Scandinavian Journal of Gastroenterology, 2010; 45: 959–970

ORIGINAL ARTICLE

Value of the different prognostic systems and biological markers forpredicting severity and progression of acute pancreatitis

ZILVINAS DAMBRAUSKAS1,2, ANTANAS GULBINAS1,2, JUOZAS PUNDZIUS2 &GIEDRIUS BARAUSKAS2

1Laboratory for Research of Digestive System, Institute for Biomedical Research, Kaunas University of Medicine, Kaunas,Lithuania, and 2Department of Surgery, Kaunas University of Medicine, Kaunas, Lithuania

AbstractObjective. Several tools have been developed for severity stratification in acute pancreatitis (AP). They include singlebiochemical markers and complex scoring systems, all of which aim at an early detection of severe AP to optimize monitoringand treatment of these patients. The aim of this study was to reassess and compare the value of some known and newly-introduced prognostic markers in the clinical context. Material and Methods. We have conducted a prospective obser-vational study. One hundred and eight patients with a diagnosis of AP and onset of the disease within last 72 h were included inthis study. Clinical data and expression results of some serum biochemical markers were used for statistical analysis. Thediagnostic performance of scores predicting severity and progression of AP, cut-off values, specificity, and sensitivity wereestablished using receiver operating characteristic curve analysis. Results. Among single biochemical markers, C-reactiveprotein remains the most useful. Despite its delayed increase, it is accurate, cheap, and widely available. Interleukin-6 andmacrophage migration inhibitory factor seem to be new promising parameters for use in clinical routine. Pancreas specificscores (Imrie-Glasgow, pancreatitis outcome prediction) and scores assessing organ dysfunction (acute physiology and chronichealth evaluation II, multiple organ dysfunction score, and Marshall score) remain of value in determining the severity,complications, and possible outcome of AP. Conclusions. Indication, timing, and consequences of the methods applied needto be carefully considered and incorporated into clinical assessments. Currently, there is no single prognostic marker thatwould cover the whole range of problems associated with the treatment of AP. The prediction of severity and progression of APcan be achieved using a series of accurate methods. The decision to undertake interventional or surgical treatment is the mostcomplex task requiring both clinical judgment and meticulous monitoring of the patient.

Key Words: Acute pancreatitis, clinical scores, prognosis, serum markers

Introduction

Acute pancreatitis (AP) is a common and potentiallylethal acute inflammatoryprocesswith ahighly variableclinical course. Although in the majority of cases thedisease is relatively mild and associated with low mor-tality, approximately 20–25% of the affected indivi-dualswill develop a severe clinical course in associationwith the development of a systemic inflammatoryresponse syndrome (SIRS), multiple organ failure,anddeath.Twopeaks, early (within thefirst twoweeks)

and late, of mortality in AP are recognized. The mor-tality rate is strongly associated with the degree ofmultiple organ failure, but the causes in early andlate mortality are distinct. The reported relative mor-tality rates in the early phase of AP range from about athird tomore than a half of the deaths and are due to theSIRS [1–3].Complications due to sepsis, inmost casescaused by infection of pancreatic necrosis, result indeteriorating multiple organ dysfunction syndromeand are the major cause of deaths in the late courseof the disease [2–6].

Correspondence: Zilvinas Dambrauskas, MD, PhD, Department of Surgery, Kaunas University of Medicine Hospital, Eiveniu Str. 2, 50009 Kaunas, Lithuania.Tel: +37068669255. Fax: +37037327163. E-mail: zilvinas.dambrauskas@gmail.com.

(Received 15 November 2009; accepted 11 March 2010)

ISSN 0036-5521 print/ISSN 1502-7708 online � 2010 Informa UK Ltd.DOI: 10.3109/00365521003770244

Despite substantial animal model research, it is stillunclear as to why some patients progress to organfailure and others do not, or at which step in theinflammatory cascade will an intervention have animpact upon disease progression [7,8]. In recentyears, clinical research has clearly shown that distantextrapancreatic organ failure and the development oflocal or systemic complications determine the courseand outcome of severe AP. Several independent clin-ical factors for predicting fatal outcome have beenproposed by applying multivariate analysis. Age, obe-sity with a body mass index of 30 kg/m2 or more, andchronic alcohol consumption are factors influencingthe course of the disease [9–11]. While some studieshave shown that the extent of necrosis and the pres-ence of infection are the most critical independentdeterminants of organ failure [8,9], the results ofother research groups have suggested that distantorgan failure can occur without the presence of pan-creatic necrosis [12–14].It is crucial to recognize patients at risk of devel-

