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UNDER CONSTRUCTION, BUT ...
LARYNGOPHARYNGEAL REFLUX (LPR) Jamie A. Koufman, M.D.,
F.A.C.S.
When it comes to
LPR, I’m an elder statesman. I have been interested in
laryngopharyngeal reflux (LPR), the backflow of gastric
(stomach) contents into the throat, my entire career.1-36
I actually coined the term laryngopharyngeal reflux more
than two decades ago to distinguish it from classical
gastroesophageal reflux disease (GERD). In the intervening
years, the manifestations, mechanisms, diagnosis and
treatment of LPR have been studied by many; but after all
this time, there is more controversy than ever.
LPR is a high-prevalence disease; but there is no
generally-accepted diagnostic gold standard.
Consequently
there are no well-accepted therapeutic endpoints. The
problem of nebulous diagnosis is compounded by the fact
that patients with LPR – with symptoms of hoarseness,
chronic cough, and difficulty swallowing -- may be seen by
many different types of doctors (e.g., primary care,
otolaryngology, gastroenterology) with different points of
view. Nevertheless, LPR is generally felt to be an
otolaryngologic disease and GERD generally
gastrointestinalologic.
Divergence
between the specialties can be blamed in part on
inadequate cross-pollination of the medical literature, in
part because of misleading and/or flawed LPR research, and
in part because of medical economic (“turf”) issues. LPR
has become like a religious war with disbelievers raging
against believers. To a great extent, the root of the
conflict is the mistaken belief that LPR and GERD are the
same disease. This war sometimes puts ailing patients in
the middle.
The purpose of this article is to examine why LPR remains
enigmatic and to encourage interdisciplinary clinical and
basic science research, especially cell biology. This is
not a methodical or comprehensive literature review; my
intension here is to share my experience, perspective, and
insight having worked in this field for half a lifetime
Silent Reflux
LPR is often
called silent reflux, because the majority of LPR
sufferers don’t have heartburn, the primary symptom of
GERD.2-5,21 We examined the esophagi of 58
consecutive patients with pH-documented LPR22 (few of whom
ever experienced heartburn) and found that only 12% had
esophagitis and 7% had Barrett’s esophagus; thus, 81% had
normal esophageal examinations. All 58, however, did have
laryngeal findings of LPR and abnormal pH-monitoring
tests.22
LPR may be epidemic in America; but no one knows for sure.
The uncertain prevalence is related to the tricky
diagnosis. Chronic cough, for example, is the most common
complaint for which people seek medical attention in the
United States, but the relationship between silent reflux
(LPR) and chronic cough is also unknown.
A few years ago, at Wake Forest (Unreported data 2004-5),
we performed impedance reflux-testing on 50 consecutive
patients with chronic cough; 68% (34/50) had documented
reflux in association with cough. LPR may be an important
cause of chronic cough, asthma, sore throat, hoarseness,
and sinus disease; but we don’t yet know how to test the
premise that LPR is a major risk factor for those
diseases.
While LPR and GERD are both due to the adverse impact of
acid and pepsin (gastric juices) on tissue, that’s where
the similarity ends. The mechanisms, patterns, and
manifestations of LPR and GERD are different;2-7,14,16,21,22,27,28
Cell Biology
of LPR
One of the most significant and overlooked differences
between LPR and GERD is that the threshold for
reflux-related injury of the laryngeal epithelium (lining
membrane) is quite low compared to that of the esophagus.5,23,33
The esophagus is biologically equipped to defend against
reflux, but larynx is not, and the magnitude of difference
may help explain why special new criteria are needed to
diagnose LPR. Using pH monitoring criteria, up to 50
reflux episodes/day in the esophagus (occurring mostly
after meals) are considered normal; but in the larynx,
just three reflux episodes a week are probably too many.5
Human and animal
research confirms that: (1) Pepsin is the primary
injurious component of the refluxate; (2) Pepsin is active
(proteolytic) above pH 5; and (3) When active pepsin binds
to laryngeal epithelium, it is associated with a cascade
of adverse consequences, in particular the depletion of
key protective proteins23,25,26,29-31,33,34.
It is important
to note that the Western blot method measures tissue-bound
(not surface) pepsin. In other words, the pepsin detected
by this technique is attached to the cell membrane or it
is intracellular.25 LPR and laryngeal cancer
have remarkably similar profiles; and HSP70 appears to be
a differentiating protein (that may turn out to be an
excellent marker for carcinoma.
The above
pepsin-activity and tissue-profile data are provocative
from the standpoint of understanding airway disease, and
they also call into question the notion of “threshold
diagnosis.” It seems doubtful that reflux events at or
below one particular measurement level of acidity (i.e., a
pH threshold) would or should consistently correlate with
(or predict) disease.
