ductal sodi- Influence of medication on saliva umand chloridetransport is controlled by the composition ␣-adrenoreceptor.65 The same study group One major group of medication affecting sali- also reported a decline of salivary total pro- va composition includes tricyclic antidepres- teins, decreased amylase activity, as well as sants, such as imipramine, which produce a changes of the calculated ratios of sialic significant decrease in saliva pH.60 Also, acid/hexosamine and hexosamine/total pro- imipramine and higher doses of zimelidine tein during treatment with ␣-adrenoreceptor produce an increase in buffer capacity, and antagonists.66 in sialic acids and hexoses.60 Contrary, no Additionally, significant increases in albu- qualitative changes in saliva composition are min secretion into saliva and salivary produced by lower doses of zimelidine (100 lysozyme, but significant decreases of total mg/day).60 No changes in the concentration salivary IgG, IgA, and IgM concentrations, of sodium, potassium, calcium, phosphate, were observed during cancer therapy with and protein were reported after administra- cytostatic drugs.67 tion of these tricyclic antidepressants.60 Another investigation reported a strong Changes of salivary composition increase in the activity of amylase and the due to radiotherapy content of proteins, glycoproteins, calcium, Radiation-induced hyposalivation is the com- potassium, and hexose in saliva, indicating a mon and most serious adverse effect in strong agonistic effect on noradrenaline patients after radiotherapy of malignant transmission after administration of amitripty- tumors in the head and neck region. The line.20 Also, single doses of maprotiline exposition of these regions to high doses of increase salivary amylase activity and protein radiation can lead to not only hyposalivation content.61 but also to other clinical consequences for The effects of psychotropic drugs (eg, flu- oral health, such as mucositis, taste loss, tris- oxetine, sertraline, paroxetine, citalopram, mus, and osteoradionecrosis (Fig 2).42,44,47 clonazepam, and lorazepam) on the concen- Apart from the reduction of salivary flow rates, trations of salivary components such as total the quality of saliva undergoes significant proteins, urea, and calcium, as well as ␣-amy- changes due to radiation therapy, including lase activity, pH, and buffer capacity have increased viscosity and pH shift to more been evaluated.62 Psychotropic users pre- acidic values.68,69 During the early phase of sented a significant decrease of 33.85% in radiation therapy, the concentrations of antimi- stimulated salivary flow rate compared to crobial proteins, lactoferrin, lysozyme, salivary controls. However, the biochemical composi- peroxidase, and myeloperoxidase in saliva tion of saliva was found to be not significant- were found to be elevated.70 However, it is dif- ly affected by the use of psychotropics.62 ficult to estimate what proportion of these

