Salivary hypofunction: An update on aetiology,diagnosis and therapeutics

Jamil Saleh, Maria Antonia Zancanaro Figueiredo,Karen Cherubini, Fernanda Goncalves Salum *

Oral Medicine Division, Pontifical Catholic University of Rio Grande do Sul – PUCRS, Brazil

a r c h i v e s o f o r a l b i o l o g y 6 0 ( 2 0 1 5 ) 2 4 2 – 2 5 5

a r t i c l e i n f o

Article history:

Accepted 28 October 2014

Keywords:

Salivary glands

Xerostomia

Radiotherapy

Therapeutics

Medications

a b s t r a c t

Saliva is of paramount importance for the maintenance of oral and general homeostasis.

Salivary hypofunction predispose patients to disorders such as dysgeusia, pain and burning

mouth, caries and other oral infectious diseases, dysphagia and dysphonia. The aim of this

study was to provide an update on the aetiology, diagnostic methods and therapeutic

strategies for the management of hyposalivation and xerostomia. The present paper

describes subjective and objective methods for the diagnosis of salivary dysfunctions;

moreover a number of drugs, and systemic disorders associated with decreased salivary

flow rate are listed. We also focused on the underlying mechanisms to radiotherapy-

induced salivary damage. Therapeutics for hyposalivation and xerostomia were discussed

and classified as preventive, symptomatic, topical and systemic stimulants, disease-modi-

fying agents, and regenerative. New therapeutic modalities have been studied and involve

stem cells transplantation, with special attention to regeneration of damage caused by

ionizing radiation to the salivary glands. More studies in this area are needed to provide new

perspectives in the treatment of patients with salivary dysfunctions.

# 2014 Elsevier Ltd. All rights reserved.

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1. Introduction

Saliva is of paramount importance for the maintenance of oral

and general homeostasis. It displays a crucial role in the

digestive function, taste, cleaning, hydratation of the oral

mucosa, and protection of the teeth, due to buffering and

remineralization properties. Besides, saliva controls the

composition of the oral microflora due to antibacterial,

antifungal and antiviral properties, protecting the body from

deleterious extrinsic influences. Saliva is composed of more

than 99% water along with electrolytes; the protein compo-

nents include immunoglobulins, digestive enzymes such as

amylase and lipase, and antibacterial and antifungal enzymes,

* Corresponding author at: Pontifıcia Universidade Catolica do Rio Gran231, CEP: 90610-000, Porto Alegre, RS, Brazil. Tel.: +55 51 3320 3254; fa

E-mail address: fernanda.salum@pucrs.br (F.G. Salum).http://dx.doi.org/10.1016/j.archoralbio.2014.10.0040003–9969/# 2014 Elsevier Ltd. All rights reserved.

as well as mucins.1–4 Salivary secretion is controlled by the

autonomous nervous system, mainly by parasympathetic

nerve signals. About 90% of saliva is produced by the major

salivary glands and the daily volume varies from 0.5 to 1.0 L.4–6

When at rest, 65% of saliva is produced by the submandibular

glands, which produce saliva rich in mucin, which supplies

lubrification for the mucosa. Under stimulation, the parotids

account for 50% of salivary volume.4,5,7

Nederfors8 suggests that salivary dysfunctions can be

divided into three aspects: xerostomia, as subjective alter-

ation; hyposalivation, as objective reduction of salivary flow

and alterations in salivary composition. In early stages,

hyposalivation is characterized by decreased salivary volume,

besides saliva is thick and dispersed. The oral mucosa

de do Sul – PUCRS, Hospital Sao Lucas, Av. Ipiranga, 6690 – Roomx: +55 51 3320 3254.

a r c h i v e s o f o r a l b i o l o g y 6 0 ( 2 0 1 5 ) 2 4 2 – 2 5 5 243

becomes dry and atrophic, and the patients can gradually

show dysgeusia, dysphagia and dysarthria, as well as risk of

developing ulcerations, caries, gingivitis, periodontitis, candi-

dosis, and bacterial sialadenitis, among others.9,10 Those

changes cause important harm to the oral homeostasis and

to the quality of life.

Considering the abovementioned, the present study is an

updated approach of the main risk factors associated to

salivary dysfunctions, such as drugs, systemic diseases,

radiation and ageing. The diagnostic methods and therapeu-

tic measures, including regenerative therapies and the use of

stem cells to restore salivary function are also discussed. A

Medline/PubMed/search was conducted using the terms

xerostomia, hyposalivation, dry mouth and salivary hypo-

function in combination with aetiology, drugs, systemic

disorders, diagnosis, management, and treatment. Articles

published in the English language were selected and

reviewed. Suitable references from these articles were also

reviewed.

2. Diagnosis of salivary dysfunctions

The diagnosis of salivary dysfunctions can be obtained by

means of subjective and objective methods. These methods

can be classified into questionnaires or interviews, secretion

tests, mucosal surface tests, qualitative analyses, functional

analyses and glandular morphology analyses11 (Table 1).

