FALSE PSA READINGS IN CANCER DETECTION:

Prostate specific antigen (PSA) level comparison is a primary diagnostic routine

used to indicate the likelihood that a patient may suffer from prostrate cancer.
Levels of PSA vary greatly, and a high level often does not indicate a problem with
the prostrate gland – likewise a low level does not always confirm a healthy
prostrate.

On detecting a high level of PSA, the next (usual) course of action taken is to obtain
a biopsy sample. The operation required is not always trouble free. It is my belief
that the number of “False High” PSA results may be significantly reduced by
combining this test with a test for Alpha-1 Antitrypsin serum levels – I believe that
A1AT levels may influence the PSA serum levels… Higher A1AT levels leading to
Lower PSA readings, and LOWER A1AT LEVELS LEADING TO ‘FALSE’ HIGH
PSA READINGS.

As A1AT is an acute phase protein, changes in levels could occur in any individual –
The following discussion however relates to persons with some form of Alpha-1
Antitrypsin deficiency. It should be noted that there are many carriers of A1ATD
who are not aware that they have this genetic disorder, and will have lower levels of
A1AT in their serum, which I believe may cause higher readings of their PSA levels
even when they have no prostrate problems.

I believe that there is the POSSIBILITY that false ‘high’ levels of Prostate specific
antigen (PSA) could be detected in persons with reduced levels of Alpha 1-
antitrypsin (A1AT).
PSA is a serine protease enzyme, and A1AT is a serine protease inhibitor.
Persons with an abnormal phenotype in gene at the 14th chromosome (14q32.1) which
relates to the synthesis of A1AT are likely to have reduced (and / or dysfunctional) A1AT
in their serum. A “carrier” of the Alpha 1-antitrypsin deficiency disease (persons
with phenotype PiMZ) are likely to have a 40% REDUCTION in serum A1AT.

As both PSA and A1AT are in the same ‘class’ (serine protease / serine protease
inhibitor) I think it is extremely likely that a reduction in the serine protease inhibitor
(A1AT) will ‘reflect’ as an increase in serine protease (PSA) leading to a false ‘high’
level for PSA (in fact, the PSA level will be higher than normal, but this would be due to
A1AT levels and may not relate to any other condition).

I have not been able to find any data directly correlating the effect of A1AT on PSA, but
have found reference to the fact that PSA is inhibited by alpha-1-antichymotrypsin [
http://www.expasy.org/cgi-bin/nicezyme.pl?3.4.21.77 ] and have cross-referenced this
protease inhibitor to the peptidase family S1 [I am not sure that I have correctly done
this, but think there is a reasonable chance that I am right] http://www.expasy.org/cgi-
bin/lists?peptidas.txt
Clan Family Representative enzyme
==== ====== ============
PA(S) S1 A Chymotrypsin / trypsin

My hypothesis from the above is that if alpha-1-antichymotrypsin inhibits PSA, then

A1AT is also likely to inhibit PSA.

Fred Mundell. 23 May 2006.

fred@fundes.co.uk
fred@mundell.org.uk

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Prostate specific antigen (PSA) http://www.expasy.org/cgi-
bin/lists?peptidas.txt
Prostate specific antigen (PSA, also known as kallikrein III, seminin, semenogelase, γ-
seminoprotein and P-30 antigen) is a protein manufactured almost exclusively by the
prostate gland; PSA is produced for the ejaculate where it liquifies the semen and allows
sperm to "swim" freely. It is also believed to be instrumental in dissolving the cervical
mucous cap, allowing the entry of sperm.

Biochemically it is a serine protease (EC 3.4.21.77) enzyme, the gene of which is located
on the nineteenth chromosome (19q13).

Higher than normal levels of PSA are associated with both localized and metastatic
prostate cancer (PCa). PSA is normally present in the blood at very low levels. Increased
levels of PSA may suggest the presence of prostate cancer. However, prostate cancer can
also be present in the complete absence of an elevated PSA level, in which case the test
result would be a false negative. PSA levels can be also elevated due to prostate
infection, irritation, benign prostatic hypertrophy (enlargement) or hyperplasia (BPH),
recent ejaculation, digital rectal exam etc., in which case it may give a false positive.
Recent research suggests that the rate of increase of PSA (the "PSA velocity") may be a
more specific marker for prostate cancer.