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radiation therapy, but decreased notably thereafter.72 The elevation of IgA was con- Systemic disease Medication Radiotherapy Miscellaneous fined largely to the first 2 weeks of irradiation, after which it remained quite constant.72 The Hyposalivation elevated concentrations of these components may provide some protection against Dietary changes Insufficient self-cleaning radiation-induced infections, at least in the first phase of radiation therapy. According to Frequent Sticky food Reduced buffer another study, the secretory IgA titer was sig- meals Sweet food Acidic plaque nificantly higher in patients with fully irradiated major salivary glands even more than 6 Increase of cariogenic and periodontopathogenic microorganisms months after radiation therapy.73 Even though total bacterial concentrations Accelerated demineralization in saliva of irradiated subjects seem to be rel- Reduced remineralization atively unchanged,74 radiation-induced hyposalivation is accompanied by pronounced Periodontitis Rampant caries shifts in specific microbial components, especially highly acidogenic microflora.72,74–76 The Marginal/apical periodontitis, pulpitis number of cariogenic microorganisms such as Lactobacillus, Streptococcus mutans, and Staphylococcus was found to be extremely Fig 2 Direct and indirect consequences of hyposalivation of different origins. (Modified from Kielbassa44 with permission.) elevated following radiation therapy.74–76 In contrast to the high colonization with streptococci, lactobacilli, and candida species, periodontal pathogens do not seem to be affected.74,75 During and following radiation therapy changes is caused primarily by tumor or sec- the incidence of periodontal pathogens (such ondarily by oral inflammatory diseases, such as Aggregatibacter actinomycetemcomitans as mucositis, in this phase of radiation thera- or Porphyromonas gingivalis) was not found py.42,44,70,71 According to other investigations, to be significantly changed.75,77 Therefore, it decreases in the activity of ␣-amylase, flow was suggested that in contrast to “radiation rate, and protein levels were observed in caries,” there seems to be no microbiologic patients after 6 weeks of radiation treatment.69 evidence for “radiation periodontitis.”77 In addition, the concentration of acidic and basic proline-rich proteins, like cystatins, histatins, and statherins also seems to be reduced in irradiated patients.68 The low sali- CONSEQUENCES vary concentration of these components OF ALTERED SALIVA could be caused by reduction in the number COMPONENTS of acinar cells, incomplete tissue regenera- FOR ORAL HEALTH tion, and late stromal effects such as delayed radiation-induced vascular damage.42,68,69 Generally, objective hyposalivation of differ- The radiation-related changes in salivary ent origins results in a change of salivary concentrations of immunoglobulins have composition, with increased viscosity, also been investigated. Salivary IgA is con- reduced buffering capacity, altered salivary sidered to play an important role in protec- electrolyte concentrations, and changed tion against dental caries. Whole saliva and nonimmune and immune antibacterial sys- serum samples collected from patients with tems (Fig 3). These alterations can lead to oral cancer display significantly elevated lev- serious consequences for oral health. For els of IgA and IgG even before radiation ther- example, the average pH falls from about 7.0 apy.70,72 Ratios of IgA and IgG to total protein to 5.0, which is considered cariogenic.42,44 were reported to be greatly increased during Because of the lowered pH and buffering

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Gy 0 20 40 60

Taste loss

Mucositis

Hyposalivation

Radiation caries

Susceptibility to osteradionecrosis

0123456 10 14 18 32 64 110 During radiotherapy (d) After radiotherapy (wk)

Fig 3 Schematic diagram of time of onset and duration of Fig 4 Radiation-related damages to dentition. radiation-induced oral sequelae. (Reprinted from Kielbassa44 with permission.)

capacity, the minerals of enamel and dentin alivation of another origin.44 A reduced sali- could easily dissolve. This event will not be vary flow inhibits transport and solubilization followed by the usual remineralization of the of gustatory stimulants, thus leading to dental hard tissue, because the conditions of decreased gustatory stimuli and a reduced the oral environment of patients with hypos- excitability of the taste buds.44 alivation are especially prone to demineral- Under these conditions and without pre- ization.42,44 As a consequence, remineraliza- ventive measures (oral hygiene) and support- tion capacity of saliva is considerably ham- ive therapy (ie, fluoridation), the dentition can pered. be destroyed within a few months (see Fig Additionally, the reduced salivary flow rates 3).22,78 Providing moisture to the oral mucosa result in a substantial immunoprotein defi- helps to relieve the symptoms of hyposaliva- ciency.42,44 Accompanied by the reduced oral tion in patients.22,78 clearance, these effects result in tremendous changes of the oral flora in patients with hyposalivation (particularly radiation induced) with an increase in acidogenic and cariogenic TREATMENT OPTIONS microorganisms.42,44 Undoubtedly, the shift in FOR HYPOSALIVATION oral microflora toward cariogenic bacteria, the reduced salivary flow (oral clearance), and the In case of a remaining functional salivary altered saliva composition (buffer capacity, gland parenchyma it is possible to treat hypos- pH, immunoproteins, and oral clearance) alivation with the administration of choliner- clearly result in an enormous increase of gics (ie, pilocarpine hydrochloride), but sys- caries risk in patients with hyposalivation, temically acting sialogogues need to be used especially after radiation therapy in the neck with caution since adverse effects are often and head area (Fig 4).42,44 observed.79 Locally acting stimulants of sali- In addition, if salivary flow is objectively vary flow may be useful by way of masticatory reduced, oral function (speech, chewing, and and/or gustatory stimulation of the salivary swallowing) is hampered, because wetting glands.80 When it is impossible to stimulate and lubrication of the mucosal surfaces and minimal salivary gland activity, saliva substi- moistening of food items will not be suffi- tutes can be prescribed.81 However, not all cient.42,44 The previously mentioned loss of functions of saliva can be adequately replaced taste is due not only to the effect of irradiation by artificial products; saliva substitutes often on the taste buds but is also related to hypos- lack sufficient lubrication and antimicrobial