Subjective methods are used to determine the intensity

and cause of xerostomia.12 A number of questionnaires have

been utilized, and there is not a consensus on the best form of

grading xerostomia, mainly due to the difficulty in obtaining a

suitable response from the patient. Pai et al.13 and Gerdin

et al.14 suggest the application of the visual analogue scale

adapted to the evaluation of xerostomia. Other authors

suggest instruments that broaden the analysis of xerostomia,

in grading aspects related to chewing, swallowing, speech,

sleep and quality of life.15

Table 1 – Diagnostic methods of salivary dysfunctions.

Subjective analysis Questionnaires ointerviews

Objective analysis Secretion tests

Mucosal surface test

Functional analyses

Qualitative analyses

Morphological analy

Source: Modified from Lofgren et al.11

a Oral Health Impact Profile-14.b Quality of Life Head and Neck 35.

The clinical method most often employed for the diagnosis

of salivary dysfunction is sialometry, which consists in the

whole saliva collection or the fluid produced by each major

gland individually. Sialometry can be done by different

methods, under stimulation or at rest. Hyposalivation is

considered when salivary flow rate (SFR) is <0.1 mL/min at rest

or <0.7 mL/min under stimulation.9,11 Sialometry provides

objective evidence of the reduction in SFR, but it does not help

to diagnosis the dysfunction aetiology. The Schirmer test is

usually employed in the diagnosis of xerophthalmia. Authors

suggest its utilization also for quantifying non-stimulated SFR,

since it consists in a simple method that provides an adequate

diagnosis of glandular function.16,17

The assessment methods for the mucosal surface include

biopsy of the minor salivary glands, the ferning test and the

mucus1 test among others. The biopsy of the lower lip glands is

used for the diagnosis of systemic disorders such as

amyloidosis, sarcoidosis, Sjogren syndrome and neonatal

hemochromatosis.18 In the ferning test, hyposalivation is

detected by electron microscopy, which evaluates the salivary

crystals.19 The mucus1 test is a noninvasive method which

analysis mucosal surface by a condenser that measures

impedance with sensitive capacitors.20

Qualitative analysis of saliva includes assaying electrolytes

and organic components.21–23 Diagnostic imaging techniques

allow the identification of alterations in anatomic character-

istics, as well as the evaluation of glandular function.24

Salivary scintigraphy provides information about parenchyma

and excretion of major salivary glands after endovenous

administration of technetium pertechnetate.25 It is a nonin-

vasive, easy to perform, reproducible technique and well

tolerated by patients.26 Like scintigraphy, the wafer test is a

semiquantitative functional analysis method, employed in the

initial diagnosis of salivary gland disorders.27

Magnetic resonance (MR) provides excellent image contrast

for soft tissues and spatial definition, with the advantage of

not using ionizing radiation.28 In sialography by MR, the saliva

itself serves as contrast in obtaining the images.24 Its

r Questionnaires on xerostomiaVisual analogue scale

OHIP-14a

QoL H&N35b

Sialometry

Schirmer oral test

s Biopsies

Ferning test

mucus1

Scintigraphy

Wafer test

Salivary composition test

Total protein test

ses Sialography

Ultrasonography

Magnetic resonance

Computed tomography

a r c h i v e s o f o r a l b i o l o g y 6 0 ( 2 0 1 5 ) 2 4 2 – 2 5 5244

disadvantages include poor availability, high cost and time-

consuming. Computed tomography (CT) is more accessible

when compared to MR. It is indicated for the diagnosis of

calculi inside the gland or duct and evaluation of bone erosion

caused by malignant lesions.29 The addition of radiodrugs

allows the differentiation between benign and malignant

lesions. It is the examination of choice in the diagnosis of

inflammatory lesions of the salivary glands, but the patient is

subjected to ionizing radiation with contrast.

Alternatively, ultrasonography is an easy to perform

method with low cost. It enables to differentiate between

intra- and extraglandular lesions, as well as between cystic

and solid lesions, besides to diagnose calculi and dilations of

salivary ducts, and to guide biopsies or drainages.30

3. Aetiology of salivary dysfunctions

3.1. Drugs

Several drugs are able of inducing hyposalivation and

xerostomia, but they rarely cause irreversible damage to the

salivary glands. In Table 2 were listed classes of drugs with

potential to cause salivary dysfunction. Unfortunately few

Table 2 – Drugs with potential to cause salivarydysfunctions.