The U.S. Food and Drug Administration (FDA) has approved the PSA test for annual
screening of prostate cancer in men of age 50 and older. PSA levels between 4 and 10
ng/mL (nanograms per milliliter) are considered to be suspicious and should be followed
by rectal ultrasound imaging and, if indicated, biopsy. PSA is false positive-prone (7 out
of 10 men in this category will still not have prostate cancer) and false negative-prone
(2.5 out of 10 men with no elevation in PSA will have prostate cancer)[1].

The current guidelines of the American Cancer Society recommend that non-African
American men over age 50 should be "offered" a prostate exam every year. African-
American men and those with a family history of prostate cancer should be screened
annually upon reaching 40 years. These guidelines may be changing. A new European
study has shown that a thorough screening for prostate cancer every 4 years is adequate.
The screening comprises a PSA blood test, a digital rectal exam, and a transrectal
ultrasound. "Very few, if any, aggressive prostate cancers escape (this) screening."

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Alpha 1-antitrypsin (A1AT) http://www.expasy.org/cgi-
bin/lists?peptidas.txt
Alpha 1-antitrypsin or α1-antitrypsin (A1AT) is a serine protease inhibitor (serpin).[1] It
protects tissue from enzymes from inflammatory cells, especially elastase, and is present
in human blood at 1.5 - 3.5 gram/liter.

A1AT is a 52 kDa serine protease inhibitor, and in medicine it is considered the most
prominent one, given the fact that the words α1-antitrypsin and protease inhibitor (Pi) are
often used interchangeably.

Most serpins inactivate enzymes by binding to them covalently, requiring very high
levels to perform their function. In the acute phase reaction, a further elevation is required
to "limit" the damage caused by activated neutrophil granulocytes and their enzyme
elastase, which breaks down the connective tissue fiber elastin.

Like all serine protease inhibitors, A1AT has a characteristic area of secondary structure
including beta sheets and alpha helices. It is in this area where mutations can lead to
polymerisation and accumulation in the liver.
[edit]

Role in disease

Disorders of the enzyme include alpha 1-antitrypsin deficiency, a hereditary disorder in

which lack of alpha 1-antitrypsin leads to uninhibited tissue breakdown during
inflammation. This causes pulmonary emphysema and leads to liver cirrhosis in severe
cases.[2]

The enzyme is called "antitrypsin" because of its ability to covalently bind and
irreversibly inactivate the enzyme trypsin. (Trypsin, a type of peptidase, is a digestive
enzyme active in the duodenum and elsewhere.)

Another name used is alpha-1 proteinase inhibitor (α1-PI).

Genetics

The gene is located on the long arm of the fourteenth chromosome (14q32.1).
Over 80 different versions of α1-antitrypsin have been described in various populations.
North-Western Europeans are most at risk for carrying a deviant form of A1AT.
[edit]

Analysis

As protein electrophoresis is imprecise, A1AT is analysed by electrofocusing (isoelectric

focusing analysis), where the protein is passed along a pH gradient.

Normal A1AT is termed "M", as it is neutral and does not run very far. Other variants are
less functional, and are termed A-L and N-Z, dependent on whether they run more
proximal or more distal to the M band. The presence of deviant bands on electrofocusing
can signify the presence of alpha 1-antitrypsin deficiency.

As every person has two copies of the A1AT gene, a heterozygote (with two different
copies of the gene), will have two different bands showing on electrofocusing.

In blood test results, the electrofocusing results are notated as in PiMM, where Pi stands
for protease inhibitor and "MM" is the banding pattern of that patient.

Alpha 1-antitrypsin levels depend on the phenotype, as deviant forms are excreted
inefficiently by the liver and polymerise in the endoplasmic reticulum:
PiMM: 100% (normal)
PiMS: 80%
PiSS: 60%
PiMZ: 60% (‘normal’ carrier – may not be aware they have lower serum levels of A1AT)
PiSZ: 40%
PiZZ: 10-15% (severe alpha 1-antitrypsin deficiency)