Analysis of gingival crevice uid

and risk of progression of

periodontitis
Gary C. Armitage
Gingival crevice fluid
Gingival crevice uid (GCF) is an inammatory exu-
date that seeps into gingival crevices or periodontal
pockets around teeth with inamed gingiva (29). It is
composed of serum and locally generated materials
such as tissue breakdown products, inammatory
mediators, and antibodies directed against dental
plaque bacteria. It is often a clear uid, but can
contain variable numbers of neutrophils that
increase its turbidity. Since 1960, when it was rst
suggested that analysis of GCF might be a way to
quantitatively evaluate the inammatory status of
gingival and periodontal tissues (20), there has been
intense interest in the diagnostic potential of GCF.
The amount of GCF produced at a given site signi-
cantly increases (P < 0.05) with the severity of gingi-
val inammation as assessed clinically (r 0.330.90)
or histometrically (r 0.330.70) (7). Although there
is extensive variation, severely inamed sites gene-
rally produce more GCF than less inamed sites.
The amount of GCF produced is directly related
to the increased vascular permeability and ulcera-
tion of the pocket epithelium at inamed sites. The
observation that there is a signicant association
between the amount of GCF and the severity of
inammation has no practical clinical applica-
tion in the management of patients. Quantitative
assessments of GCF volume have, however, been
extensively used in research studies as a relatively
objective measurement of gingival inammation
that can supplement assessments made using
somewhat subjective clinical indices of inamma-
tion.
Thesearchforaclinicallyuseful GCF
marker of the progression of
periodontitis challenges and
opportunities
In the current practice of periodontics there is no
way a clinician can tell, from a one-time examina-
tion of a site with gingivitis or periodontitis, if that
site is currently breaking down (i.e. progressing) or
is on the verge of doing so. Progression in this context
refers to the occurrence of additional clinical attach-
ment loss or bone resorption. Because of this diag-
nostic problem, despite the knowledge that all
inamed sites are not necessarily progressing (8,
39, 40), clinicians must assume that such sites are
at an increased risk of progression. Since GCF is an
inammatory exudate that reects 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 periodontitis (8,
4148, 90).
Over 65 GCF components have been preliminarily
examined as possible markers for the progression of
periodontitis. These components fall into three gen-
eral categories:
host-derived enzymes and their inhibitors
(Table 1);
inammatory mediators and host-response modi-
ers (Table 2);
tissue-breakdown products (Table 3).
Although many different approaches and study
designs have been used to address the issue,
109
Periodontology 2000, Vol. 34, 2004, 109119 Copyright
#
Blackwell Munksgaard 2004
Printed in Denmark. All rights reserved
PERIODONTOLOGY 2000
the systematic evaluation of some of these GCF
markers has often involved the following types of
studies:
Biological plausibility (mechanism)
Cross-sectional (case-control) studies in humans
Experimental animal studies
Longitudinal studies in humans with untreated
periodontitis
Longitudinal studies of nonsurgical treatment in
humans with periodontitis
Treated and maintained patients
Biological plausibility studies
The quest for potential disease markers in GCF
always starts with the question, ``Is there any reason
to believe that a specic GCF component should be
associated with the progression of periodontitis?'' In
some cases the specic GCF components are tissue-
breakdown products such as bone-specic proteins.
In other instances, proposed involvement of GCF con-
stituents centers around their tissue-destructive cap-
ability (e.g. enzymes) or proinammatory potential
Table 1. Host-derived enzymes and their inhibitors in gingival crevice uid. Many of them have been preliminarily
studied as possible markers for the progression of periodontitis
Aspartate aminotransferase (10, 79, 89, 111, 118, 123, 136, 139, 148)
Alkaline phosphatase (14, 24, 25, 112)
Acid phosphatase (14)
b-Glucuronidase (21, 28, 62, 91, 94)
Elastase (9, 11, 27, 35, 65, 66, 73, 76, 77, 108, 110, 121, 140, 150)
Elastase inhibitors
a
2
-Macroglobulin (1, 3, 26, 137)
a
1
-Proteinase inhibitor (1, 3, 73, 108)
Cathepsins
Cysteine proteinases (B, H, L) (26, 35, 37, 86)
Serine proteinase (G) (88, 141)
Cathepsin D (21)
Trypsin-like enzymes (35, 63)
Immunoglobulin-degrading enzymes (63)
Glycosidases (13)
Dipeptidyl peptidases (30, 35, 36, 38, 56)
Nonspecific neutral proteinases (12, 19)
Collagenases
Matrix metalloproteinase-1 (MMP-1) (74, 145)
Matrix metalloproteinase-3 (MMP-3) (5, 74, 130)
Matrix metalloproteinase-8 (MMP-8) (22, 27, 74, 84, 106, 130, 140)
Matrix metalloproteinase-13 (MMP-13) (84)
Gelatinases
Matrix metalloproteinase-2 (MMP-2) (104)
Matrix metalloproteinase-9 (MMP-9) (11, 74, 104, 143)
Tissue inhibitor of MMP-1 (TIMP-1) (5, 67, 74, 145)
Stromyelysins (67)
Myeloperoxidases (21, 150)
Lactate dehydrogenase (10, 91)
Arylsulfatase (91)
Creatinine kinase (10)
b-N-acetyl-hexosaminidase (21)
Armitage
110
(e.g. host-response modiers). Occasionally, the pro-
posed marker is associated with protection from
infection, has potent anti-inammatory activities,
or is an indicator of wound healing.