Drug Subclass

Anticholinergic drugs

Tricyclic antidepressants33,34

Antipsychotics - Haloperidol36

- Phenothiazine derivatives37

- Antiparkinsonian drugs38

- Anticonvulsants65

Antihistamines39

Anticholinergic drugs for

overactive bladder40,41

Anticholinergic Bronchodilators42

Sympathomimetic drugs

Antidepressant - Monoaminoxidase

inhibitors66,67

- Serotonin reuptake

inhibitors33,47,68

Appetite suppressants69,70

Decongestants45

b2-agonists Bronchodilators46

Skeletal muscle relaxants43

Antihypertensive48,49 - Angiotensin converting

enzyme inhibitors

- Angiotensin II receptor

antagonists

- Calcium channel blockers

- Alpha Adrenergic blockers

-Beta Adrenergic blockers

- Alpha2 agonists

- Diuretics

Cytotoxic drugs -Antineoplastics55

-Interferon53

- Ribavirin54

Anti-HIV drugs57,58

Opioids and Benzodiazepines35,59–61

Antimigraine agents63,64

studies have examined salivary flow, much of the data, being

based on a subjective complaint of dry mouth. Besides, little

data about the effects of many supposed xerostomia-inducing

drugs on salivation are available. Although the exact mecha-

nisms whereby some drugs cause xerostomia are still

unknown, salivary dysfunction associated to drugs may occur

through anticholinergic, sympathomimetic, cytotoxic action

or by damaged ion transport pathways in the acinar cells.31,32

Drugs with anticholinergic activity, mainly against the M3

muscarinic receptor are the most reported cause of reduced

salivation. Tricyclic antidepressants present anticholinergic

effects in a variety of degrees.33,34 They block the effects of

acetylcholine on the muscarinic receptors, resulting in a

decreased salivary flow rate. Therefore, sympathetic stimula-

tion predominates, which leads to more viscous saliva

production.35 Furthermore, because these medications act

on the central nervous system, they can cause alterations in

saliva by means of indirect actions on the salivary glands.

Antipsychotics36–38, antihistamines,39 drugs for overactive

bladder,40,41 and anticholinergic bronchodilators42 also show

anticholinergic activity, causing salivary hypofunction.

The actual mechanism whereby sympathomimetic agents

cause salivary hypofunction is often obscure and its xerogenic

effects may be exerted at different levels. Skeletal muscle

relaxants, such as tizanidine, act as agonists at alpha

2-adrenergic receptors and have been shown to cause

xerostomia.43 Appetite suppressants act by central mecha-

nisms involving alpha-adrenoceptors, while indirectly cause

secretion of protein by releasing noradrenaline from glandular

nerve terminals.44 Decongestants45 and beta 2-agonists

bronchodilators46 are sympathomimetics drugs that also are

associated with salivary dysfunction.

Within the antidepressant class, the major part of the

serotonin reuptake inhibitors causes salivary dysfunction. It is

not clear yet which mechanism is used by these drugs to

induce hyposalivation, xerostomia or changes in the salivary

composition.33,47 Owing to the lack of anticholinergic activity

of the serotonin uptake inhibitors, it was not believed that a

low salivary flow rate and xerostomia would occur. However,

there are many other endogenous substance receptors in the

salivary glands that mediate the salivary flow rate, such as

substance P and vasoactive intestinal peptide receptors.

Xerostomia may occur as an indirect action of these drugs

on the central nervous system, through mechanisms that are

difficult to identify and, probably, by means of the serotonin

action on the 5HT receptors present in the peripheral

microcirculation.35

Xerostomia has been related as a side effect of different

classes of drugs for antihypertensive therapies, which cause

salivary dysfunction in distinct ways.48,49 Diuretics cause an

overall decrease in intravascular and extracellular fluid

volume. As a consequence, there is a decrease on the salivary

flow rate.32 Anti-hypertensive drugs that act on central alpha

2-adrenergic receptors, such as clonidine, usually cause dry

mouth. Takakura et al.50 demonstrated that activation of

alpha 2-adrenoceptors in the lateral hypothalamus (LH)

inhibits salivation, suggesting that LH is one of the possible

central sites involved in anti-salivatory effects. Hattori e

Wang51 investigated the mechanism by which calcium

channel blockers cause dry mouth. Since the intracellular

a r c h i v e s o f o r a l b i o l o g y 6 0 ( 2 0 1 5 ) 2 4 2 – 2 5 5 245

Ca2+ concentration is closely related to saliva secretion, the

authors suggest that Ca2+ antagonists depress Ca2+ influx by

inhibiting the voltage-dependent Ca2+ channels, thereby

decreasing the acetylcholine-induced Ca2+ elevation and

leading to inhibition of salivation. Alpha and beta adrenergic

blockers, angiotensin converting enzyme inhibitors and

angiotensin II receptor antagonists are classes of antihyper-

tensive, which are also associated with salivary dysfunction.52

Xerostomia is one of the adverse events observed during

interferon (IFN) therapy.53 Aghemo et al.54 demonstrated that

changes in salivary flow in patients receiving both interferon

and ribavirin might result from an alteration of exocytosis

and/or liquid transport of the exocrine glands. This effect

promptly reverts to normal upon cessation of treatment.

Chemotherapy treatment also causes transient xerostomia,

with recovery of salivary levels after the end of treatment

cycles.55 According to Jensen et al.55, chemotherapeutic drugs

such as cyclophosphamide, epirubicin or methotrexate, and

5-fluorouracil appear to affect the function of acinar and

ductal cells, by influencing cell division. Chemotherapeutic

agents can induce dilation of the excretory duct, acinar

degeneration and inflammation of glandular tissue.56

Navazesh et al.57 showed a significant decrease in the

stimulated flow rates among HIV positive women on protease

inhibitors (PI) based highly active antiretroviral therapy

(HAART). Is still unclear as to why PI might produce a

significant decrease in the salivary flow rate; Navazesh

et al.58 suggested that the chemical structure of the PI alter

the structure and composition of saliva. They may affect the

salivary flow rates by causing lipotrophic changes or deposi-

tion of adipose tissue within the gland.

