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Clinical Chemistry 47: 231-236, 2001;
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(Clinical Chemistry. 2001;47:231-236.)
© 2001 American Association for Clinical Chemistry, Inc.

Articles

The Ratio of Trypsin-2-{alpha}1-Antitrypsin to Trypsinogen-1 Discriminates Biliary and Alcohol-induced Acute Pancreatitis

Jan M. Andersén1, Johan Hedström1, Esko Kemppainen2, Patrik Finne1, Pauli Puolakkainen2 and Ulf-Hkan Stenman1,a

1 Department of Clinical Chemistry and
2 Second Department of Surgery, Helsinki University Central Hospital, Haartmaninkatu 4, FIN 00290 Helsinki, Finland.
a Address correspondence to this author at: Department of Clinical Chemistry, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland. Fax 358-9-47174804; e-mail ulf-hakan.stenman{at}huch.fi.


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Rapid determination of the etiology of acute pancreatitis (AP) enables institution of appropriate treatment. We evaluated the ability of trypsinogen-1, trypsinogen-2, trypsin-1-{alpha}1-antitrypsin (AAT), and trypsin-2-AAT in serum to identify the etiology of AP.

Methods: The study consisted of 67 consecutive patients with AP admitted to Helsinki University Central Hospital. Forty-two had alcohol-induced AP, 16 had biliary AP, and 9 had unexplained etiology. Serum samples were drawn within 12 h after admission. Trypsinogen-1, trypsinogen-2, trypsin-1-AAT, and trypsin-2-AAT were determined by time-resolved immunofluorometric assays. Logistic regression was used to estimate the ability of the serum analytes to discriminate between alcohol-induced and biliary AP. The validity of the tests was evaluated by ROC curve analysis.

Results: Patients with alcohol-induced AP had higher median values of trypsin-1-AAT (P = 0.065), trypsinogen-2 (P = 0.034), and trypsin-2-AAT (P <0.001) than those with biliary AP, who had higher values of amylase (P = 0.002), lipase (P = 0.012), and alanine aminotransferase (P = 0.036). The ratios of trypsin-2-AAT to trypsinogen-1, lipase, or amylase efficiently discriminated between biliary and alcohol-induced AP (areas under ROC curves, 0.92–0.96).

Conclusions: Trypsinogen-2 and trypsin-2-AAT are markedly increased in AP of all etiologies, whereas trypsinogen-1 is increased preferentially in biliary AP. The trypsin-2-AAT/trypsinogen-1 ratio is a promising new marker for discrimination between biliary and alcohol-induced AP.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Acute pancreatitis (AP)1 is an often violent inflammatory process of the pancreas with frequent involvement of regional tissues and remote organ systems (1). Gallstones and alcohol consumption are the two main causes of AP. There is great geographical variation in the proportion of alcohol abuse and gallstones as etiological factors in various countries (2).

The etiology can often be determined on the basis of an accurate history and imaging procedures, but in 5–10% of AP episodes, the etiology remains uncertain (2). Ultrasonography is the most sensitive method in evaluating the etiologic role of the biliary system in AP, but its usefulness is often limited by the presence of overlying bowel gas (3). Repeated ultrasonography may occasionally show gallstones despite no prior evidence of disease (4)(5). Determination of the etiology of AP is important because patients with severe gallstone-induced AP benefit from early treatment by endoscopic retrograde cholangiopancreatography and common bile-duct clearance (6)(7)(8)(9). In biliary AP, elective cholecystectomy should be performed after the pancreatitis resolves to avoid recurrent disease (2).

Biochemical markers are of some value in determining the etiology of AP. Serum amylase concentrations at admission are typically lower in patients with alcohol-induced AP than in those with nonalcoholic AP, (10)(11)(12)(13)(14)(15)(16)(17), and serum amylase is normal at admission in 10–32% of the patients (18)(19). In some studies, increased serum lipase has been found equally as often in alcohol-induced and nonalcoholic AP (10)(11)(16), whereas higher lipase concentrations in nonalcoholic AP have been reported in others (13)(14)(15)(17). An increased ratio of lipase to amylase in serum has been reported to discriminate between alcohol-induced and nonalcoholic AP in some studies (10)(11), but not in others (13)(14)(15)(17).

