JIDAM “An Official Journal of IDA - Madras Branch” ©2021. Available
online

ISSN No: 2582-0559

Volume No: 8, Issue No: 2

REVIEW ARTICLE

“GINGIVAL CREVICULAR FLUID AS A BIOMARKER OF

PERIODONTAL DISEASE”- A NARRATIVE REVIEW

Dr. Indumathi M, Dr.R.Shanmuga Priya, Dr.Sabitha Sudarsan, Dr.U.Arun Mozhi, Dr.R.Kadhiresan,

Department of Periodontics and Oral Implantology, Sri Venkateswara Dental College and Hospital Off OMR road,

near Navalur, Thalambur, Chennai, Tamilnadu, India

DOI:1.37841/jidam_2021_V8_I

2_04

Address for Correspondence

Dr.M.Indumathi,

Post Graduate Student

Department of Periodontics and Oral Implantology,

Sri Venkateswara Dental College and Hospital

Off OMR road,near Navalur, Thalambur, Chennai-603103

Email id: induvasan50@gmail.com

Received:

26.04.2021 First Published

31.05.2021

Accepted:

28.05.2021

Published:

27.06.2021

ABSTRACT

Periodontitis is one of the most common oral

diseases in the world. Periodontitis when diagnosed early
have  the  better  prognosis  for  the  individual  to  save  the
tooth.  Diagnostic  markers  are  useful  to  indicate  the
presence  of  a  disease  process  before  excessive  clinical
damage  occurs.  One  such  main  source  of  biomarker  is
gingival  crevicular fluid.   This  review  article  deals  with
Gingival crevicular fluid(GCF) as a source of biomarkers
for  periodontal  disease  progression  and  severity  which
helps  in  diagnosis  and  prognosis  in  the  field  of
Periodontology  and  also  details  about  available  various
chairside diagnostic kits for the biomarkers.

KEY WORDS:

Biomarkers, Gingival crevicular Fluid,

Periodontal Disease

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online

ISSN No: 2582-0559

Jaishree et al: Lipoxins for Resolution of Inflammation

Volume No: 8, Issue No: 2

INTRODUCTION:

Periodontitis is one of the most prevalent oral diseases

in  the  world.  Approximately  5–20%  of  adults  worldwide
suffer  from  severe  periodontitis  which  may  lead  to  tooth
loss1.  Thus,  the  complex  interaction  between  the  pathogens
and  the  host  response,  in  addition  to  environmental  and
genetic  factors  is  considered  as  the  common  bacterial
infection  in  the  world2.  Even  though  disease  initiation  is
brought  about  by  specific  bacteria,  tissue  destruction
subsequent to disease progression is caused by an imbalance
between the protective and destructive host mechanisms that
are  triggered  with  the  infection.  Further,  periodontitis  is
thought  to  be  a  multifactorial  disease;  risk  factors  such  as
uncontrolled  systemic  diseases  (e.g.  diabetes),  smoking  and
genetic  predisposition  can  contribute  to  the  progression  of
periodontal  disease

. Currently, most medical fields are

searching  for  useful  biological  diagnostic  markers  that  can
indicate  the  presence  of  a  disease  process  before  extensive
clinical damage has occurred. As far Dentistry is concerned,
various  fluids  in  the  oral  cavity  are  being  considered  as  a
source of diagnostic biomarkers in predicting disease and its
progression.

GCF AS A DIAGNOSTIC TOOL:

Early

diagnosis

and

treatment

progressive

Periodontitis is important because of the irreversible nature
of this disease

. .One of the goal of periodontal diagnostic

procedures  is  to  provide  useful  information  to  the  clinician
regarding  the  current  periodontal  disease  type,  location  and
severity.  These  findings  serve  as  a  basis  for  treatment
planning  and  provide  essential  data  during  periodontal
maintenance and disease monitoring phases of treatment.

