Clinical applications of the Pancreatitis-Associated Protein (PAP)
In1984, 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 of pancreatitis.

Acute pancreatitis
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).

Chronic alcoholics
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 pancreatitis.

Kidney-pancreas transplantation
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).

Neonatal 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.

Coeliac desease
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).

Inflammatory bowel diseases
Besides coeliac disease, and for the same reasons, PAP is a useful marker in the follow up of patients with Crohn's disease (14,15).

Alzheimer's disease
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).

Cancer
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 (17,18), and is a biological marker of pancreatic (19,20) and other gastrointestinal cancers (21).