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8]

 Review Article

Betel nut chewing and its deleterious

effects on oral cavity
ABSTRACT Richa Anand,
The habit of chewing betel nut has a long history of use. Betel nut and products derived from it are widely used as a masticatory Chandan Dhingra3,
product among various communities and in several countries across the world. Over a long period, several additives have been
Sumanth Prasad2,
Ipseeta Menon1
added to a simple betel nut preparation; thus, creating the betel quid (BQ) and encompassing chewing tobacco in the preparation.
Betel nut has deleterious effects on oral soft tissues. Its effects on dental caries and periodontal diseases, two major oral diseases Departments of Public
are less well‑documented. Betel‑induced lichenoid lesions mainly on buccal mucosa have been reported at quid retained sites. In Health Dentistry ,
chronic chewers, a condition called betel chewers mucosa is often found where the quid is placed. Betel nut chewing is implicated I.T.S  Dental College,
in oral submucous fibrosis (OSF) and its use along with tobacco can cause leukoplakia, both of which are potentially malignant Hospital and Research
Centre, Greater Noida,
in the oral cavity. Oral cancer often arises from such precancerous changes. Thus, public health measures to quit betel use are 1
I.T.S Centre for Dental
recommended to control disabling conditions such as OSF and oral cancer. Studies and Research,
Ghaziabad, Uttar
Pradesh, 2Sri Gobind
KEY WORDS: Betel nut chewing, betel quid, oral health Tricentenary Dental
College, Hospital
and Research
Institute, Gurgaon,
INTRODUCTION potentially harmful effects on the oral cavity. These 3
Sudha Rustagi College
effects can be divided into two broad categories: of Dental Scinces and
The habit of chewing betel (or areca) nut is a habit Those affecting the dental hard tissues, which Research, Faridabad,
of great antiquity. Its use is globally acceptable Haryana, India
include teeth, their supporting periodontium and
among all sections of society, including women the temporomandibular joint (TMJ) and the soft For correspondence:
and quite often children.[1] Four factors form the tissues, which make up the mucosa that lines the Dr. Richa Anand,
foundation for the popularity of chewing betel nut 5E 46 BP,
oral cavity.[8] This article aims to review the effects
are: Social acceptability, religious beliefs, perceived New Industrial
of chewing betel nut on oral health. Township,
health benefits, and addiction.[2] Faridabad ‑ 121 001,
EFFECTS ON HARD TISSUES Haryana, India.
Betel nut is the fourth most commonly used E‑mail: richa_anand@
psychoactive substance in the world after caffeine, ymail.com
Excessive tooth abrasion and fractured teeth
alcohol, and nicotine. Betel nut is present in a The hard fibrous nature of the betel nut causes
number of chewing products like mawa, paan, fractured teeth and extensive abrasion of the
gutkha, khaini, and paan masala. Reasons for using
occlusal tooth surface of regular users. The
betel nut include achieving euphoria, combating
molars, premolars, and canine teeth frequently
fatigue, increasing salivation, attaining satiation,
completely lose their cuspal form and the incisors
and even seeking relief of toothaches.[3,4]
become shortened.[9] The loss of enamel may also
Chewing betel nut on a habitual basis is known expose the underlying dentine and as this is softer
to be deleterious to human health.[5] The World than enamel wears at an increased rate. The
Health Organization and International Agency exposure of dentine may also result in dentinal
for Research on Cancer classified betel nut as a sensitivity.[10] Access this article online
group 1 human carcinogens.[6] The International Website: www.cancerjournal.net
Agency for Research on Cancer considers paan and The degree of attrition is dependent upon several DOI: 10.4103/0973-1482.137958
gutkha as substances containing known human factors, which include the consistency (hardness) PMID: ***

carcinogens, of which the betel nut is believed to of the betel, the frequency of chewing, and the Quick Response Code:

be the main culprit.[7] A growing body of evidence
over the last 40 years, mainly in the form of
large‑scale epidemiological and experimental
studies, has shown that even when consumed
in the absence of tobacco or lime betel may have
duration of the habit. Root fractures have also
been demonstrated in chronic betel chewers and
this is likely to be a consequence of the increased
masticatory load that is placed upon the teeth and
is not direct effect of betel.[10]

Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3 499
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Anand, et al.: Betel nut and oral health
Betel staining
Chewing betel nut produces copious red saliva. With regular