There is a need for the development of new diagnostic

tests  that  can  detect  the  presence  of  active  disease,  predict
future  disease  progression  and  evaluate  the  response  to
periodontal  therapy,  thereby  improving  the  clinical
management  of  periodontal  patients.  Advances  in  oral  and
periodontal  disease  diagnostic  research  are  moving  toward
methods  whereby  periodontal  risk  can  be  identified  and
quantified by objective measures such as biomarkers.

The collection of GCF is a minimally invasive

procedure  and  the  analysis  of  specific  constituents  in  the
GCF  provides  a  quantitative  biochemical  indicator  for  the
evaluation  of  the  local  cellular  metabolism  that  reflects  a
person’s  periodontal  health  status.  Since  GCF  is  an
inflammatory  exudate  that  reflects  ongoing  events  in  the
periodontal  tissues  that  produce  it,  an  extensive  search  has
been made for GCF components that might serve as potential

diagnostic or prognostic markers for the progression of
periodontal disease. (Fig 1)

FIGURE 1: Gingival crevice fluid – a window to periodontal

disease. Gingival crevice fluid is composed of substances

derived from serum, leukocytes, bacteria, activated epithelial

cells, connective tissue cells, and bone cells.

Several techniques have been employed for the

collection  of  GCF  and  the  technique  chosen  depends  upon
the  objectives  of  the  stud,  as  each  technique  has  its  own
advantages  and  disadvantages.  The  methods  of  collection
may be broadly divided into the intracrevicular and the extra
crevicular techniques. The former depends on the strip being
inserted  into  the  gingival  crevice,  whereas  in  the  latter,  the
strips  are  overlaid  on  the  gingival  crevice  region  in  an
attempt to minimize trauma.

BIOMARKERS IN GCF:

Host-derived enzymes and their inhibitors

•

Aspartate aminotransferase

It is a cytoplasmic enzyme that is released upon cell

death and elevated levels of total enzyme activity were found
to be strongly associated with active disease sites.[5] Sites
with severe gingival inflammation and progressive
attachment loss demonstrate marked elevation in AST levels
in GCF samples

•

Alkaline Phosphatase

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online

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Jaishree et al: Lipoxins for Resolution of Inflammation

Volume No: 8, Issue No: 2

It is a membrane-based glycoprotein produced by many

cells  within  the  area  of  the  periodontium  and  gingival
crevice.  Alkaline  phosphatase  is  thought  to  play  a  role  in
bone metabolism and mineralization and collagen formation.
The  activity  of  alkaline  phosphatase  has  shown  to  be
correlated  with  pocket  depth  and  the  percentage  of  bone
loss

, this activity was found to be 20 times greater in GCF

from active sites than in serum.

•

Acid phosphatase

It has been widely investigated amongst the lysosomal

enzymes  and  has  often  been  used  as  a  lysosomal  marker.
Quantitative  analysis  confirmed  that  gingival  fluid  contains
10-20  times  more  acid  phosphatase  than  serum.  The  host
sources  are  the  PMNs  and  desquamating  epithelial  cells8.
About  60%  of  the  total  acid  phosphatase  in  whole  gingival
fluid originates from bacteria. The levels of acid phosphatase
do  not  correlate  with  measurements  of  disease  severity  or
activity.

•

β –Glucuronidase

It is one of the hydrolases found in the azurophilic or

primary  granules  of  PMNs.  The  enzyme  is  liberated  from
macrophages,  fibroblasts  and  endothelial  cells  of  healthy  or
chronically  inflamed  gingival  tissues.  The  level  of  β-
glucuronidase  correlates  significantly  with  attachment  loss
that  may  subsequently  occur  in  individuals  with  adult
periodontitis

•

Elastase

Neutrophil elastase is a serine proteinase confined to the

azurophil  granules  of  PMNs  which  are  analogous  to
lysozymes.  It  acts  upon  elastin,  proteoglycans,  hemoglobin,
fibrinogen and collagen. Leukocyte elastase degrades mature
collagen  fibers.  Amounts  of  GCF  elastase  are  greater  in
periodontitis patients than healthy controls

•

Macroglobulins (Alpha 2,Beta 2):

Macroglobulins play a major role in the immune

system. They have the ability to inactivate varied microboita,
thereby  protecting  oral  tissues.  Alpha  2M  has  been
associated  with  tissue  destruction  whereas  Beta  2M  plays  a
role  in  T  and  B  lymphocytes  response.  Inflammed  tissues
release  Alpha  2M  and  Beta  2M  to  stall  inflammation  and
negate proliferation of micro-organisms.