oping severe AP at an early stage in order to optimizetherapy and monitoring. However, many authorsshowed that clinical evaluation is of little help inpredicting severity of the disease, as clinical symptomsand the findings on physical examination vary innature and degree [15]. On admission, clinical exam-ination is not able to identify more than 44% of thepatients who develop severe AP [16]. Therefore,several tools have been introduced and tested for earlyand easy stratification of severity in AP; they includeclinical signs, biochemical markers, imaging methods,and complex scoring systems [17]. This study gives acritical overview of some widely used and new mar-kers for predicting severity and progression of AP,with special emphasis on those applicable in currentclinical routine.

Patients and methods

Study design and patient population

We have conducted a prospective observational studyin the period between June 2005 and December2007. All patients admitted to the Department ofSurgery, Kaunas University of Medicine Hospital(Lithuania) with a diagnosis of AP and onset of thedisease within last 72 h were included in this study(n = 108). The Regional Ethics Committee approvedthe study (protocols no. BE-2-47 and P1-113/2005)and all the patients provided written informedconsent.The diagnosis was established on the basis of acute

abdominal pain, at least three-fold elevated levels of

serum amylase and typical radiological findings. Thecontrast-enhanced CT scan was performed on daysfour to seven after onset of the disease to demonstratethe presence of pancreatic necrosis. Clinical datarelated to the severity of disease, development oforgan dysfunction, and/or septic complications wereprospectively collected in a standardized fashion.Patients with underlying chronic pancreatitis andpatients with AP referred to our hospital from otherinstitutions after management for more than threedays were excluded from this study. Data necessaryfor the calculation of the multifactorial clinical scoresused for the statistical analysis were collected within12–24 h after admission to the hospital but not laterthan 72 h after onset of the disease. Blood samples forthe assessment of serum markers were drawn on theadmission to the hospital, processed immediately, andstored in -70�C before analysis. Levels of cytokinesin blood serum were measured by ELISA accordingto the manufacturer’s instructions (Sigma-AldrichGmbH, Steinheim, Germany).According to the clinical course and clinical severity

scores (acute physiology and chronic health evalua-tion II > 7) patients were stratified into mild andsevere AP groups. Clinical data and results of serumbiochemical markers were used for analysis. The mainclinical characteristics of patients, differences in clin-ical course, and outcome of patients with mild andsevere disease are disclosed in Tables I and II.

Statistical analysis

Statistical analysis was performed using SPSS� forWindows release 14.0 (SPSS, Chicago, Illinois,USA). The diagnostic performance of different testsin prediction of severity, pancreatic necrosis, infec-tious complications, need for interventional treat-ment (ultrasound-guided drainage and/or surgery),and possible fatal outcome were assessed usingreceiver operating characteristic (ROC) curve analy-sis. The ROC curves were obtained by calculatingthe sensitivity and specificity of a test at every possi-ble cut-off point, and plotting sensitivity against1-specificity. The curves were used to select optimalcut-off values for a test result. The diagnostic accu-racy of the test was measured by the area under thecurve (AUC), which were tested using AUC = 50%as reference.Variables are shown as mean ± standard deviation.

The unpaired t test was employed to compare normaldistribution variables, whereas c2 test was used toanalyze non-continuous (categorical) variables.The two-sided p values of less than 0.05 were

considered statistically significant.

960 Z. Dambrauskas et al.

Results

Within a relatively short period of time, we havecollected the data of 108 patients representing a

typical AP population of a tertiary care center. Allpatients included in our study were admitted withinfirst 72 h after the onset of disease, which allowed us agood comparison of various clinical and biochemicalparameters used for prediction of clinical course andoutcomes of AP. In all cases, diagnosis was confirmedby contrast enhanced abdominal CT scanning and thevolume of pancreatic necrosis was assessed if present.The overall mortality rate in our series of patients was13%, with the combined ICU (intensive care unit)and hospital mortality rate of 62.5% for those withAPACHE II score >17, which is comparable to thedata reported by Harrison et al. [18,19]. There was abiphasic distribution in hospital stay for the pancre-atitis patients. Non-survivors (8.4%) with high first24-h APACHE II scores (‡11) died soon after admis-sion (average 5.85 ± 5.40 days), presumably influ-enced by the multiple organ failure. However, thosewith lower scores (£11) who eventually died (4.6%)did so after an average ICU stay of 15.17 ± 4.10 days,suggesting continuing physiologic deterioration in thisinitially lower severity subset or late-onset complica-tions, presumably related to infected necrosis [20,21].The converse was seen with survivors, which is also inaccordance with numerous earlier publications.Within this study, we have analyzed the value and