Metaanalysis has shown that alanine aminotransferase (ALT) is the most useful marker of biliary AP, and a cutoff of 150 U/L has a specificity of 96%, but a sensitivity of only 48%. Aspartate aminotransferase (AST) performed nearly as well, whereas bilirubin and alkaline phosphatase (ALP) were not useful (20).

Trypsin is produced in the exocrine pancreas as two major proenzymes, trypsinogen-1 (cationic) and trypsinogen-2 (anionic), which typically are activated in the duodenum by enterokinase to trypsin-1 and trypsin-2, respectively. Once it reaches the circulatory system, active trypsin is rapidly inactivated by complexation with {alpha}2-macroglobulin and {alpha}1-antitrypsin (AAT) (21). Premature intrapancreatic activation of trypsinogen to trypsin is thought to be a key mechanism in the development of AP (21)(22)(23). This is supported by the finding that hereditary pancreatitis is associated with mutations in the trypsinogen-1 gene (24)(25)(26). Significantly increased trypsin activity has been found in patients with alcohol-induced AP, and it discriminates between alcohol-induced and nonalcoholic AP (27). In spite of these promising results, this method has not become accepted.

Previously, we developed immunofluorometric assays for the measurement of trypsinogen-1, trypsinogen-2, trypsin-1-AAT, and trypsin-2-AAT in serum (28)(29). In AP, trypsinogen-2 is markedly more increased than trypsinogen-1 (28). Trypsin-2-AAT has been found to be an accurate marker for severe pancreatitis (30)(31). Here we report the results of our studies on whether determination of trypsinogen-1, trypsinogen-2, trypsin-1-AAT, and trypsin-2-AAT in serum can be used to identify the etiology of AP.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
patients
We studied a consecutive series of 67 patients with AP admitted to the Second Department of Surgery at the Helsinki University Central Hospital between August 1997 and August 1998. The diagnosis was based on characteristic clinical findings (e.g., epigastric pain, nausea, and vomiting) and clearly increased amylase concentrations (serum amylase >900 U/L; i.e., three times the upper reference limit) or characteristic clinical findings combined with an increased amylase concentration (>300 U/L in serum) and imaging findings typical of AP or a characteristic clinical presentation and positive findings on contrast-enhanced computed tomography in patients without a serum amylase increase at presentation (Table 1 ). Contrast-enhanced computed tomography was performed when severe pancreatitis (n = 21) or AP in a patient with serum amylase concentrations within the reference interval was suspected. Ultrasonography was performed on all patients.


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  		Table 1. Etiology, age, and gender of patients with AP.

The severity of the disease was classified according to the 1992 Atlanta Symposium criteria (1). AP was classified as severe if one or several local or systemic complications were present (e.g., shock, renal failure, respiratory insufficiency, disseminated intravascular coagulation, pancreatic necrosis, an abscess, a pseudocyst, or intestinal perforation or bleeding).

The etiology was regarded as biliary when gallstones were demonstrated by ultrasonography, endoscopic retrograde cholangiopancreatography, or laparotomy (16 patients). An alcohol-induced etiology was deduced when there was a history of marked alcohol use before admission and there was no evidence of gallstones (42 patients). The etiology was considered as "unexplained" when evidence of alcohol consumption or gallstones could not be detected (9 patients).

Patients were excluded from the study when the primary admission was at another hospital or the patient had preexisting chronic pancreatitis. The study was done with the approval of the ethics committee of the hospital.

samples
Serum samples from all patients were collected within 12 h after admission. The samples were stored at -20 °C until analyzed.

laboratory methods
Serum amylase was measured by an enzymatic method. The reference interval for amylase was 70–300 U/L. Serum C-reactive protein (CRP) was assayed by an immunoturbidimetric method. The upper reference limit for CRP was 10 mg/L. Serum AST, ALT, and ALP were measured enzymatically with kinetic methods and bilirubin with a colorimetric method. The reference intervals for AST and ALT were 10–35 U/L in women and 10–50 U/L in men. The reference intervals were 60–275 U/L for ALP and 2–20 mg/L for bilirubin. All analyses were performed on a Vitros 250 analyzer with reagents from the manufacturer (Johnson & Johnson Clinical Diagnostics). Lipase was measured on stored samples with a Roche Cobas Integra using reagent set 07 6300 4 (Roche Diagnostics). The upper reference limit for lipase was 190 U/L.