•

Cathepsins:

It is an enzyme belonging to the class of cysteine

proteinases. In GCF, macrophages are the main producers of
cathepsin B11. GCF concentrations of cathepsin B were
found to be elevated in patients with periodontal disease, but
lower in patients with gingivitis

. Cathepsin D, a carboxy

endopeptidase,  is  present  at  high  concentration  in  inflamed
tissues.  Its  concentration  is  found  to  be  10  times  higher  in
GCF  during  periodontal  destruction.  Cathepsin  G  is  serine
endopeptidase contained in the azurophil granules of PMNs.
It  hydrolyzes  hemoglobin  and  fibrinogen,  casein,  collagen
and  proteoglycans.  Measurements  of  cathepsin  and  neutral
proteases,  have  also  shown  a  relationship  to  the  severity  of
inflammation  but  no  association  with  disease  activity  has
been demonstrated.

•

Dipeptidyl Peptidases (DPP)

They are derived from lymphocytes, macrophages, and

fibroblasts.  DPP  II  has  been  localised  to  macrophages  and
fibroblasts  in  gingival  tissue  and  in  cells  in  GCF13.  DPP
Eley and Cox, monitored GCF levels of DPP II and IV and
reported  higher  levels  of  both  enzymes  in  sites  with  rapid
and  gradual  attachment  loss  than  in  paired  sites  without
attachment loss

•

Collagenase-2 (MMP-8)

MMP-8 is also called collagenase-2. It is predominant

collagen  in  GCF.  Increased  levels  of  MMP-8  in  GCF  is
associated  with  severity  of  periodontitis.  It  is  released  from
PMNs  during  maturation.  Increased  levels  of  MMP-8  are
signify  conversion  of  gingivitis  into  periodontitis.  No
associations  are  found  between  MMP-8  levels  and  a  bone
loss. It was found that 18-fold increase of MMP-8 in patients
experiencing  active  periodontal  tissue  breakdown  as
compared with patients under stable condition

•

Gelatinase (MMP-9)

Gelatinase

(MMP-9),

another

member

the

collagenase family, is produced by neutrophils and degrades
collagen  extracellular  ground  substance.  There  is  a  twofold
increase  in  mean  MMP-9  levels  is  reported  in  patients  with
recurrent attachment loss.

•

Collagenase-3 (MMP-13)

Collagenase-3, referred to as MMP-13, is another

collagenolytic  MMP  with  exceptionally  wide  substrate
specificity.  The  expression  of  MMP13  is  specifically
induced  in  undifferentiated  epithelial  cells  during  chronic
inflammation  due  to  exposure  to  cytokines  and  collagen.
MMP-13  has  also  been  implicated  in  peri-implantitis.
Elevated  levels  of  both  MMP-13  and  MMP-8  are  correlate

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Jaishree et al: Lipoxins for Resolution of Inflammation

Volume No: 8, Issue No: 2

with irreversible peri-implant vertical bone loss around
loosening dental implants

•

Tissue inhibitors of matrix metalloproteinases
(TIMPs)

They are locally produced and their main role is

defending  connective  tissues  in  the  very  local  area  around
the  cell  from  which  metalloproteinases  are  secreted.  The
tissue  degradation  is  further  thought  to  be  induced  by  an
imbalance  between  MMPs  and  TIMP

. The mean amounts

of SL and TIMP in diseased sites (gingivitis and
periodontitis) is significantly higher than the mean amount of
these GCF components in healthy sites