betel quid (BQ) chewing, this stain becomes embedded in
the teeth, gingival, and oral mucosa[9] [Figure 1]. The color
ranges from red to black depending on the preparation and
the number of years of use. The darkening has been reported
to be caused by polymers of orthoquinones. Traditionally,
this tooth coloration was regarded as esthetically pleasing
by some societies, but with western influence it seems to be
becoming less.[11]
Dental caries
It has been suggested that betel chewing may confer protection
against dental caries. Epidemiological studies carried out in
southeast Asia suggest that the prevalence of dental caries in
betel chewers is lower than in non‑chewers.[12,13] The possible
reasons that BQ chewing diminishes dental caries are:
1. Betel stain which often coats the surface of the teeth, may
act as a physical barrier to tooth demineralization[14]
2. Tannin content of betel may have antimicrobial properties
and this may contribute to the cariostatic role of betel[15]
3. Chronic chewers have marked attrition of cusps of teeth
leading to loss of occlusal pits and fissures, which may
reduce the risk of pit and fissure caries by eliminating
potential stagnation areas
4. The process of chewing itself brings copious amounts of
saliva to the mouth and in the presence of added slaked
lime may increase the pH in the oral environment
5. The increased production of sclerosed dentine in response
to attrition may confer protection against microbial
invasion.
Some investigators, however, have shown that there is no
difference in the prevalence of dental caries between betel
chewers and non‑chewers in other Asian populations.[16]
TMJ pathology
It has been speculated that the chewing forces generated
during habitual betel nut use could give rise to deterioration
Figure 1: Stains due to betel nut consumption
500 Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
of the TMJ. However, there is no reliable data to substantiate
an increased prevalence in betel users and further studies
are required. Furthermore, this is difficult to prove because
many of the symptoms associated with TMJ pathology,
e.g. trismus, also occurs in fibrotic conditions linked to betel
nut use. It is difficult to distinguish a direct effect on the TMJ
from the fibrotic involvement of the oral musculature that
may contribute to limitation of mouth opening in chronic
chewers.[8]
EFFECTS ON SOFT TISSUES
Periodontal disease
The betel nut may be cytotoxic to periodontal fibroblasts
and may exacerbate preexisting periodontal disease as well
as impair periodontal reattachment. Some investigators
have shown that loss of periodontal attachment and
calculus formation is greater in betel chewers.[17‑20] However,
it is difficult to interpret such facts, as there are several
confounding variables such as the level of oral hygiene, dietary
factors, general health, and dental status, not to mention
tobacco smoking, which may have a significant influence on
periodontal status.
Oral mucosal lesions and conditions associated with BQ
chewing habits
Definition of quid
The term “quid” may be defined as “a substance or mixture of
substances (in any manufactured or processed form), placed in
the mouth or chewed and remains in contact with the mucosa,
usually containing one or both of the two basic ingredients,
tobacco, or betel nut, in raw or any manufactured or processed
form”. Thus, BQ is to be considered as a specific variety of quid;
it indicates any type of mixture or quid that includes betel leaf.[21]
Categories of quid
1. Quid with betel nut but without tobacco products (betel
nut quid) which may involve chewing only the betel nut
or betel nut quid wrapped in betel leaf (paan)
2. Quid with tobacco products but without betel nut (tobacco
quid) including chewing tobacco, chewing tobacco plus
lime, mishri (burned tobacco applied to the teeth and
gums), moist snuff, dry snuff, niswar (a different kind of
tobacco snuff), and naas (a stronger form of niswar)
3. Quid with betel nut as well as tobacco products (tobacco
and betel nut quid).[22]
Some oral mucosal lesions and conditions are specifically
associated with BQ chewing habits. Two categories of
quid‑related lesions are recognized:
• Lesions or conditions that are diffusely outlined, that
involve more than one site or that represent a widespread
alteration, such as those due to mechanical or chemical
trauma. Clinical lesions or conditions such as chewer’s
mucosa fall into this category, but transient states of the
mucosa, such as quid stains, are excluded[21]
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Anand, et al.: Betel nut and oral health
• Lesions that are localized to the site where quid is regularly
placed. These lesions are equivalent to snuff induced
lesions or tobacco lime user’s lesions, which arise only on
