applications of the Pancreatitis-Associated Protein (PAP)
Pr Keim reported (1) that a
new protein was strongly overexpressed in the pancreas during
pancreatic disease and called it the Pancreatitis-Associated
Protein. Patients with pancreatitis had elevated serum levels
of PAP, suggesting that it could be a new biological marker
of the disease (2). Advantages
of PAP over existing markers : Routine markers of pancreatitis
are pancreatic enzymes such as amylase, lipase, and trypsin.
They are very useful for diagnosis because they increase in
blood during the early phase of pancreatitis. However, they
have no prognostic value because their increase is transient.
From day 2-3, levels in mild or severe pancreatitis are similar.
In fact, the pancreas reacts to aggression by turning on a
stress-response mechanism (3).
Synthesis of enzymes is strongly repressed, explaining why
enzyme levels decrease in blood. But synthesis of stress proteins,
including PAP, is concomitantly over-expressed. Hence, contrary
to enzymes, PAP level in blood will parallel the intensity
of pancreatic stress. PAP is therefore a prognostic marker
A multicenter study (4) actually
demonstrated that serum PAP reflects pancreatitis severity.
Increased serum PAP in successive assays indicates a worsening
of the patient's condition, whereas decrease predicts resolution
of the acute phase.
Besides pancreatitis per se, serum PAP assay proved
useful in other situations where detection of pancreatic alteration
is important (5,6).
Alcoholism is the main etiology of pancreatitis. In alcoholics,
there is progressive degradation of the pancreas without clinical
symptoms, until acute, often severe pancreatitis occurs. Elevated
PAP reveals pancreatic alteration in many chronic, asymptomatic
drinkers (7). Patients with
high serum PAP are particularly at risk of developing acute
pancreatitis. Testing PAP in alcoholics provides the clinician
with biological data that support a warning on the risks of
Patients with kidney failure are often diabetics. When kidney
transplantation is required, the pancreas can also be grafted.
Success of the double graft is directly conditioned by the
behaviour of the pancreatic graft. If signs of rejection develop,
biopsy of the pancreatic graft is the only way of getting
reliable information, but the procedure is potentially harmful.
Because the compatibility of the graft is never complete,
the pancreatic graft always shows inflammation leading to
PAP overexpression. The intensity of inflammation can be monitored
with serum PAP, which allows early and precise modulation
of the immunosuppressive treatment (8).
screening of Cystic Fibrosis
The pancreas of cystic fibrosis (CF) babies is already altered
in utero, as a consequence of mutations in the CFTR gene.
As in acute pancreatitis, they show increased pancreatic enzymes
in blood (9). The neonatal
screening test presently available is the assay of immunoreactive
trypsinogen (IRT) in blood spots. However, IRT shows insufficient
specificity. It is therefore coupled to the screening of CFTR
mutations. That two-tier procedure is used in several countries
with good results. Yet, it is hardly applicable in countries
such as France, where genetic screening is subject to prior
written consent of the parents. Also, genetic analysis leads
to the unwarranted detection of many heterozygotes and mild
forms of the disease. Finally, the choice of which mutations
to include in the panel used for screening can be difficult
in multi-ethnic countries.
For these reasons, an alternative to the IRT/CFTR strategy
might become necessary. Evaluation of PAP in newborn CF screening
showed that this marker had similar performances as those
of IRT (10) Interestingly,
few babies showed elevation of both PAP and IRT but they included
all CF cases. A two-tier strategy with PAP assay followed,
for babies with elevated PAP, with IRT assay was evaluated.
The final population was indeed small enough to allow sweat-test
diagnosis (11), without recourse
to genetic analysis. These results were recently confirmed
(12) That strategy using two
biological tests alleviates legal and ethical problems related
to gene testing and is cost-efficient. It is therefore a good
alternative to the present strategy.
PAP being overexpressed in animals upon induction of intestinal
inflammation, experiments were conducted to test whether elevated
serum PAP could be a marker of severity in coeliac disease.
All children with coeliac disease had elevated serum PAP.
When inflammation was controlled by a gluten-free diet, PAP
decreased to normal values. PAP can therefore be used to monitor
the efficacy of the treatment and as index of compliance (13).
Besides coeliac disease, and for the same reasons, PAP is
a useful marker in the follow up of patients with Crohn's
In animals, PAP can be expressed by neurones upon cytokine
stimulation associated with inflammation. Because Alzheimer's
disease is suspected to involve an inflammatory process, PAP
concentration was estimated in the cerebrospinal fluid of
patients. It was already found elevated at very early stages
of the disease, compared to controls. It is therefore a useful
marker of the disease, inasmuch as patients with multiple
sclerosis have normal PAP (16).
Ectopic expression of PAP occurs during development of some
cancers. In association with a-fetoprotein, it allows follow-up
of patients with cirrhosis who may develop hepatocarcinoma
and is a biological marker of pancreatic (19,20)
and other gastrointestinal cancers (21).