Benign prostatic hyperplasia (BPH)
is not a single disease but a spectrum of symptoms arising
from different causes, according to new research in
the Journal of Urology. A simple blood test,
the authors suggest, could predict which patients are
likely to develop serious problems and bladder damage
as a result of the common condition.
It's long been obvious that some
cases of BPH are considerably more severe than others.
"We've known that not all BPH is the same; patients
experience different degrees of prostate enlargement
and experience different symptoms, ranging from none
to renal failure, but we didn't know why," University
of Pittsburgh urologist Dr Robert Getzenberg, lead author
of the study, said in a press release.
Now, researchers from Johns Hopkins
have found clear differences in the underlying disease
process by performing DNA microarray analysis on patients
with both symptomatic and asymptomatic disease. "What
we're looking at," said Dr Getzenberg, "is two diseases:
BPH that produces more mild symptoms and is less likely
to lead to bladder and other urinary tract damage, and
BPH that is highly symptomatic with increased potential
to do damage to the bladder."
SEVERITY
SCALE
The most important difference was the expression of
the androgen-related gene known as JM-27. The protein
expressed by this gene is prevalent in the testes, prostate
and uterus, but the quantities can vary widely. In fact,
on average it's 17 times more common in symptomatic
BPH patients than in age-matched controls without the
disease.
The finding led the Hopkins team
to speculate that a test for JM-27 levels might identify
those BPH patients most likely to develop troubling
symptoms. More than half of all men, it's now estimated,
will eventually develop some form of BPH.
Using antibodies raised against
the cloned protein, the researchers devised an enzyme-linked
immunosorbent assay (ELISA) to detect JM-27 in serum
and tested it in 85 blood samples from patients with
known disease characteristics.
Twenty-nine of the patients had
no BPH symptoms or very mild ones, defined as an American
Urological Association (AUA) symptom score of 15 or
less, while 39 had symptomatic disease, with a score
of 16 to 32. Seventeen had confirmed prostate cancer,
but minimal urinary symptoms, with a maximum AUA score
of eight.
UNANSWERED
QUESTIONS
The worst symptoms of BPH often stem not from the enlarged
prostate gland itself, but from damage to the bladder
and urinary tract. The JM-27 protein appears closely
linked to the inflammatory processes behind this damage,
so one would expect it to be found at higher levels
in the tissue of symptomatic patients.
But the ELISA test measures blood
serum, not tissue samples, and so here the trend is
reversed — the more severe the symptoms of BPH,
the lower the level of JM-27 in the blood. It may be,
the authors suggest, that receptors in the local tissue
are binding JM-27 more in patients with more severe
disease, leaving less free to find its way into the
serum. But an alternative hypothesis is that the disease
process is itself causing the degradation of JM-27 in
the serum of the most symptomatic individuals.
This is a question that would need
to be resolved if treatment decisions are to be based
on the test. Doxazosin, an alpha-blocker used to treat
symptomatic BPH, downregulates JM-27 synthesis. If JM-27
is already being degraded in severe cases of BPH, the
drug wouldn't do any good. Figuring out which drugs
work best on which form of the disease as differentiated
by JM-27 is the next step, Dr Getzenberg said.
SO
FAR, SO GOOD
For now, the team has produced a test for serum JM-27
that seems to distinguish symptomatic patients with
a high degree of sensitivity and specificity. When the
JM-27 cut-off is set at 16.55 ng/mL, the great majority
of severely symptomatic patients fall below the line
while most of the less troubled patients measure above
it. Six of the 29 asymptomatic patients would have been
misdiagnosed by the test, and just four of the 39 who
did have symptoms. This gives a sensitivity of 90% and
a specificity of 77%.
Prostate cancer patients, for their
part, scored similarly to those with asymptomatic BPH.
This, Dr Getzenberg said, vindicates the test as a predictor
of symptoms. "Our experiments show that the expression
of this marker is related to the presence of the severe
form of BPH and not to the size of the prostate or to
the presence or risk of prostate cancer."
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