Although studies show that patients treated with opioids

exhibit xerostomia,59–61 the effect of opioids in salivary

function is not clear. Secretions of some exocrine glands such

as the pancreas are diminished by morphine, and the same

may occur to salivary glands.59

Zaclikevis et al.62 measured salivary flow rate of rats under

chronic treatment with benzodiazepine (diazepam) and

analysed by histomorphometry the effects of the drug in

the parotids glands. Diazepan caused hyposalivation in rats

and acinar hypertrophy in their parotid glands, confirming

thus, the saliva retention into the acinar cells. The benzodia-

zepines (BZDs) decrease the salivary flow rate through the BZD

receptors in the salivary glands and by indirect action on the

salivary glands through the central BZD receptors.35

Antimigraine agents such as rizatriptan and rofecoxib have

also been associated with dry mouth.63,64

3.2. Ageing

Different studies have investigated the effects of ageing on the

salivary glands, but there is still controversy as to the salivary

dysfunctions in the elderly. While some authors have

demonstrated impaired glandular function, others have not

found salivary dysfunctions in the healthy and non-users of

drugs elderly.71–77 According to Tylenda et al.74, ageing leads to

the loss of about 30% of acinar cells, with substitution of

secretory components by fibrous and adipose tissue. Ghezzi

and Ship75 found that after the use of an anticolinergic drug,

glandular function is more affected in the elderly than in

young individuals. Besides, there are changes in salivary levels

of sodium, potassium, IgA, proline-rich protein, lactoferrin

and lysozyme in elderly.78,79 Yeh et al.80 identified a reduction

in the SFR of elderly, even those not using systemic drugs,

suggesting a relation between salivary dysfunction and

ageing. Smith et al.71 investigated whole stimulated saliva

and demonstrated that healthy adults aged 70 and older had

lower levels of salivary flows than younger adults (<50).

On the other hand, there are authors that defend the

hypothesis that the decrease of SFR in elderly results exclusively

from the action of drugs and systemic disorders, more common

in this age group than in young individuals. According to

Locker76 and Shetty et al.77 xerostomia is proportional to the

number of drugs that the elderly utilize. The different results are

likely due to varying methodologies of the studies, such as the

age and the number of patients, the exclusion and inclusion

criteria and the method of saliva collection.71

3.3. Systemic disorders

Qualitative and quantitative salivary changes can be associ-

ated with systemic disorders that cause dysfunctions in

neurotransmitter receptors, destruction of glandular paren-

chyma, immune dysregulation that may interference with the

secretion process or alterations in fluids and electrolytes.81 In

Table 3 were listed a number of systemic disorders, which

were classified accordingly their aetiology and/or pathogene-

sis. Controlled clinical studies, showing association of those

disorders with salivary hypofunction were included.

3.3.1. Rheumatological chronic inflammatory disordersOne of the disorders most associated with hyposalivation is

Sjogren syndrome, an autoimmune disease that affects the

exocrine glands, mainly the salivary and lacrimal glands.16

The disease may include impaired pulmonary, articular, renal

and neurological functions in its spectrum.82,83 Its autoim-

mune profile is due to the circulating antibodies and glandular

lymphocytic infiltrate, composed mainly of TCD4 lympho-

cytes.16,84 The American College of Rheumatology proposed, in

2012, classification criteria for Sjogren’s syndrome based on

objective measures such as serum antibody titre, presence of

focal lymphocytic sialadenitis and ocular staining score.85

Besides Sjogren, others rheumatological chronic inflam-

matory disorders may be associated with salivary hypofunc-

tion such as rheumatoid arthritis,86,87 systemic lupus

erythematosus,88,89 juvenile idiopathic arthritis,90 and prima-

ry biliary cirrhosis.91 Autoimmune inflammation of the

salivary glands is frequently observed in those patients.

Furthermore, concomitant occurrence of Sjogren’s syndrome

is also described in patients with those rheumatological

disorders.

3.3.2. Endocrine disordersBoth diabetes mellitus type 1, as type 2 have been associated

with xerostomia.92–94 Screebny et al.,95 demonstrated that the

salivary flow rate among the diabetic patients was significant-

ly lower than that of nondiabetic subjects. The decreased

salivary flow could be due to damage to the gland parenchy-

ma, alterations in the micro-circulation to the salivary glands,

dehydration and to disturbances in glycemic control.

Table 3 – Systemic disorders that may be associated withsalivary dysfunctions.

Rheumatological

chronic inflammatory

disorders

- Sjogren syndrome129,130

- Rheumatoid arthritis86,87

- Juvenile idiopathic arthritis90

- Systemic lupus erythematosus88,89

- Primary biliary cirrhosis91

Endocrine disorders - Diabetes mellitus92–94

- Hyperthyroidism/

hypothyroidism96,97

Neurologic disorders - Depression98,99

- Parkinson’s disease38,100

Genetic disorders - Agenesis of salivary glands107

- Ectodermic dysplasia108,109

- Prader-Willi syndrome101

- Down syndrome105,106

- Familial amyloidotic

polyneuropathy102

- Gaucher disease104

- Papillon-Lefevre syndrome110

- Hereditary hemochromatosis103

Metabolic disorders - Dehydration111,112

- Chronic renal failure113,114

- Bulimia116

- Anaemia118

- Alcohol abuse117

Infectious disorders - HIV/AIDS131–133

- HCV infection121

Others - Fibromyalgia128

- Graft-versus-host disease124,134

- Sarcoidosis125,126

- Chronic pancreatitis127

a r c h i v e s o f o r a l b i o l o g y 6 0 ( 2 0 1 5 ) 2 4 2 – 2 5 5246

Thyroid dysfunctions also affect salivary gland function,

especially in hypothyroid subjects.96 Muralidharan

et al.97attribute salivary hypofunction in patients with

thyroid disorders to parotid gland sialosis and atrophy.