Tissue Breakdown Products

•

Glycosaminoglycans

Proteoglycans have a core protein on which one or

more heteropolysaccharides (called glycosaminoglycans) are
bound covalently. In general, chondroitin-4-sulfate is the
most common glycosaminoglycan in the periodontium.
Chondroitin-4-sulfate

appears

the

major

glycosaminoglycan  in  untreated  chronic  periodontitis  sites,
as  shown  in  both  animal  and  human  studies.  Elevated
glycosaminoglycan  concentrations  were  also  found  in
aggressive  periodontitis,  and  associations  have  been  made
with  periodontal  pathogens  such  as  P.  gingivalis

. It is

elevated in peri implantitis patient.

•

Hydroxyproline

It is a characteristic amino acid and is a major

component of the collagen. Hydroxyproline and proline play
key role for maintaining collagen stability. They permit the
sharp twisting of the collagen helix. Thus it is a major
breakdown product of collagen present in the GCF

•

Fibronectin fragments

It is one of the components of the extracellular matrix

(ECM) of periodontal tissue

its main role is in cell

adhesion  and  proliferation,  which  explains  its  potential  use
in  regenerative  strategies.  The  presence  in  GCF  would
indicate  fibronectin  fragmentation  due  to  tissue  destruction
and not simply inflammation

Connective tissue and Bone proteins

•

Osteonectin

Also referred to as secreted protein acidic and rich in

cysteine and basement membrane protein (BM-40),
osteonectin is a single-chain polypeptide that binds strongly

to hydroxyapatite and other extracellular matrix proteins
including collagens. Because of its affinity for collagen and
hydroxylapatite, osteonectin has been implicated in the early
phases of tissue mineralization

•

Osteocalcin

It is a small calcium-binding protein of bone and is the

most abundant non collagenous protein of mineralized
tissues

. Osteocalcin is predominantly synthesized by

osteoblasts  and  it  has  an  important  role  in  both  bone
resorption  and  mineralization  [25].  Elevated  serum
osteocalcin levels have been shown in periods of rapid bone
turnover.  Serum  osteocalcin  is  presently  considered  a  valid
marker of  bone  turnover  when  resorption  and formation  are
coupled,  and  a  specific  marker  of  bone  formation  when
formation and resorption are uncoupled.

•

Type I collagen peptides:

The most common extracellular matrix component is

collagen,  which  is  synthesized  in  a  pro-form  containing  a
terminal propeptide. Collagen I carboxy-terminal propeptide
and  collagen  III  amino-terminal  propeptide  were  detectable
in the GCF of patients with periodontitis, but not in healthy
subjects, suggesting that turnover is higher in inflamed sites.
The  GCF  levels  of  these  collagens  are  increased  after
nonsurgical  periodontal  treatment  and  return  to  baseline
levels after a few days.

•

Receptor activated nuclear factor-kappa B ligand
(RANKL):

Receptor activated nuclear factor-kappa B ligand

(RANKL)  was  another  frequently  reported  biomarker  that
was  reported  in  six  studies.  These  studies,  except  (Inanc  et
al.,  2014)

reported an increased concentration of RANKL

in GCF of patients with periodontitis versus that of control
patients.

•

Osteopontin (OPN):

It is a single-chain polypeptide. In bone matrix, OPN is

highly concentrated at sites where osteoclasts are attached to
the  underlying  mineral  surface,  that  is,  the  clear  zone
attachment  areas  of  the  plasma  membrane.  In  2006,
published  findings  from  an  investigation  of  GCF  OPN  that
its  concentrations  increased  proportionally  with  the
progression  of  disease  and  when  nonsurgical  periodontal
treatment was provided, its levels were significantly reduced.

•

Laminin:

It is a 900-kDa glycoprotein found in all basement

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membranes. During gingival inflammation, neutrophils leave
the blood vessels and migrate through the connective tissue
towards the inflammatory lesion, and some of them invade
the gingival crevice.