Cross-sectional (case-control) studies in
humans
Usually the next step in the evaluation of GCF com-
ponents as potential markers of disease progression
is a cross-sectional study comparing sites that are
periodontally healthy (i.e. not inamed, no clinical
attachment loss), those that have gingivitis (i.e.
inamed but no clinical attachment loss), and those
that have periodontitis (i.e. inamed with consider-
able clinical attachment loss). A useful marker should
be able to distinguish between these three groups.
Most proposed markers can easily distinguish
between healthy and inamed sites. However, use
of a GCF test to obtain this piece of information
adds nothing to what the clinician has already deter-
mined from a clinical examination of the sites. Since
both gingivitis and periodontitis are inammatory
lesions, many GCF components that are some sort
Table 2. Inammatory mediators and host-response modiers in gingival crevice uid. Many of them have been
preliminarily studied as possible markers for the progression of periodontitis
Cytokines
Interleukin-1a (107, 127, 128)
Interleukin-1b (34, 52, 54, 71, 125, 127, 128, 131, 144, 147)
Interleukin-1ra (125)
Interleukin-2 (34)
Interleukin-6 (17, 64, 127)
Interleukin-8 (28, 53, 77, 107, 119, 144)
Tumor necrosis factor a (16, 17)
Interferon a (107)
RANTES (chemoattractant and activator of macrophages and lymphocytes) (55)
Prostaglandin E
2
(34, 70, 77, 97, 112, 114, 124, 131, 140, 149)
Leukotriene B
4
(50)
Acute-phase proteins
Lactoferrin (2, 3, 53, 66, 109, 110)
Transferrin (1, 3)
a
2
-Macroglobulin (1, 3, 26, 137)
a
1
-Proteinase inhibitor (1, 3, 73, 108)
C-reactive protein (137)
Autoantibodies
Anti-desmosomal antibody (60)
Antibacterial antibodies
IgG
1
, IgG
2
, IgG
3
, IgG
4
(16, 33, 34, 62, 78, 92, 126, 133, 134, 147)
IgM (62, 92, 133, 134)
IgA (16, 33, 34, 61, 62, 92, 133)
Plasminogen activator (PA) (85, 151)
PA inhibitor-2 (PAI-2) (85, 151)
Substance P (68, 98, 102)
Vasoactive intestinal peptide (99)
Neurokinin A (98, 102)
Neopterin (120)
Platelet-Activating Factor (51)
CD14 (75)
Cystatins (15, 26)
Calgranulin A (MRP-8) (101, 103)
111
Gingival crevice fluid and periodontitis
of inammatory marker are signicantly elevated in
both conditions. In other words, analysis of GCF is
often unable to distinguish gingivitis sites from those
with periodontitis.
Another serious impediment to the evaluation of
GCF components as potential markers of the pro-
gression of periodontitis is that only a small percen-
tage of sites that have been assigned the clinical
diagnosis of periodontitis actually progress in a given
period of time. In untreated human populations, if a
2 mm increase in clinical attachment loss is used as
the criterion for progression, only about 510% of
sites with periodontitis will progress in a 12-month
period (9, 32, 59, 69). Therefore, even if a GCF com-
ponent distinguishes between gingivitis and period-
ontitis, it may not be able to reliably separate
progressing and non-progressing periodontitis sites.
Finally, it is impossible from cross-sectional studies
to identify progressing lesions; only longitudinal stu-
dies can detect sites that have progressed (i.e. by
documenting increases in clinical attachment loss
measurements).
