The ratio of trypsin-2-[[alpha].sub.1]-antitrypsin to trypsinogen-I discriminates biliary and alcohol-induced acute pancreatitis.
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 (6-9). 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, (10-17), 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 (13-15, 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 (13-15, 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].sub.2]-macroglobulin and [[alpha].sub.1]-antitrypsin (AAT) (21). Premature intrapancreatic activation of trypsinogen to trypsin is thought to be a key mechanism in the development of AP (21-23). This is supported by the finding that hereditary pancreatitis is associated with mutations in the trypsinogen-1 gene (24-26). 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
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.
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.
Serum samples from all patients were collected within 12 h after admission. The samples were stored at -20[degrees]C until analyzed.
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 [micro]g/L for trypsinogen-1, 18-90 [micro]g/L for trypsinogen-2, 8.9-33 [micro]g/L for trypsin-1-AAT, and 2.3-12 [micro]g/L for trypsin-2-AAT (28, 29, 32).
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 square] 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.
[FIGURE 1 OMITTED]
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).
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 square] 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).
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).
A ratio of trypsin-2-AAT to trypsinogen-1 [less than or equal to]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).
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.
[FIGURE 2 OMITTED]
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. 2). 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.
This work was supported by grants from the Liv and Halsa Foundation, the Finska Lakaresallskapet, and the Sigrid Juselius Foundation.
Received July 25, 2000; accepted November 9, 2000.
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 Nonstandard abbreviations: AP, acute pancreatitis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, allcaline phosphatase; AAT, [[alpha].sub.1]-antitrypsin; CRP, C-reactive protein; and AUC, area under the curve.
JAN M. ANDERSEN,  JOHAN HEDSTROM,  ESKO KEMPPAINEN,  PATRIK FINNE,  PAULI PUOLAKKAINEN,  and ULF-HAKAN STENMAN  *
 Department of Clinical Chemistry and
 Second Department of Surgery, Helsinki University Central Hospital, Haartmaninkatu 4, FIN 00290 Helsinki, Finland
* Address correspondence to this author at: Department of Clinical Chemistry, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland. Fax 358-9-47174804; e-mail email@example.com.
Table 1. Etiololgy, age, and gender of patients with AP. Alcohol-induced Biliary Unexplained etiology Total, n 42 16 9 Mild, n 24 13 8 Severe, n 18 3 1 Male, n 36 6 3 Female, n 6 10 6 Age, median 46 (31-72) 69 (27-82) 65 (23-83) (range), years Table 2. Median and range values of serum markers in AP of various etiologies. Alcohol-induced Biliary (n = 16) (n = 42) Median Range Median Range Trypsinogen-1, [micro]g/L 232 14-1970 329 65-4790 Trypsin-l-AAT, [micro]g/L 77 14-570 54 11-98 Trypsinogen-2, [micro]g/L 1278 41-20 100 526 103-5020 Trypsin-2-AAT, [micro]g/L 1533 36-11 500 247 30-970 Amylase, U/L 1380 294-9960 5605 399-20 400 Lipase, U/L 2030 268-9600 4290 615-33 730 CRP, mg/L 38 5-420 22 5-210 ALT,U/L 52 5-331 216 13-833 AST,U/L 71 19-594 188 23-723 Bilirubin, mg/L 22 11-52 23 6-134 ALP,U/L 202 73-430 200 89-672 Unexplained (n = 9) Median Range Trypsinogen-1, [micro]g/L 484 46-1660 Trypsin-l-AAT, [micro]g/L 29 7-218 Trypsinogen-2, [micro]g/L 1195 331-2070 Trypsin-2-AAT, [micro]g/L 705 47-990 Amylase, U/L 2660 164-16 680 Lipase, U/L 4040 257-20 720 CRP, mg/L 17 5-290 ALT,U/L 33 17-452 AST,U/L 31 19-460 Bilirubin, mg/L 14 9-43 ALP,U/L 240 66-389 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). Area under ROC curve ([+ or -]SE) Trypsinogen-1 0.600 [+ or -] 0.076 Trypsin-1-AAT 0.658 [+ or -] 0.094 Trypsinogen-2 0.682 [+ or -] 0.076 Trypsin-2-AAT 0.838 [+ or -] 0.071 Amylase 0.748 [+ or -] 0.069 Lipase 0.623 [+ or -] 0.085 ALT 0.682 [+ or -] 0.069 AST 0.619 [+ or -] 0.079 Bilirubin 0.522 [+ or -] 0.079 ALP 0.564 [+ or -] 0.078 CRP 0.426 [+ or -] 0.095 Trypsinogen-1/trypsinogen-2 0.923 [+ or -] 0.04 Trypsinogen-1/trypsin-1-AAT 0.772 [+ or -] 0.062 Trypsin-2-AAT/trypsinogen-1 0.957 [+ or -] 0.034 Trypsin-2-AAT/lipase 0.957 [+ or -] 0.034 Trypsin-2-AAT/amylase 0.924 [+ or -] 0.058 Trypsin-2-AAT, trypsinogen-1, ALT (LR) 0.961 [+ or -] 0.027
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|Title Annotation:||Enzymes and Protein Markers|
|Author:||Andersen, Jan M.; Hedstrom, Johan; Kemppainen, Esko; Finne, Patrik; Puolakkainen, Pauli; Stenman, Ul|
|Date:||Feb 1, 2001|
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