3.3.3. Neurologic disordersPatients with depression usually have medication-induced

salivary hypofunction, as described in the previous item,

related to drugs. However, studies indicate that in some cases,

xerostomia may be of psychological origin. Bergdahl et al.98

observed that healthy patients, but with a subjective sensation

of dry mouth were significantly more depressive than age- and

gender-matched controls. Antilla et al.99 associated depressive

symptoms with xerostomia, indicating the possibility of

depression as an underlying factor of the sensation of dry

mouth.

Studies have demonstrated that salivary secretion rate is

significantly lower in Parkinson’s disease patients. A decrease

in salivation could contribute to dysphagia, which affects up to

75% of patients with that disorder. Autonomic dysfunction

could explain the decrease in salivary flow in Parkinson’s

disease patients.100 On the other hand, Proulx et al.38 observed

that levodopa therapy could increase this problem.

3.3.4. Genetic disordersGenetic disorders such as Prader-Willi syndrome, familial

amyloidotic polyneuropathy, hereditary hemochromatosis,

Gaucher disease and Down syndrome are also associated to

salivary dysfunction. Prader-Willi syndrome (PWS) is a

complex genetic disorder resulting from failed expression of

paternally inherited genes on chromosome 15q11–13.101

Saeves et al.101 demonstrated that in PWS patients saliva

presents extremely thick and sticky; it is possible that the

protein secretion in salivary glands may be functioning

properly or even be overexpressed, whereas fluid secretion

is reduced.

Familial amyloidotic polyneuropathy (FAP) is a hereditary

systemic disease characterized by incorporation of an amyloid

material in all tissues of the body. Johansson et al.102 showed

that patients with this disorder had a decreased salivary flow

rate and the degree of salivary hypofunction was positively

correlated to the progress of the disorder. Impaired salivary

secretion in FAP patients might be caused by an autonomic

dysfunction, malnutrition, and/or deposition of amyloid in the

salivary glands. Hereditary hemochromatosis (HH) is an

autosomal recessive disease characterized by increased

intestinal absorption of iron, which progresses to a progres-

sive deposition of iron in various organs. Sanchez-Pablo

et al.103 demonstrated a decline in total stimulated salivary

flow in patients with HH, which was significantly correlated

with ferritin levels. The most likely cause for hyposalivation

may be metabolic in origin, namely sialosis caused by iron

deposition in parenchymal cells.

Gaucher disease (GD) is an autosomal recessive disorder

caused by mutations in the beta-glucocerebrosidase gene

leading to deficient activity of this lysosomal enzyme. Dayan

et al.104 demonstrated that the salivary output was signifi-

cantly lower in patients with GD. A possible explanation would

be infiltration of Gaucher cells into the salivary glands,

interfering with saliva production. Siqueira et al.105 investi-

gated salivary flow rate of Down syndrome patients aged

between 6 and 18 years. Salivary flow rate was 36% lower in

Down syndrome children compared to their siblings.

Patients with agenesis107 of salivary glands or ectodermic

dysplasia108,109 also feature salivary hypofunction due to

absence or hypoplasia glandular. In addition to this, an

impaired water secretion in saliva and an altered saliva gland

function have been shown in children and young adults with

Papillon-Lefevre Syndrome.110

3.3.5. Metabolic disordersThe primary constituent of saliva is water and decreased body

water homeostasis has been linked with salivary dysfunc-

tion.111 Ship and Fisher112 studied the effect of body dehydra-

tion upon parotid salivary flow rates. The results suggest that

body dehydration is associated with decreased parotid flow

rates.

Salivary gland function is also impaired among the chronic

renal failure patients (CRF),113 and the most common oral

finding in these patients is xerostomia.114 Postorino et al.115

investigated the prevalence of salivary hypofunction in a

group of dialysis patients. Salivary and lacrimal secretions

were markedly reduced in uraemic patients compared with

healthy controls, and alterations in salivary gland function

were related strongly to salivary gland fibrosis and atrophy.

Other disorders associated with salivary dysfunction are

nervous bulimia (NB) and alcoholism. Dynesen et al.116

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demonstrated that salivary function was reduced in persons

with NB, primarily due to the intake of potentially xerogenic

drugs, although this disorder may itself be related to

reductions in the salivary flow rates. Dutta et al.117 analysed

parotid saliva samples from alcoholic subjects without

evidence of cirrhosis. The data suggested that chronic alcohol

ingestion was associated with significant changes in parotid

saliva secretion and may be related to sialosis and dehydra-

tion. In addition to this, Wu et al.118 demonstrated that iron

deficiency anaemia patients had higher frequencies of oral

manifestations, including xerostomia.