Experimental animal studies
One way to be certain that sites are breaking down
(i.e. progressing) is to experimentally produce peri-
odontitis in animal models. This is often done by
tying ligatures around the teeth, thus promoting
the accumulation and retention of periodontitis-pro-
ducing biolms. Studies of ligature-induced period-
ontitis in dogs (23, 58, 113, 135) and monkeys (114)
have been conducted to determine if peak production
of certain GCF components coincide with ongoing
destruction of the periodontium. These studies have
shown signicant associations between periodontal
breakdown and increases in the GCF content of
aspartate aminotransferase (23), prostaglandin E
2
(113, 114), pyridinoline cross-links (58), and certain
glycosaminoglycans (135). Although the information
from ligature-induced periodontitis studies is inter-
esting, the experimental model produces short-lived
and massive bursts of destruction that have no coun-
terpart in the pathogenesis of chronic periodontitis.
Nevertheless, surges in certain GCF components
during periods of destruction support the notion that
these components might be good candidates for
markers of the progression of chronic periodontitis.
Longitudinal studies in humans with
untreated periodontitis
Another common approach for evaluating the poten-
tial value of GCF components as markers of disease
progression is to follow a group of untreated period-
ontitis patients over a specied time period (9, 31, 91,
92, 121). In this type of study one looks for associa-
tions between increased production of putative GCF
markers and increased clinical attachment loss mea-
surements. Such studies serve a valuable function in
that they narrow the eld of candidates for diagnostic
or prognostic markers. However, there is no guaran-
tee that GCF components that appear to be good
markers of progression in untreated sites or patients
will also be good markers in treated patients or sites.
Treatment such as scaling and root planing pro-
foundly alters (at least temporarily) the subgingival
ecosystem and changes the spectrum of GCF com-
ponents. The important point is that progression-
associated factors found at untreated versus treated
sites might be quite different. Finally, if a validated
marker of progression existed, it would not be prac-
tical or cost-effective to use it at all untreated sites
since the majority of treated sites are not at high risk
for progression. The test would be wasted on a large
number of treatment-responsive sites.
Longitudinal studies of nonsurgical
treatment in humans with periodontitis
These studies usually evaluate the short-term effect
of scaling and root planing on the level of GCF com-
ponents. As might be expected, nonsurgical treat-
ment usually results in a decline of most potential
Table 3. Tissue-breakdown in gingival crevice uid.
Many of them have been preliminarily studied as
possible markers for the progression of periodontitis
Glycosaminoglycans
Hyaluronic acid (49, 132, 138)
Chondroitin-4-sulfate (49, 93, 116, 132, 138)
Chondroitin-6-sulfate (49, 116)
Dermatan sulfate (49)
Hydroxyproline (4)
Fibronectin fragments (72, 100)
Connective tissue and bone proteins
Osteonectin (18)
Osteocalcin (87, 96, 112)
Type I collagen peptides (18)
Osteopontin (83)
Laminin (53)
Calprotectin (81, 82, 109, 111)
Hemoglobin b-chain peptides (105)
Pyridinoline crosslinks (ICTP) (6, 57, 58, 117, 122, 142)
112
Armitage
markers for progressive periodontitis (62, 134, 138).
Conversely, some studies have demonstrated that
potential markers remain elevated at sites that did
not respond to treatment (127, 128). This latter
observation potentially has some clinical importance
since it would be very useful to know if a given site
was still at an increased risk of progression at an
evaluation visit 46 weeks after completion of scaling
and root planing procedures. Continued elevation of
such a marker might indicate that additional treat-
ment is required prior to placing the patient on a
maintenance program. The difculty, of course, is
how to identify post-scaling and root planing sites
that might still be at high risk for progression. In
other words, how can the clinician identify those
sites that need to be tested? Unfortunately, there is
no satisfactory answer to this question. The only
thing that the clinician can do is to rely on clinical
judgment as to what sites should be tested. Such
judgments might be based on such factors as:
previous history of progression at the site,
persistence of clinical signs of inammation,
persistence of probing depths 5 mm that might
be difcult to clean at future maintenance visits,
teeth of high strategic importance in the overall
treatment plan.
Treated and maintained patients
Although all of the above approaches have provided
interesting information on uctuations in GCF com-
ponents with various states of health and disease,
they do not address a fundamentally important ques-
tion. If a fully validated site-specic GCF test for the
progression of periodontitis were discovered, in what
clinical situations would it be most useful? High on
the list of clinical applications of such a test would be
in patients who have been treated and are in the
maintenance phase of therapy. Indeed there is very
little information to help clinicians detect high-risk
sites before additional damage has occurred. Based
on a limited meta-analysis it has been established
that sites that repeatedly exhibit bleeding on probing
at multiple maintenance visits are approximately at a
3-fold increased risk of losing further attachment (8).