the mucosa in contact with the quid.[22,23]
Betel chewer’s mucosa
A condition of the oral mucosa where, because of either
direct action of the quid or traumatic effect of chewing, or
both, there is a tendency for the oral mucosa to desquamate
or peel [Figure 2]. Loose and detached tags of tissue can
also be seen and felt. The underlying areas assume a
pseudomembranous or wrinkled appearance. The area may
also show evidence of incorporation of ingredients of the quid
in the form of yellowish or reddish‑brown encrustations.[24]
The lesion is usually localized and is associated strongly with
the habit of BQ chewing, particularly in elderly women who
have been chronic chewers for long durations.[25] Several
epidemiological studies have shown that the prevalence of
betel chewer’s mucosa may vary between 0.2 and 60.8% in
different southeast Asian populations.[26‑29]
This lesion should be distinguished from morsicatio buccarum
and/or labiorum, cheek or lip biting, which are very similar to
betel chewer’s mucosa in terms of clinical appearance (without
stains) and histology. The differences are: Cheek biting is
unintentional; whereas, chewer’s mucosa results from an
intentional habit and the average age of the individuals with
chewer’s mucosa is usually higher, 50 years and older;[24]
whereas, in cheek biting it is generally younger, around
20-35 years.[30‑32]
Pathogenesis
Although the exact mechanisms underlying the development
of this condition are not fully understood, it is thought that
the chemical and traumatic effects of the BQ on the oral
mucosa may be significant factors. Betel chewing produces
reactive oxygen species (ROS) that is detrimental to oral
mucosa and can be directly involved in tumor initiation
a
b
c d
Figure 2: (a) Betel chewers mucosa, (b) betel-quid lichenoid lesion,
(c) oral leukoplakia, and (d) oral submucous fibrosis
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
process, by inducing mutation, or by making the mucosa
susceptible to BQ ingredients and environmental toxicants.
The production and release of ROS occurs under alkaline
conditions during the autoxidation of betel nut polyphenols,
in the BQ chewer’s saliva. The ROS can be directly involved
in the tumor initiation process, by inducing genotoxicity and
gene mutation, or by attacking the salivary proteins and
oral mucosa, leading to structural change in the oral mucosa
that may facilitate the penetration by other BQ ingredients
and environmental toxins. The nitrosation of betel alkaloids
to  AN‑specific nitrosamines occurs in the saliva of BQ chewers.
These AN‑specific nitrosamines are mutagenic, genotoxic, and
capable of inducing tumors in animal model.[33]
Furthermore, there is also evidence that the presence of
tobacco in the quid is not essential for the development of
betel chewers mucosa. At present betel chewers mucosa is not
considered to be potentially malignant, although the condition
often co‑exists with other mucosal lesions such as leukoplakia
and oral submucous fibrosis (OSF), which are well known for
their potential for malignant change.[34]
Quid‑Induced lesion
A quid‑induced lesion is a localized lesion of the oral mucosa
corresponding to the regular site of placement of quid. It is
characterized by one or more of the following characteristics:
change of normal color, wrinkled appearance, thickening of
the mucosa, scrapable or non‑scrapable epithelial surface, and
presence of ulceration. Examples of such quid‑induced lesions
are: Tobacco and lime user’s lesion, snuff‑induced lesions, and
BQ lesions.[23,35]
Betel nut‑related lesion
Betel nut chewers, as in chewers of other kinds of quids,
may have clinically healthy mucosa with no textural or color
changes. However, buccal mucosa, either bi‑ or unilaterally,
may show an ill‑defined whitish gray discoloration that
cannot be rubbed off. The mucosa, in addition, may show a
rough linen‑like texture and histologically show ortho‑ and/
or para‑keratinized epithelium.[36]
BQ lichenoid lesion
A quid‑induced lichenoid oral lesion has been reported
exclusively among BQ users.[37] It resembles oral lichen planus
but there are specific differences. It is characterized by the
presence of fine, white, wavy, parallel lines that do not overlap
or criss‑cross, are non‑elevated, and in some instances radiate
from a central erythematous area [Figure 2]. The lesion generally
occurs at the site of placement of the quid. This lesion was
described as a lichen planus‑like lesion, but it is now termed
a “betel‑quid lichenoid lesion”. This lesion may regress with
decrease in frequency, duration, or change in site of placement of
the quid. There may be complete regression when the quid habit
is given up. This lesion has been found to demonstrate a different
natural history from lichen planus in intervention studies, and