Trypsinogen-1, trypsinogen-2, trypsin-1-AAT, and trypsin-2-AAT were determined on stored samples by time-resolved immunofluorometric assays. The reference intervals were 5.6–69 µg/L for trypsinogen-1, 18–90 µg/L for trypsinogen-2, 8.9–33 µg/L for trypsin-1-AAT, and 2.3–12 µg/L for trypsin-2-AAT (28)(29)(32).

statistical analysis
The distribution of the analytes was log-normal, and logarithmic transformation was performed before analysis by logistic regression and Pearson correlation. The Mann–Whitney U-test was used to compare the concentrations of serum analytes between diagnostic groups. The {chi}2 test was used for assessing the correlation between discrete variables and the Pearson correlation for the correlation between continuous variables. Logistic regression was used to estimate the ability of the analytes to discriminate between alcoholic and biliary AP. P <0.05 was considered statistically significant.

The diagnostic accuracy of the tests was evaluated by ROC curve analysis. The area under the curve (AUC) of the ROC plot describes the accuracy of the test: 1 indicates 100% sensitivity and specificity, and 0.5 indicates no discriminatory power (33). A univariate z-score test was used to estimate the significance of the difference between the areas under the ROC curves (34).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patients with alcohol-induced AP had higher values for trypsinogen-2 (P = 0.034), trypsin-2-AAT (P <0.001), and trypsin-1-AAT (P = 0.065) than those with biliary AP (Table 2 and Fig. 1 ). In contrast, patients with biliary AP had higher values for amylase (P = 0.002), lipase (P = 0.018), and ALT (P = 0.036) than those with alcohol-induced AP. Trypsinogen-1 typically was higher in patients with biliary AP (P = 0.245; Table 2 and Fig. 1 ). The duration of symptoms before admission (P = 0.064) and age (P = 0.348) did not differ significantly between patients with biliary and alcohol-induced AP. No correlation was found between sex and etiology (P = 0.899) or severity and etiology (P = 0.077, {chi}2 test). Trypsinogen-1 correlated with amylase (r = 0.59; P <0.001) and lipase (r = 0.74; P <0.001), which also correlated with each other (r = 0.76; P <0.001).


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  		Table 2. Median and range values of serum markers in AP of various etiologies.



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  		Figure 1. Boxplots of serum trypsinogen-1, trypsin-1-AAT, trypsinogen-2, trypsin-2-AAT, amylase, and lipase in patients with alcohol-induced AP, biliary AP, and AP of unexplained etiology, respectively.

The upper reference limit is indicated by a dashed line. The box-and-whisker plots show the 10th, 25th, 50th, 75th, and 90th centiles. Values outside the range of the whiskers ({circ}) are plotted individually. *, P <0.05; ***, P <0.001.

We tested the discriminative ability of single analytes and their combinations using unconditional logistic regression with biliary or alcohol-induced AP as the binary outcome. ALT (P = 0.014), amylase (P = 0.002), lipase (P = 0.009), trypsin-2-AAT (P = 0.001), and trypsinogen-2 (P = 0.050) differentiated between biliary and alcohol-induced AP as single variables. Trypsinogen-1 did not contribute to the diagnosis alone, but when combined bivariately with trypsin-1-AAT, trypsinogen-2, or trypsin-2-AAT, it contributed significantly to the discrimination. Because trypsinogen-1, amylase, and lipase were highly correlated, only one of these variables could be used at a time in the regression model. ALT was the only variable to contribute independently when added as a third variable to bivariate combinations. Sex, age, and severity did not affect these results when added to the model.

The ability of various analytes to differentiate between biliary and alcohol-induced AP was evaluated by ROC analyses (Table 3 ). Trypsin-2-AAT had the highest AUC for a single analyte (AUC = 0.838). In bivariate logistic regression, the combination of trypsinogen-1 and trypsin-2-AAT had the highest AUC (0.951). When we used the ratios between two analytes, the AUC values for the ratios of trypsin-2-AAT to trypsinogen-1, lipase, or amylase were 0.92–0.96 (Table 3 ). A logistic regression model with the three variables, trypsinogen-1, trypsin-2-AAT, and ALT, had an AUC of 0.961. The AUC for the ratio of trypsin-2-AAT to trypsinogen-1 was significantly better than ALT (P = <0.001) and amylase (P = 0.005), but not significantly better than the AUC for trypsin-2-AAT alone (P = 0.156) or for ALT, trypsinogen-1, and trypsin-2-AAT combined by logistic regression (P = 0.689).