In
gastroenterology, the accepted threshold for esophageal
injury is pH<4.0 despite the fact that that level was
selected relatively arbitrarily by Johnson and DeMeester
more than 30 years ago.37 When prolonged
esophageal pH monitoring became popularized, pH<4.0 was
selected because it was believed that pepsin was not
active above pH 4.0, and because symptomatic GERD patients
undergoing pH monitoring often experienced heartburn with
reflux below pH 4.0.38
LPR is the
exception that begs the rule. In 1996, using a hemolytic
(modified Anson) method, we measured pepsin in the airway
secretions of 88 patients with clinical LPR who had
undergone ambulatory 24-hour (simultaneous pharyngeal and
esophageal) pH monitoring and 12 controls; see below.39
The pepsin levels in the 88 patients were different than
the controls (P <0.05). The conceptual problem with the
data was that most of the patients with the highest
assayed pepsin levels didn’t appear to have associated
pharyngeal reflux events pH<4. In addition, the mean
number of pharyngeal reflux events (pH<4.0) for the 88
patients was a meager 1.4. Disappointed, we reanalyzed the
pH monitoring data.
When we raised
the threshold to pH<4.1, the mean number of pharyngeal
reflux events was 4.5. Using a threshold of pH<4.5, the
mean number of pharyngeal events was 9.1; and using pH<5.0
as the threshold, the population of 88 patients averaged
29.7 pharyngeal reflux events.38
What then is the proper pH threshold for LPR diagnosis? If
there is 40% peptic activity at pH 5 and 10% of peptic
activity at pH 6(Fig. 1), what happens to the laryngeal
epithelium if the mean pH over the course of the day is
4.9, or 5.9 for that matter? The problem has been that up
until now, there was no way to quantify the peptic injury
profile across the range of pH values observed in LPR
patients undergoing pharyngeal pH testing.
The Reflux Injury Profile (RIP) and the Reflux Injury
Score (RIS)
Recently, we
began to reexamine pH monitoring data by looking at the
entire “area under the curve,” that is, the acid exposure
at all pH levels (from 1 to 7), using the actual pepsin
activity curve (Fig. 1) to modify the relative risk of
tissue damage at each pH level. A new system for
interpreting pharyngeal pH monitoring data is currently
under investigation, as outlined below.
Because of limitations using any specific pH threshold
level, we derived the pepsin injury coefficient (PIC) for
each pH level (Table 3) using 1.00 (i.e., 100%) for peak
peptic activity at pH 2.0. Then, the number of minutes of
pharyngeal exposure in each pH range (intervals 0.0-1.0,
1.1-2.0, 2.1-3.0, etc.) was multiplied by its
corresponding PIC, corrected for a complete 24-hour study
(1440 minutes). This produced a reflux injury profile
(RIP), an injury score for each pH level (Table 3); and
the sum of RIP scores was then reported as the reflux
injury score (RIS).
In Table 3, there are four case illustrations, one normal
(A) and three abnormal (B-D). In the normal example, the %
time pH<5.0 is only 1% and the RIS is 48. In abnormal case
example 3-B, the % time pH<4.0 is 10%; the % time pH<5.0
is 17%; and the RIS is 176. It is instructive to compare
case examples 3-C and 3-D. By traditional pH criteria,
study C would have been considered to be profoundly
abnormal and study D would have been considered normal.
For 3-C and 3-D, the % time pH<4.0 are 27% and 0%
respectively, but for % time pH<5.0, they are 51% and 69%
respectively. For 3-C, the RIS is 428 and it is 440 for
3-D.
Using the RIP/RIS scoring method, it appears that
prolonged pharyngeal exposure at weakly acidic pH may be
more damaging than shorter periods of exposure at low pH.
It is important to remember that RIP/RIS scoring is
designed for interpretation of pharyngeal reflux testing.
The concept of examining the entire pH profile is
appealing, because it avoids the “which threshold?”
question. Time will tell whether or not the RIP and RIS
prove to be good clinical measures.
More important
than the RIP and RIS scoring system is the concept that
LPR is not a threshold disease. The relationship between
LPR and the laryngeal epithelium is probably interactive
with epithelial defenses determining the outcome, namely,
health or disease. It also appears that bound pepsin leads
to tissue injury; whereas, surface or intraluminal pepsin
does not (Table 2).
We examined 20
carefully-selected asymptomatic controls (“normals”) for
pharyngeal reflux, and we found that 85% had some
pharyngeal reflux pH<5 events.40 If those subject were
truly asymptomatic (which they were), since 95% (19/20)
did not have pepsin (Western blot) in laryngeal pinch
biopsies,25 then it seemed logical to conclude
that healthy tissues does not contain pepsin.