therefore it should be recognized as a specific entity.[21]
501
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Anand, et al.: Betel nut and oral health
Pathogenesis
These quid induced lesions are considered to be a type IV
contact hypersensitivity‑type lesion.[8]
Oral leukoplakia
Leukoplakia can be defined as a predominantly white patch
or plaque on the oral mucosa that cannot be characterized
clinically or pathologically as any other disease and is not
associated with any other physical or chemical agent except
tobacco [Figure 2]. Based on clinical appearance, leukoplakia
can be divided into several subtypes: Homogeneous (white),
speckled (red/white), nodular, or verrucous leukoplakia.[38]
Although there is considerable controversy and debate about
how to define oral leukoplakia there is little doubt that both
tobacco, in any form, and betel nut use are major risk factors
for developing this condition. Evidence of its relationship
with betel chewing has come from epidemiological data.[39‑43]
OSF
OSF was initially described in 1966 by Pindborg and Sirsat[3]
as an insidious, precancerous, chronic disease that may
affect the entire oral cavity and that sometimes extends
to the pharynx.[44,45] Although it is occasionally preceded
by the formation of vesicles, OSF is always associated
with a subepithelial inflammatory reaction followed by
fibroelastic changes of the lamina propria, accompanied
by epithelial atrophy. This process leads to stiffness of
the oral mucosa, which results in trismus and inability to
eat [Figure 2].[45] Various factors have been implicated in the
development of OSF, the most common of which is chewing
betel nut.[42,46‑48] Associations with tobacco use and vitamin
deficiency have also been reported.[49] Other causes which have
been proposed in the past but have not been substantiated
include excessive consumption of chilies, autoimmune
reaction, and nutritional factors, particularly iron deficiency.
The potentially malignant nature of this condition has been
well‑documented. A malignant transformation rate of 7.6%
over a period of 10 years was described in an Indian cohort.[50]
Clinical stages
Clinically, the earliest sign of OSF is mouth soreness, with
constant burning when eating spicy foods. OSF is categorized
clinically into three stages: Stomatitis, fibrosis, and sequelae.[51]
During the stomatitis phase, the oral mucosa contains areas of
erythema in which vesicles appear. These vesicles later rupture
and produce ulcers that heal via fibrosis (the second stage).
During the sequelae stage, the fibrosis extends and thickens
the floor of the mouth, decreasing tongue size, and causing
difficulty in speech and mastication. The buccal mucosa has
a mottled marble‑like appearance, with thick vertical fibrous
bands. These bands limit the mandibular range of motion and
cause the characteristic trismus. In addition, the dentition
often is stained as a scarlet color, and periodontal disease
typically is associated with OSF. Loss of auditory acuity may
occur secondary to fibrosis of the Eustachian tubes. Fibrosis
can extend down the oropharynx to the esophagus, causing
502 Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
dysphagia when eating solid foods. The primary complaint
of patients with this disease is progressive trismus resulting
from fibrosis of the buccal submucosa [Table 1].[51]
Pathogenesis of OSF
The betel nut has psychotropic and antihelminthic property
due to presence of betel alkaloids. Four alkaloids have been
conclusively identified in biochemical studies, arecoline,
arecaidine, guvacine, and guvacoline, of which arecoline is the
main agent. These alkaloids have powerful parasympathetic
properties which produce euphoria and counteract fatigue.[52]
Recently suggested pathogenesis of OSF is by dual action of
betel nut. It is suggested that arecoline not only stimulates
fibroblastic proliferation and collagen synthesis, but also
decreases its breakdown. This suggests that arecoline is the
active metabolite in fibroblast stimulation.[52]
Collagen accumulation
OSF results from increased production of collagen by
fibroblasts. In addition to this there is decreased breakdown
leading to accumulation of excessive amount of collagen.[52]
Increased collagen production
Under the influence of betel nut, fibroblasts differentiate into
phenotypes that produce more collagen. The alkaloids present
in betel nut, arecadine and arecoline are responsible for this.
Arecoline gets converted in to arecadine which is the active
metabolite. There is dose‑dependent increase in production of
collagen by fibroblasts under influence of these factors [Figure 3].[53]
Various cytokines are increased in OSF. These are: Transforming
growth factor beta (TGF‑beta), platelet‑derived growth
factor (PDFG), and basic fibroblast growth factor (bFGF).