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  		Table 3. AUC values (SE) discriminating between biliary and alcohol-induced AP for single analytes, ratios, and a trivariate model calculated by logistic regression (LR).

A ratio of trypsin-2-AAT to trypsinogen-1 <=1.5 identified biliary AP with a sensitivity of 0.81, a specificity of 0.95, and a positive predictive value of 0.87 (Fig. 2 ).



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  		Figure 2. Ratio of trypsin-2-AAT to trypsinogen-1.

{circ}, values for patients with mild AP; •, values for patients with severe AP. The cutoff at 1.5 is indicated by a dashed line.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The ratio of serum trypsin-2-AAT to trypsinogen-1 provided the best discrimination between biliary and alcohol-induced AP because trypsin-2-AAT was most strongly increased in patients with alcoholic AP, whereas trypsinogen-1 typically was higher in biliary AP. Interestingly, the ratio between trypsin-2-AAT and lipase or amylase performed equally well. Trypsinogen-1, amylase, and lipase were strongly correlated, and there was no difference in the AUCs of the ratios between these and trypsin-2-AAT. The combined impact of trypsinogen-1, trypsin-2-AAT, and ALT determined by logistic regression provided slightly larger AUC values in ROC analysis than the ratio of trypsin-2-AAT to trypsinogen-1, but the difference was insignificant.

It has recently been shown that trypsinogen is expressed in the epithelium of benign intrahepatic bile ducts (35) and extrahepatic peribiliary glands (36), and increased concentrations of serum trypsinogen-1 and normal or slightly increased concentrations of trypsin-1-AAT have been observed in patients with benign biliary tract diseases (37). We have also found increased concentrations of trypsin-1-AAT in patients with biliary tract cancer (32). It is therefore tempting to speculate that a portion of the trypsinogen-1 occurring in serum from patients with biliary AP is at least partially derived from the biliary epithelium.

The marked increase of trypsinogen-2 and trypsin-2-AAT in alcohol-induced AP suggests that early activation of trypsinogen-2 to trypsin-2 is a crucial feature in the pathogenesis of alcohol-induced AP. In contrast, the passage of a biliary stone appears to cause leakage of inactivated trypsinogen-1 into the circulatory system. Interestingly, amylase and lipase were also preferentially increased in patients with biliary AP. Currently, we cannot explain why these pancreatic enzymes are more markedly increased in gallstone-induced AP, whereas trypsinogen-2 is more markedly increased in the alcohol-induced form of the disease. It has been suggested that the pathological events in the acinar cell are different in alcohol- and biliary-induced AP (38). Our results appear to support this hypothesis.

The ratio of trypsin-2-AAT to trypsinogen-1 was similar in patients with severe and mild biliary AP (Fig. 2Up ). Thus, the ratio does not appear to be related to the severity of AP. In patients with unexplained etiology of AP, the ratio of trypsin-2-AAT to trypsinogen-1 was <1.5 in 7 of 10 cases, suggesting that the cause of AP might have been biliary, e.g., gallstones or biliary sludge, which were not identified by the imaging techniques used (4)(5).

Currently, immunoassay of the various forms of trypsin takes ~3 h; however, with an automated analyzer, the time could be reduced to 15–30 min. If the assays were available on a daily basis, the results could be used to support clinical decision making.

In conclusion, trypsinogen-2 and trypsin-2-AAT are markedly increased in all etiologies of AP. They are markedly more increased in alcohol-induced AP than in biliary AP, whereas the opposite is true for trypsinogen-1, amylase, and lipase. The ratio of trypsin-2-AAT to trypsinogen-1 is a promising new indicator for discriminating between biliary and alcohol-induced AP.


   Acknowledgments
 
This work was supported by grants from the Liv and Hälsa Foundation, the Finska Läkaresällskapet, and the Sigrid Juselius Foundation.


   Footnotes
 
1 Nonstandard abbreviations: AP, acute pancreatitis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; AAT, {alpha}1-antitrypsin; CRP, C-reactive protein; and AUC, area under the curve.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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