Higher amounts of laminin in GCF from patients with

periodontitis suggest the presence of hyperactive neutrophils
during

the

transmigration

process

through

the

endothelium/epithelium

•

Calprotectin

It is a 36-kDa protein composed of a dimeric complex

of  8-  and  14-kDa  subunits.  It  also  plays  a  role  in  immune
regulation  through  its  ability  to  inhibit  immunoglobulin
production  and  acts  as  a  proinflammatory  protein  for
neutrophil recruitment and activation.

The expression of calprotectin from inflammatory cells

appears to offer protection of the epithelial cells against
binding and invasion by P. gingivalis. In periodontal disease,
it appears to improve resistance to P. gingivalis by boosting
the barrier protection and innate immune functions of the
gingival epithelium

•

Hemoglobin β-chain peptides

Two peptides derived from the hemoglobin (Hb) are β-

chain  decapeptide  and  a  dodecapeptide.  They  are
pharmacologically  and  physiologically  active,  and  act  as
inflammatory  mediators

. Both peptides may also act as

substrates  of  proline-specific  peptidases  studied  in
treponemes  isolated  from  the  human  subgingival  dental
plaque.  These  two  particular  Hb  β-chain  sequences  were
present  in  GCF  and  successful  periodontal  therapy  will
reduce the levels of these peptides

•

Pyridinoline crosslinks (ICTP)

They represent a class of collagen-degrading molecules

that include pyridinoline, deoxypyridinoline, N-telopeptides,
and  C-telopeptides31.  Subsequent  to  osteoclastic  bone
resorption  and  collagen  matrix  degradation  these  molecules
are  released  into  the  circulation.  Given  their  specificity  for
bone  resorption,  pyridinoline  cross-links  represent  a
potentially  valuable  diagnostic  aid  in  periodontics,  because
biochemical  markers  specific  for  bone  degradation  may  be
useful  in  differentiating  the  presence  of  gingival
inflammation from active periodontal and peri-implant bone
destruction

Inflammatory mediators and host response modifiers:

•

Interleukin 1ß:

Studies reported a presence of IL-1β in diseased sites,

low  levels  of  IL-1β  in  healthy  peri-implant  sites,
significantly  high  levels  of  IL-1β  in  periodontal  disease
patients  as  compared  to  controls  and  a decrease  in  the  level
of  IL-1β  with  an  improvement  in  clinical  parameters
following treatment.

•

Prostaglandin E2:

Arachidonic acid metabolites like PGE2 play a key role

in  the  progression  of  periodontal  destruction.  PGE2,  a
metabolite  of  cyclooxygenase  pathway,  is  considered  to
induce  fibroblasts  and  osteoblasts  activity  for  the  synthesis
of  MMPs,  IL-1b  and  other  cytokines.  PGE2  levels  are
enhanced  and  have  been  correlated  with  the  severity  of
periodontal disease.

PERI IMPLANT CREVICULAR FLUID (PICF) IN
PERI IMPLANTITIS:

•

Bone Markers: (RANK, RANKL)

Soluble RANKL and OPG levels were evaluated in 84

samples of PICF from implants showing different peri-
implant tissue clinical conditions without demonstrating any
correlation between these levels and the studied clinical
outcomes

However, one study demonstrated the presence of OPG

in 79% of the PICF samples and showed a positive
correlation between BOP, while RANKL was only detected
in 12% of PICF samples and did not show any positive
correlation with clinical inflammation.

