Procalcitonin Is Not a Reliable Marker for the Assessment of Severity in Acute Pancreatitis without Infectious Complications

The clinical spectrum of acute pancreatitis (AP) ranges from mild, self-limiting symptoms to a fulminating, rapidly lethal disease. Early objective identification of the risk of major complications or death is essential for appropriate management of individual patients and for the efficacy of treatment. However, clinical judgment alone is of low sensitivity in predicting severity and outcome in AP (1), and clinicobiochemical criteria such as those of Ranson (2) and Blamey et al. (3) suffer from a lack of simplicity and a 48-h delay in final assessment. Radiological methods enable a reliable diagnosis of necrotizing pancreatitis, but their availability often is limited (4). Several newer single-factor markers have been described as being effective in identifying severe AP. The acute phase reactant, C-reactive protein (CRP), is a most useful single marker that is cheap and easy to measure, but it also requires 48 h for maximal response (5)(6). Recently, procalcitonin (PCT), a 116-amino acid propeptide (Mr 13 000) of calcitonin with a long half-life in the systemic circulation, was found in high concentrations in patients with severe bacterial or fungal infections and sepsis (7), and it was reported as a marker in assessing the infection of necrotizing pancreatitis in late-stage disease (8) and in evaluating the biliary origin of the AP (9). In contrast to the classical acute-phase protein CRP, PCT is not increased after operative trauma (10). The aim of this study was to examine the ability of PCT to provide early prediction of severity and to assess the etiology of AP and in addition examine the relationship between PCT and the acute phase protein, CRP. We studied 31 consecutive patients with AP (14 males and 17 females; mean age, 66.4 years; range, 34–87 years), with onset of pain <24 h before admission. We measured serum PCT and CRP within the first 24 h after admission. The diagnosis of AP was based on typical clinical symptoms associated with at least a twofold increase in serum lipase, and was confirmed by abdominal ultrasonography and/or contrast-enhanced computed tomography. In 25 patients, pancreatitis was of biliary origin (defined by one or more of the following criteria: increased cholestasis laboratory parameters, history of gallstones, and presence of dilated common bile duct and biliary sludge and/or stones by ultrasonography and/or contrast enhanced computed tomography and/or endoscopic retrograde cholangiography). In the six other patients, the pancreatitis was attributable to alcohol abuse in one and of unknown origin in five. The severity of pancreatitis was assessed on the basis of the Atlanta criteria (11), which are largely used to assess a posteriori the severity of AP. In brief, these criteria define AP as mild if local and/or systemic complications are absent or are present with only minimal organ dysfunction; the pancreatitis is defined as severe if local complications (necrosis, pseudocysts, or abscess) and/or one or more organ dysfunctions are present. According to the Atlanta criteria, the pancreatitis was mild in 19 patients and severe in 12. The 31 healthy subjects included in the present study were in general good health, free from medication, and without clinical or laboratory signs of hepatic, biliary, renal, intestinal, or endocrinological malfunction. After study participants gave informed consent, blood samples were taken on admission and then daily for 5 days. All serum samples were stored at −20 °C until assayed. All samples were analyzed in duplicate within 6 months of collection. PCT was measured by a manual procedure with an immunoluminometric assay (12) (LUMI test PCT; Brahms Diagnostica GmbH) that requires ∼180 min to perform. Serum CRP was determined using a nephelometric technique (CRP; Dade Behring). The inter- and intraassay analytical imprecision (CV) for the two markers was as follows: 11% and 19% for PCT (mean, 0.62 μg/L), and 2.7% and 4.9% for CRP (mean, 4.8 mg/L), respectively. The upper reference limits reported in the package inserts for PCT and CRP were 0.5 μg/L and 5.0 mg/L, respectively. All statistical evaluations were performed with the SPSS/PC+ statistical package on a personal computer. The data were not gaussian distributed; therefore, a nonparametric test was used. During the first 6 days, the concentrations of CRP and PCT in the patients with pancreatitis were significantly higher than those in healthy subjects (P <0.001, Mann–Whitney U-test). As shown in Fig. 1 , the peak for both CRP and PCT in the severe group was observed at the 3-day time point. PCT in the mild group was not significantly different from that in the severe group at any point in the study, whereas the CRP was significantly lower in the mild group than in the severe group on days 2–6. The values of all samples obtained from the 31 patients were pooled and used for the calculation of the best cutoff for the two markers. Receiver-operating curves in differentiating between severe and mild disease showed that CRP had a larger area under the curve than did PCT (0.776 ± 0.026 vs 0.456 ± 0.036; P <0.001) (13)(14). The cutoff value, with maximal likelihood ratios (15), was 0.252–0.255 μg/L for serum PCT and 128–129 mg/L for serum CRP. (These cutoff values represent the range in which the likelihood ratio did not change.) The sensitivity and specificity of the two markers at these cutoffs in assessing the severe form of AP for the entire period are reported in Table 1 . No significant differences in PCT or CRP were found between patients with biliary and nonbiliary AP. Our data confirm that CRP is a good marker of severity in later stages of AP. PCT has been proposed as a marker for the noninvasive, accurate prediction of infected necrosis as well as for the selection of patients with persisting septic complications after surgical debridement (8). In our population, PCT serum concentrations were similar in patients with severe AP and in those with the mild form of the disease. The absence of a significant difference is in accordance with the clinical course of patients who did not develop infectious complications. In fact, only 1 of our 12 patients with severe pancreatitis underwent pancreatic surgery because of infected necrosis; he died on the fifth day. Even this patient’s serum PCT was lower than the upper reference limit. In conclusion, our data indicate that CRP is better than serum PCT in assessing in severity of AP. However, we cannot exclude that PCT could be useful in detecting and following patients with AP with infectious complications because PCT appears to be one of the best indicators of bacterial sepsis (7)(10) and a useful marker of the severity of infection (16), although much remains to be understood about its role in normal physiology and in sepsis (17). The possible role of PCT as a marker for biliary pancreatitis is still controversial. Rau et al. (8) found no correlation between the etiology of AP and PCT, whereas Brunkhorst et al. (9) reported that PCT may be an early marker of biliary pancreatitis. Our data, although based on a limited number of patients, are in agreement with the findings of Rau et al. (8), indicating that PCT is an insensitive marker for the recognition of the biliary etiology of AP. Box-and-whisker plots of serum PCT (A) and CRP (B) in healthy subjects (HS; filled box) and in patients with mild (gray boxes) and severe (open boxes) AP during the study period. Boxes illustrate the 25th and 75th percentiles; the lines inside the boxes represent the median value; whiskers are extended to the smallest and largest observations in a group that are <1.5 box-lengths from the box. ○ indicates values >1.5 box-lengths but <3 interquartile ranges from the end of the box (outlier values). P values, patients with severe AP vs patients with mild AP. Sensitivity and specificity of PCT and CRP in assessing the severity of AP.1 Sensitivities and specificities of PCT and CRP were compared by means of the McNemar test (18). Sensitivity and specificity of PCT and CRP in assessing the severity of AP.1 Sensitivities and specificities of PCT and CRP were compared by means of the McNemar test (18). This study was supported by University Hospital Policlinico S. Matteo of Pavia, Italy.