3.3.6. Infectious disordersBetween 2 and 10% of patients infected by HIV present with

xerostomia and up to 37% reduction in SFR.119 The principal

causes of dysfunction are disease of the salivary glands

associated with HIV, Kaposi sarcoma, non-Hodgkin lympho-

ma, intraglandular lymphadenopathy and acute suppurative

sialadenitis.120 In addition to this, xerostomia in HIV-positive

patients can also be the consequence of highly active

antiretroviral therapy (HAART).57

Henderson et al.121 demonstrated a reduced salivary rate in

a cohort of HCV-infected patients. There are a number of

possible causes for a reduced salivary flow rate in hepatitis C

infected individuals. The principal theories include infiltration

of the salivary gland by the virus or a possible virus induced

immune mechanism.

3.3.7. Other disordersGraft-versus-host disease is an association of clinical altera-

tions that appear after bone marrow transplantation. The

disease is mediated by autoreactive T lymphocytes which

infiltrate several tissues and organs.122,123 The disease shows

different degrees of morbidity, with cutaneous, oral, ophthal-

mologic, pulmonary, articular and genitourinary manifesta-

tions. Xerostomia is the result of fibrosis of the parotid glands

and alterations in the chemical composition of saliva, with

decreased levels of sodium and increased potassium. In the

chronic course of the disease, the muscarinic receptors are

harmed.124

Sarcoidosis is a multi-system granulomatous disease; its

aetiology is unknown, but it is believed to be due to

immunodysregulation. Salivary gland swellings, xerostomia

and hyposalivation are also seen in patients with sarcoido-

sis.125,126

Kamisawa et al.127 assessed the frequency of salivary gland

dysfunction in patients with chronic pancreatitis of various

etiologies. Salivary gland function was frequently impaired in

the course of this disorder. Salivary gland dysfunction might

be the result of a common pathophysiological effect of alcohol

in patients with alcoholic chronic pancreatitis and the

immune mechanism against the salivary ducts in patients

with autoimmune and idiopathic chronic pancreatitis. In

addition to this, xerostomia is also a common symptom in

patients with fibromyalgia.128

3.4. Radiotherapy

The major salivary glands are often involved in the radiation

portals because they are in the proximity of the primary

tumour sites and lymphatic chains of the head and neck

region. As a consequence of radiotherapy, they undergo a

process of degeneration, resulting in hyposalivation and

xerostomia.135 The severity of dysfunction is determined by

factors such as dose, radiation portals and individual response

of the patient.136,137 In malignant tumours located in the

posterior portion of the mouth and in the oropharynx,

radiotherapy includes parallel and opposing lateral fields on

the upper region of the neck and side of the face. In these

cases, both parotids are irradiated, leading to greater levels of

xerostomia.138

Radiotherapy-induced hyposalivation ranges from a small

degree of dry mouth to total lack of saliva and oral mucosa

atrophy. The saliva undergoes qualitative alterations, there

are decreased activity of amylases, buffering capacity and pH,

with consequent acidification. There are also increased levels

of calcium, chloride, magnesium and proteins and reduction

in bicarbonate These alterations indicate that the parotids

function is more affected than that of the other glands.139,140

Eisbruch et al.135 suggested that on the radiotherapy the

decrease in SFR can be related to development of mucositis,

which occurs due to reduction in mucins, and epidermal and

fibroblast growth factors.

Damage to the acinar cells becomes irreversible after

cumulative doses of 26–39 Gy, causing the patients to have a

SFR less than 10% of that prior to radiotherapy.141 Xerostomia

is perceived in the initial phases of radiotherapy, with

reductions of 50 to 60% in SFR in the first week, and up to

about 80% at the end of the seventh week.142

Despite being stable, because they do not have a high

mitotic rate, acinar cells respond readily to radiation.143 The

mechanisms that lead to tissue destruction and greater

sensitivity of salivary glands are still inconclusive.143,144 The

glandular alterations begin with damage to the plasma

membrane, loss of response to autonomic control, oedema,

degeneration and necrosis of acinar cells. The acute effects

begin 24 h after the start of therapy and stabilize in 72 h. The

late effects are a consequence of fibrosis and acinar atrophy,145

which occur because of mesenchymal alterations, including

changes in the extracellular matrix, especially laminin and

collagen IV.146

Hakim et al.147 evaluated, in the parotids of rabbits,

functional changes and Ki67, smooth muscle actin (SMA)

and tenascin-C immunodetection after irradiation with 15 Gy.

There was a significant change in the absorption of 99mTc-

pertechnetate, decreased Ki67detection and marked redis-

tributions of SMA and tenascin-C. According to the authors,

the increased tenascin-C detection, caused by the damage to

the basal membrane of acinar cells, and the reduction in SMA

expression can be responsible for the functional glandular

changes.

Avila et al.148 demonstrated that ionizing radiation induced

apoptosis in the acinar cells of the parotids of rodents.