•

Enzymes: (MMP,CATHEPSIN K)

CatK is a known marker of bone turnover due to its key

role  in  remodeling  and  cartilage  breakdown  in  bone  by
hydrolyzing  extracellular  bone  matrix  proteins.  CatK  is
highly  and  quite  selectively  expressed  in  active,  resorbing
osteoclasts.  This  suggests  its  role  in  the  pathogenesis  of  PI.
CatK  levels  were  evaluated  in  PICF  to  assess  the  levels  of
CatK  in  healthy  implants  and  PI  in  order  to  correlate  these
findings  with  clinical  parameters34.  The  authors  concluded
that  increased  levels  of  MMP-8  and  IL-1_  in  PICF  or  GCF
may  be  associated  with  inflammation  around  teeth  and
implants  while  lower  levels  of  MMP-1/TIMP1  may  be  an
indicator of disease progression around implants

CHAIRSIDE DIAGNOSTIC KITS: -

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Jaishree et al: Lipoxins for Resolution of Inflammation

Volume No: 8, Issue No: 2

•

Biochemical tests: (Fig-2)

•

Microbial tests: (Fig-3)

•

Genetic Test

The Periodontitis Susceptibility Trait test (PST) is the

test which identifies the genetic predisposition of the patient
for  periodontitis  by  detecting  the  polymorphism  in  IL-1
gene.  Polymorphism  in  two  positions  of  IL-1  i.e  position  -
889  and  +  3953  has  been  associated  with  periodontal
disease35.  Within  both  polymorphisms  allele  1  harbors  a
cytidin  (C),  whereas  allele  2  carries  a  thymidin  (T)  at  the
respective  position.  In  particular,  when  both  genes  carry
allele  2  a  strong  over-production  of  the  local  inflammatory
mediator, interleukin-1 will occur.

•

Implant Safe Rapid Test Kit

The ImplantSafe® device may be useful in

differentiating  active  from  inactive  periodontal  and  peri-
implant  sites  easily,  quickly  and  inexpensively  with  high
sensitivity  and  specificity  (sensitivity  of  90%  and  a
specificity  of  70%–85%)

[36]

. Elevated levels of MMP-8 in

PICF are associated with peri-implant inflammation while

low MMP-8 levels (<20 ng/mL) indicate healthy peri-
implant tissues. Pathologically elevated levels of MMP-8
(>20 ng/mL) can be detected by a quantitative MMP-8 chair-
side device, ImplantSafe®

37.

CONCLUSION:

GCF as a diagnostic and prognostic tool has been

explored  since  the  initial  studies  on  GCF  which  aimed  to
demonstrate  that  the  flow  of  gingival  fluid  was  sufficiently
indicative  of  the  inflammatory  state  of  the  periodontal
tissues. Over time, research methods have evolved to enable
the  assessment  of  the  transition  phase  between  health  and
inflammation  at  the  gingival  level  to  disease  progression.
More  recently,  metabolomic  analysis  that  measure  small
degradation  molecules  associated  with  host  and  bacterial
metabolism  show  promise.  There  may  be  many  different
cytokine  inflammatory  pathways  or  microbial  stimuli  that
are  associated  with  the  causal  pathway  of  periodontal
pathogenesis.

Prospective healthcare is a new approach that

incorporates  all  the  power  of  current  disease-oriented
medicine  but  is  based  on  the  concept  of  strategic  health
planning,  a  proactive,  prospective  approach  to  care.  In  this
system, individuals are evaluated to determine their baseline
risk  for  a  specific  disease,  their  current  health  status,  and
their  likelihood  of  developing  specific  clinical  problems
given  their  risks.  As  mentioned  before,  allocation  of
resources  to  prevent  periodontitis/peri-implantitis  would  be
optimized  and  may  help  to  reduce  costs  if  diagnostic
information  would  assist  in  identifying  susceptible  patients
and  help,  providing  more  specific  prevention/treatment
strategies for high-risk and low-risk patients.

ACKNOWLEDGEMENT

‘a’  designed  the  study,  searched  relevant  articles  and
collected  data.  ‘a’  and  ‘b’  participated  in  the  data
interpretation  and  analysis.  ‘a’  and  ‘c’  prepared  the
manuscript. All the three authors read and approved the final
manuscript.

CONFLICTS OF INTEREST

There are no conflicts of interest.

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Volume No: 8, Issue No: 2

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