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activity.82 Therefore, various thickening agents of these etiologic factors can be accompa- (eg, carboxymethylcellulose [CMC], linseed, nied with quantitative and qualitative ptyalin, or mucin) have been added to saliva changes of salivary components including substitutes to improve their viscoelastic prop- increased viscosity, reduced buffering erties.82 However, some artificial salivas con- capacity, altered salivary electrolyte concen- taining these thickeners (Ptyalin, ptyalin based, trations, and changed nonimmune and TMP Tüshaus; Salinum, linseed based, immune antibacterial system. These alter- Sinclair) have recently been withdrawn from ations can lead to serious consequences for the (German) market because of pH instabili- oral health such as hyposalivation, rampant ties and occasionally observed bacterial caries and oral yeast infection, reduced ability growth.81 Although it is not a natural lubricant, to ingest food, speech impairment, and CMC still seems to be a good clinical choice many others. Providing moisture to the oral as a basis of a saliva substitute. A recent mucosa helps to relieve the symptoms of prospective crossover study showed that hyposalivation in patients. For this purpose, most patients suffering from xerostomia pre- saliva substitutes have been developed. To ferred a CMC spray (Glando sane, Cell date, clinical studies evaluating the effect of Pharm) compared to solutions based on cel- saliva substitutes on dental hard tissues are lulose gel, oil, or mucin, because of taste and still missing. With the results of several in vitro handling.83 None theless, preference of saliva studies in mind, clinicians should consider substitutes by various groups of patients has saliva substitutes that contain fluorides, and been discussed controversially.84–88 Because those that are supersaturated with calcium Glandosane revealed a high demineralizing and phosphate. potential in several in vitro studies, it has not been recommended for dentate patients.78,89,90 As mentioned above, saliva substitutes often have a demineralizing potential or are at the REFERENCES utmost neutral; only a few offer a remineralizing potential.78,91,92 For example, Saliva natura (poly- 1. Brosky ME. The role of saliva in oral health: saccharide based, Medac) was introduced to Strategies for prevention and management of xerostomia. J Support Oncol 2007;5:215–225. substitute Saliva medac (Medac) in 2006. 2. Dowd FJ. Saliva and dental caries. Dent Clin North However, a demineralizing effect on dentin,92 Am 1999;43:579–597. and also on enamel after longer storage peri- 3. Pedersen AM, Bardow A, Jensen SB, Nauntofte B. 78,93 ods, could be observed. Remineralization Saliva and gastrointestinal functions of taste, masti- could be achieved in vitro with an experimen- cation, swallowing and digestion. Oral Dis 2002;8: tally modified Saliva natura solution slightly 117–129. supersaturated with octacalcium phosphate 4. Abiko Y, Nishimura M, Kaku T. Defensins in saliva and and dicalcium phosphate dihydrate.92,94 In con- the salivary glands. Med Electron Microsc 2003;36: 247–252. clusion, a stable remineralizing saliva substitute 5. Mese H, Matsuo R. Salivary secretion, taste and preventing dental caries has been found in hyposalivation. J Oral Rehabil 2007;34:711–723. vitro, and these results should be verified in clin- 6. Schneyer LH. Method for the collection of separate ical studies. submaxillary and sublingual salivas in man. J Dent Res 1955;34:257–261. 7. Chiappin S, Antonelli G, Gatti R, De Palo EF. Saliva specimen: A new laboratory tool for diagnostic and CONCLUSION basic investigation. Clin Chim Acta 2007;383:30–40. 8. Nederfors T. Xerostomia and hyposalivation. Adv Dent Res 2000;14:48–56. Hyposalivation is common among patients 9. Goode RL, Smith RA. The surgical management of with different systemic autoimmune, hormon- sialorrhea. Laryngoscope 1970;80:1078–1089. al, neurologic, and psychogenic diseases, but 10. Dawes C. Salivary flow patterns and the health of also after intake of various medications or after hard and soft oral tissues. J Am Dent Assoc 2008; exposure to radiation therapy directed against 139(suppl):18–24. the head and neck region. The occurrence

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