In the past, the
presumption was that reflux disease resulted from
excessive exposure of tissue to gastric juices. But since
virtually everyone has some weakly-acidic LPR, it seems
likely that the effluence of the refluxate is less
important than epithelial resistence.36
The Internal
Environment
The external
environment has gotten a lot of attention in the past two
decades; however, it is but one component of the internal
environment. The internal environment is dynamic. Table 4
summarizes some of the elements of the internal
environment. These humoral and cellular elements are under
the influence of neuromuscular, hormonal, vascular and
genetic control, and they are also interdependent.
The internal environment is the aerodigestive tract
conceptualized as an integrated, multicomponent,
multifunction biologic system. That is in balance in
health seems reasonable; however, surprisingly little is
known about how all the elements interact, and
specifically which factors and sequences cause
decompensation and disease. It seems likely, for example,
that LPR predisposes to upper respiratory infection (URI)
and visa versa. In 2006, I reviewed a series LPR patients
diagnosed by pH-monitoring; 26% (15/57) had the onset of
their symptoms with a URI [unreported data]. In addition,
seemingly important relationships between LPR and reactive
airway diseases remain to be elucidated.
COMPONENTS OF THE INTERNAL ENVIRONMENT
Cells
Saliva
Acid and pepsin
Immunoglobulins
Inflammatory mediators (e.g., kinins)
Food and dink (that which is ingested)
Mucus and mucus breakdown products
Gastricin, bile salts and other digestive enzymes
The external environment (that which is inhaled/breathed)
The concept of LPR as an uncomplicated all-or-nothing
(“threshold”) disease should be abandoned. Within this
context, any single pH threshold diagnostic measure seems
woefully inadequate. As of this writing, poorly conceived
clinical studies (e.g., treatment outcome studies41) have
only further fueled a confusing and anachronistic model of
reflux disease.
The challenge for future clinicians and researchers will
be to integrate the whole that has been fragmented, and
cell biology holds the key. Multidisciplinary
translational research is going to unravel the LPR
conundrum.
Meanwhile, internal environment concept will spawn
development of new diagnostics and therapeutics. In the
future, examination of the expectorate for mucus breakdown
products, kinins, and immunoglobulins, in addition to
pepsin, may make the diagnosis of LPR non-invasive and
definitive. As treatment alternatives to acid-suppression,
anti-pepsin therapeutics will be possible by: (1)
suppression of production, (2) suppression of secretion,
(3) prevention of activation of pepsinogen, (4)
inactivation of pepsin, and/or (5) prevention of binding
of pepsin to tissue.
Comments: With GERD, the symptom heartburn is almost
the sine qua non, but there is no equivalent LPR symptom.
LPR rarely causes a single symptom; and single-symptom
outcomes measures usually fall short. I began using the
reflux symptom index (RSI) in about 1982. Now, it is a
validated outcomes instrument,17 but still, there is no
threshold number for the surefire diagnosis of LPR.
Recently, I saw a patient with an RSI of 28 who didn’t
have LPR, and a patient with an RSI of 7 who did. Still,
the RSI is an important index (Table A). The RSI is
especially useful when combined with the glottal closure
index (GCI) and the reflux finding score (RFS)17,18
Like the RSI, the GCI is a self-reported symptom index. It
is specific for glottal closure problems such as vocal
fold paralysis, paresis, presbylaryngis, and striking-zone
mass lesions or scarring. It is useful to use the GCI in
conjunction with the RSI, because it helps identify
patients with problems in addition to LPR, especially
those with neuropathic syndromes. The point is that the
RSI and GCI measure different things. It is unusual for a
patient with LPR alone to have a high (>10) GCI. The GCI
is a useful screening tool for glottal closure problems;
and it helps prevent the inexperienced clinician from
over-diagnosing LPR.
The RFS
(Table C) also evolved during the 1980s. I should point
out that I rarely score for erythema unless it is very
obvious, as this appears to be a highly variable and
subjective finding that is dependent to a great extent on
the lighting during the examination. In my experience, as
a diagnostic duo, pseudosulcus and ventricular
obliteration seem to work the best.
While the
reliable application of the RFS does require practice, I
have found that unsophisticated observers can be trained
to score larynges with a remarkable degree of consistency
and accuracy with thirty minutes of training. When the RFS
is used in conjunction with the RSI, the clinical
diagnosis of LPR can be made with greater certainty. As a
busy clinician who has used both indices every day for
virtually every patient visit for more than two decades, I
feel that a RSI of >20 combined with a RFS of >10 is
virtually diagnostic of LPR.
_____________________________
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