Apoptosis induced by radiation was dose-dependent and was

correlated with salivary dysfunctions. In addition, the apopto-

tic response seen after irradiation was dependent on p53

expression. Cannon et al.149 demonstrated radiotherapy

toxicity to the parotid gland by means of fluorodeoxyglu-

cose-labelled positron emission tomography-computed to-

mography (FDG-PET-CT).

a r c h i v e s o f o r a l b i o l o g y 6 0 ( 2 0 1 5 ) 2 4 2 – 2 5 5248

The alterations in SFR and viscosity can persist for years

and recovery depends on the characteristics of each patient.139

Currently, with the use of intensity-modulated radiotherapy

(IMRT), the tissues located in the proximity of the tumour are

more preserved in comparison with conventional radiothera-

py. IMRT is a technique that allows radiation to be dosed and

distributed in the tumour more precisely, thereby sparing

surrounding tissues.141

4. Therapeutic options

The therapeutic approach of salivary dysfunctions depends

basically on residual glandular function and is aimed at the

alleviation of symptoms and prevention and correction of

eventual sequelae, as well as at the treatment of associated

systemic diseases. The treatment of hyposalivation and

xerostomia can be classified as (1) preventive, (2) symptomat-

ic, (3) topical and systemic stimulants, (4) disease-modifying

agents, and (5) regenerative.81,150

4.1. Preventive therapies

Cytoprotective drugs, used to minimizing the effects of

radiotherapy, have been studied. Amifostine is an organic

thiophosphate utilized in patients subjected to radiothera-

py.151 Its protective effect prevents the formation of free

radicals and provides DNA repair, reducing the intensity and

duration of xerostomia, without interfering with the control of

the tumour and patients survival.152 Despite these benefits,

amifostine has adverse effects such as nausea, vomiting,

hypotension, transient, hypocalcemia and allergic reac-

tions.153 Another cytoprotector described in the literature is

tempol, a stable nitroxide that still needs clinical studies to

support its use in humans. Cotrim et al.154 demonstrated that

tempol maintained normal SFR in irradiated animals.

The insulin-like growth factor and keratinocyte growth

factor (KGF) in animals suppress apoptosis and favour the

survival and proliferation of acinar cells after radiothera-

py.155,156 Zheng et al.157 demonstrated that KGF prevented

hyposalivation in mice, since the transgenic animals showed a

higher number of acinar and endothelial cells.

Teymoortash et al.158 suggested the utilization of botu-

linum toxin as an alternative preventive against salivary

damage caused by ionizing radiation. The intraglandular

application of the toxin, prior to radiotherapy, significantly

prevented functional and histological changes in rats.

In irradiated patients, the transfer of the submandibular

gland to the submental space is also indicated as a preventive

method. The transfer allows the structure to receive a lower

quantity of radiation, therefore maintaining its excretory

function.159

Some preclinical studies of genetic transfer for glandular

protection have been conducted. Baum et al.160 and Delporte

et al.161 in studying human aquaporin-1 (hAQP1) in animals,

observedthat its action on the salivary glands causes an increase

in aqueous secretion in response to an osmotic gradient.

Another study indicated positive results with use of manganese

superoxide dismutase-plasmid/liposomes (MnSOD-PL) in the

prevention of the noxious effects of ionizing radiation on the

salivary glands.162 Palaniyandi et al.163 identified a splice variant

of a cellular kinase, Tousled-like kinase 1B (TLK1B), which when

overexpressed protected normal epithelial cells against ionizing

radiation-induced cell death. The results demonstrated a

reduction in acinar atrophy, glandular fibrosis and inflammato-

ry infiltrate.

4.2. Disease-modifying agents

Disease-modifying agents especially include immunomodu-

latory and immunosuppressive drugs, utilized in patients with

Sjogren syndrome, with the objective of reestablishing the

altered immunologic mechanisms. Interferons are proteins

that regulate cell proliferation and differentiation, cellular

expression of surface antigens and induce enzymes.18 The

results with respect to the use of interferon alpha for

xerostomia are controversial. Ferraccioli et al.164 found that

parenteral administration of interferon alpha-2 three times a

week produced an increase in salivary and lachrymal

secretions. Ship et al.165 observed that this drug enhanced

SFR under stimulation but did not alter flow at rest. On the

other hand, Cummins et al.166 found considerable elevation in

SFR at rest and small alteration in stimulated SFR.

Another disease-modifying agent is rituximab, a monoclo-

nal antibody that crossreacts with the antigen CD20, present

in more than 90% of B cells. Its benefit with regard to

xerostomia is related to reducing glandular lymphocytic

infiltrate occurring in Sjogren syndrome.167

4.3. Symptomatic therapies

Drinking water frequently is an alternative more commonly

used by patients with xerostomia, but saliva substitutes can

provide higher viscosity and protection to the oral mucosa.

The ideal agent should provide long-lasting and intense

hydration of the oral mucosa, requiring a minimal number

of applications, without adverse effects. Saliva substitutes

differ in chemical composition and viscosity. They are mostly

composed of carboxymethylcellulose (CMC), mucins, xanthan

gum, hydroxyethylcellulose, linseed oil or polyethylene

oxide.168,169 When lubricants containing CMC are compared

to those with mucins and xanthan gum, their rheologic and

moisturizing properties are inferior.170 Gelatinous substitutes

of saliva, containing polyglycerylmethacrylate has also been

suggested and are indicated for periods of decreased SFR.171

According to Dost and Farah172, the length of salivary

substitutes tends to be limited and there is a need for frequent

reapplication.