Conversely, sites that do not exhibit any clinical signs
of inammation (i.e. redness, swelling, bleeding on
probing) are at a negligible risk of progressing (8).
Only a few studies have attempted to longitudin-
ally evaluate GCF markers in treated and maintained
populations of patients (3638, 78, 95, 143). Prelimin-
ary results suggest that GCF levels of cathepsin B
(37), dipeptidyl peptidases (36, 38), MMP-9 (gelati-
nase) (143), and collagenase activity (95) show some
promise as potentially useful markers of the risk of
disease progression. Although these studies are dif-
cult to conduct, they are necessary to validate the
clinical utility of GCF markers. Among the difculties
encountered are uncertainties regarding which sites
should be tested and the very low number of sites
that break down in treated and maintained patients.
If one actually had a validated GCF marker of pro-
gression, the nal evaluation step would be to con-
duct randomized controlled clinical trials designed
to determine if use of the test resulted in better treat-
ment outcomes (e.g. decreased number of sites with
progression, retention of teeth). These types of stu-
dies are nonexistent since a validated marker has not
emerged.
What type of GCF markers have the most
promise?
Some of the enzymes listed in Table 1 have the
potential to be useful markers of disease progression.
However, a major problem with enzymes is that it is
often difcult for them to distinguish between gingi-
vitis and periodontitis sites or between non-progres-
sing and progressing periodontitis sites. Since most
of the enzyme activity in GCF comes from inam-
matory cells (80), a considerable amount of overlap
occurs between inamed non-progressing sites and
progressing sites. All enzyme tests evaluated so far
have yielded fairly high rates of false-positive results
(i.e. the test is positive, but there is no progression).
Some of the inammatory mediators and host
response modiers listed in Table 2 also have the
potential to be useful markers of disease progression.
However, the confounding effects of non-progressing
inammatory lesions are considerable. As is the case
with enzymes, all GCF tests of progression based on
inammatory mediators give unacceptable rates of
false-positive results.
Some of the host breakdown products shown in
Table 3 are the most promising potential GCF mar-
kers of disease progression. This is especially true of
markers that reect the degradation of bone. Of par-
ticular interest is chondroitin-4-sulfate (C-4-S), a
bone-specic glycosaminoglycans. Approximately
94% of the glycosaminoglycans content of alveolar
bone is C-4-S (146). Statistically signicant correla-
tions between the GCF content of C-4-S and probing
depth (r 0.55) and attachment loss (r 0.53) have
been reported (138). However, longitudinal studies
evaluating the potential diagnostic or prognostic
value of C-4-S have not been done.
113
Gingival crevice fluid and periodontitis
Pyridinoline crosslinks of the carboxyterminal tel-
opeptide of type I collagen is a good marker of bone
collagen degradation (129). This degradation product
of bone has been preliminarily examined as a GCF
marker for the progression of periodontitis (6, 57, 58,
117, 122, 142). In one report, GCF levels were found
to be signicantly higher at sites with deep pockets
compared to those with shallow probing depths (6).
However, one session of scaling and root planing did
not signicantly decrease the GCF levels of ICTP
measured at 1, 3, and 6 months after SRP (6).
Further studies should be done on both C-4-S and
ICTP to determine how closely their GCF levels
reect the risk for progression of periodontitis. Both
markers have considerable appeal for this purpose
since they are relatively bone-specic.
Regulatory issues of in-office testing
In the United States there are Federal regulations
that govern the conditions under which all in-ofce
diagnostic tests are performed. The legislation was
designed to reduce serious patient-safety problems
in medical facilities where practitioners often incor-
rectly performed and interpreted diagnostic tests.
The legislation also applies to dental ofces and
practitioners. Therefore, any GCF-based diagnostic
tests fall under these regulations. This legislation is
called the ``Clinical Laboratory Improvement
Amendment (CLIA)'' that came into effect in 1992.
The basic features of this legislation are the following
requirements:
state approval of the dental ofce and its personnel
as a licensed clinical laboratory (fee required),
periodic state inspections of the facility where the
tests are performed,
documentation of special training of the personnel
who perform and interpret the tests,
quality control procedures to ensure that the test
results are valid (e.g. positive and negative controls).
This legislation has diminished the interest of
industry in funding the development of in-ofce
diagnostic tests for dentistry. Nevertheless, interest
in GCF components as potential markers of disease
progression continues. This is particularly true out-
side of the United States in countries where regula-
tory restrictions comparable to CLIA do not exist.
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