These are fibrogenic growth factors that stimulate collagen
production. Another cytokine that has anticollagen effect is
interferon‑alpha (IFN‑alpha). This is decreased in OSF. Thus,
overall there is stimulation of collagen synthesis through
different mechanisms.[54]
Stabilization of collagen structure and decreased collagen
breakdown
One of the mechanisms that can lead to increased fibrosis is
by reduced degradation of collagen by forming a more stable
collagen structure. Betel nut contains tannin. Tannin has ability
to stabilize collagen by cross‑linking it. With the progression
of the disease type III collagen is almost completely replaced
Table 1: Clinical features of oral submucous fibrosis
Early Late
Blanching of mucosa Fibrous bands
Intolerance to spicy food Trismus
Petechiae Flattening of palate
Depapillation of tongue Hockey‑stick uvula
Oral ulceration Reduced tongue mobility
Leathery mucosa Xerostomia
Taste disturbance Keratosis
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Anand, et al.: Betel nut and oral health

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by type I.[55] Type I collagen is more resistant to degradation
than type III. An important finding from these studies is the
identification of excess alpha‑1 chains relative to alpha‑2,
suggesting an alteration of collagen molecules during the
progression of the disease. Although, the biological function
of this trimer is not known, it is regarded as more resistant to
degradation than the normal collagen molecule.[56]
Another component of betel nut that aids this cross‑linking
is copper. It is a constituent of enzyme lysyl oxidase. This
enzyme also causes cross‑linking and makes collagen resistant
to degradation by collagenase. Due to action of tannin and
copper, collagen that is produced in OSF is highly resistant to
remodeling and phagocytosis [Figure 3].[56]
It is fibroblast that brings about remodeling and phagocytosis
of collagen. As in OSF, these firoblasts are affected and
phenotypically changed, they cannot degrade collagen.
Studies on the effects of arecoline on both normal and OSF
fibroblasts in culture revealed an elevated rate of collagen
synthesis by OSF fibroblasts as compared to normal fibroblasts.
Although the reason for this elevation is not clear, some
authors proposed that it could reflect the clonal selection
of a highly fibrogenic cell population in the altered tissue
under the influence of local factors such as interleukin‑1 from
inflammatory cells. This leads to decrease in phagocytosis and
accumulation of collagen in oral mucosa [Figure 3]. Glycogen
consumption is physiologically related to cellular activity of
muscle fibers. Overactivity of muscles results in excessive
glycogen consumption; leading to its depletion. In betel nut
chewers there is overactivity of muscles due to repeated,
Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3
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continuous chewing and use of heavy force to crush the hard
nut. This increased muscle activity along with diminished
blood supply, following connective tissue changes leads to
muscle degeneration and fibrosis.[55]
Oral squamous cell carcinoma
There is historical evidence dating back nearly a century
that suggests that the betel nut may be involved in the
development of oral squamous cell carcinoma.[57‑59] Although
it is widely accepted that the presence of tobacco in BQ plays
an important role in the pathogenesis of oral squamous cell
carcinoma, the carcinogenic potential of betel in the absence of
other ingredients is less clear.[60] There are epidemiological data
from several studies that confirm that the habit of BQ chewing
increases the relative risk of developing oral squamous cell
carcinoma.[48,61‑64]
CONCLUSION
It is clear from the literature that betel nut use may have
significant effects on dental hard and soft tissues. Thus, there
is an urgent need to curb this ongoing epidemic of betel nut
habit. Legislation against open sale and use of such products
should be stricter and more states and countries should
bring out such legislations sooner than later. Public health
programs regarding the harmful effects of betel nuts, coupled
with increased awareness by healthcare professionals of the
signs and symptoms of this disease, can limit its prevalence
significantly. In addition to educating consumers about the
health risks of betel nut use, dental professionals need to
educate paan shop vendors about the repercussions of betel
503
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Anand, et al.: Betel nut and oral health
nut consumption and persuade them not to sell betel nut
products to minors.
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Cite this article as: Anand R, Dhingra C, Prasad S, Menon I. Betel
nut chewing and its deleterious effects on oral cavity. J Can Res Ther
2014;10:499-505.
Source of Support: Nil, Conflict of Interest: None declared.
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