Other symptomatic strategies include the slow release and

continuous oral lubrication mechanisms.173 Tsibouklis et al.174

cite hydrogel films that allow the continuous release of

substances for treatment of xerostomia. However, these can

interfere with speech in patients.175

4.4. Topical and systemic stimulants

Pilocarpine is a parasympathomimetic, non-selective musca-

rinic agonist, which has been indicated for the treatment of

xerostomia. Its recommended initial dose is 5 mg/day up to a

maximum of 30 mg/day.176 In patients subjected to radiotherapy

a r c h i v e s o f o r a l b i o l o g y 6 0 ( 2 0 1 5 ) 2 4 2 – 2 5 5 249

ofthe headandneck, themaximal effect of pilocarpineis obtained

between two and three months after the start of treatment.177

Its adverse effects include hyperhidrosis, nausea, rhinitis,

dizziness, intestinal colic and pollakiuria. Its use is contra-

indicated in heart patients, individuals with chronic obstruc-

tive pulmonary disease, asthma and glaucoma.178 Epstein

and Schubert179 proposed the association of pilocarpine and

anethole trithione (ANTT) to potentiate the effect of both on

the salivary function. ANTT does not have a cholinergic

action, but increases the availability of muscarinic receptors

in the post-synaptic membrane.180

Cevimeline is a selective muscarinic agonist for M1 and M3

receptors, found in the salivary and lacrimal glands. Since it

has no effect on M2 receptors, it shows fewer adverse effects

when compared to pilocarpine, and besides, it has a long-

lasting action. The most common associated side effect is

dyspepsia. The recommended dose is 30 mg administered

three times a day.181

Another systemic sialogogue is bethanecol, a carbamic

ester of b-methylcholine resistant to cholinesterase, whose

action is concentrated in the M3 receptors. Jham et al.182, in a

randomized phase III trial, observed a significant increase in

SFR at rest and a decrease in xerostomia in patients treated

with head and neck radiotherapy. The dose indicated is 25 mg,

three times a day. Its adverse effects, despite being infrequent,

include nausea and diarrhoea.

To stimulate salivary secretion, other drugs such as

bromhexine183 and nizatidine184,185 are described in the

literature. Bromhexine is a drug with mucolytic properties,

used in respiratory infections, which also enhances salivary

and lachrymal secretion. Nizatidine is an H2 receptor

antagonist which inhibits acetylcholinesterase, allowing a

greater availability of acetylcholine. Both have shown favour-

able results in SFR and have been used in patients with Sjogren

syndrome.183–185

Sugar-free chewing gum and jellybeans can be utilized as

topical salivary stimulants. They usually contain xylitol (low

calorie sugar), which inhibits the growth of cariogenic bacteria

and reduces the incidence of caries.186 Kleinegger187 describes

SalivaSure1 as a topical stimulant that does not irritate soft

tissues or cause tooth decay. Its composition includes citric

acid and xylitol.

Electrostimulation has been used in patients with salivary

dysfunction; meanwhile, the results with this technique are

still inconclusive.188 Acupunture is also cited as an alternative

for xerostomia. Subjective and objective aspects of salivary

function are improved with those technique.189,190

In addition to this, hyperbaric oxygen in irradiated patients

demonstrates increased salivary function191 and reduction in

the number of cariogenic bacteria and Candida albicans. Teguh

et al.192 pointed out that hyperbaric oxygen favours neoan-

giogenesis and recruitment of bone marrow stem cells.

4.5. Regenerative therapies

Stem cell transplantation is emerging as an alternative for the

reestablishment of glandular function, since these cells have

the capacity to self-renew and differentiate into any type cell

constituent of the salivary glands.193–195 Bone marrow stem

cells and adipose tissue-derived stromal cells have been

tested.196–199 Yamamura et al.200 suggested the utilization of

dental pulp cells as a form of treatment for hyposalivation

after radiotherapy.

5. Conclusions

Salivary dysfunctions are common, have a negative impact on

the quality of life, and can be caused by a number of local and

systemic conditions. In the present study we described

subjective methods, as well as objective methods for deter-

mining alterations in salivary secretion. In addition to this, we

addressed the possible etiologic factors and established

treatments in the literature, as well as new therapeutic

strategies still under investigation. Clinicians must be aware

of the signs and symptoms of salivary disorders and be able to

diagnose and treat them. The patient must be informed about

the etiologic factors and adverse effects of hyposalivation, and

instructed about oral hygiene. Clinicians, together with the

patient, should select a therapeutic modality most suited for

each case. New therapeutic modalities have been studied and

involve stem cells transplantation, with special attention to

regeneration of damage caused by ionizing radiation to the

salivary glands. More studies in this area are needed to provide

new perspectives in the treatment of patients with salivary

dysfunctions.

Funding

There is no funding source to state in this research.

Competing interest

There is no conflict of interest in this research.

Ethical approval

Not applicable.

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