clinical role of two pancreas specific clinical scores,Imrie-Glasgow score and pancreatitis outcome pre-diction (POP) score. We have also evaluated the use-fulness of other three scoring systems relying on theevaluation of the function of the major organ systemsand assessment of multiple organ failures, includingthe APACHE II score, multiple organ dysfunctionscore (MODS) and Marshall score, as well as fourdifferent single serum parameters (CRP [C-reactiveprotein], IL-6 [interleukin-6], MIF [macrophagemigration inhibitory factor] concentration, lympho-cyte count). The diagnostic performance of differenttests in prediction of severity, pancreatic necrosis,infectious complications, need for interventional treat-ment (ultrasound-guided drainage and/or surgery),and possible fatal outcome were assessed usingROC curve analysis (Figures 1 and 2). ROC analysisnot only allowed for the visual and statistical compar-ison of the prognostic value of the different multifac-torial scores and single serum markers, but alsogenerated the theoretical predicted cut-off values forthe most important outcomes of AP (Tables IIIand IV). The statistical analysis produced the cut-offvalues for the severity of the diseases similar to thosereported in numerous other publications, while thecut-off values for predicting other complications, suchas pancreatic necrosis (>30% volume), early death(within first two weeks of the disease), and infectiouscomplications were significantly higher. In our study,

Table I. Main clinical characteristics of patients.

Patient characteristicsMean ± SDor n (%)

Sex

Male 56 (51.9%)

Female 52 (48.1%)

Age (years) 53.2 ± 16.6

Body mass index (kg/m2) 34.6 ± 8

Etiological factors of acute pancreatitis

Alcohol 46 (42.6%)

Alimentary (high-fat diet) 28 (25.9%)

Biliary 27 (25%)

Idiopathic 7 (6.5%)

Presence of pancreatic necrosis

Edematous 56 (51.9%)

Necrotizing 52 (48.1%)

Quantification pancreatic necrosis by CT

No detectable necrosis (0%) 56 (51.9%)

Low volume necrosis (<30%) 18 (16.7%)

High volume necrosis (30–50%) 11 (10.2%)

Subtotal necrosis (>50%) 23 (21.3%)

Presence of pancreatic infection

Without pancreatic infection (sterile necrosis)* 101 (93.5%)

With pancreatic infection (infected necrosis)* 7 (6.5%)

Severity of disease (APACHE II > 7)

Mild acute pancreatitis 60 (55.6%)

Severe acute pancreatitis 48 (44.4%)

Presence of MOF (>2 systems)

Without MOF 90 (83.3%)

With MOF 18 (16.7%)

Duration of in-hospital stay (days)

Duration of treatment in ICU 7.1 ± 11.5

Total duration of in-hospital stay 15.4 ± 14.1

Mortality of patients

Survivors 94 (87%)

Number of early deaths (<2 weeks) 9 (8.4%)

Number of late deaths (>2 weeks) 5 (4.6%)

Total number of patients 108 (100%)

Abbreviations: APACHE II = acute physiology and chronic healthevaluation II; ICU = intensive care unit; MOF = multiple organfailure; SD = standard deviation.*Infected/sterile necrosis-based on the presence of positive bacterialcultures in FNA samples from peripancreatic fluid collections.

Predicting the severity of acute pancreatitis 961

ROC analysis did not show any significant differencebetween the AUC for the clinical scores or serummarkers in predicting the severity, development ofpancreatic necrosis or infectious complications, andfatal outcome. However, APACHE II system (meanAUC: 0.867 ± 0.106; sensitivity: 81.10 ±1 3.70; spec-ificity: 85.11 ± 11.32) and Imrie-Glasgow score (meanAUC: 0.826 ± 0.027; sensitivity: 80.24 ± 10.39; spec-ificity: 75.11 ± 7.10) were superior to the other prog-nostic systems. Among single biochemical markers,CRP (mean AUC: 0.688 ± 0.049; sensitivity:70.84 ± 7.94; specificity: 69.50 ± 7.29) remains veryuseful because it is accurate, cheap, and widely avail-able. In our opinion, IL-6 (mean AUC: 0.815 ± 0.094;sensitivity: 83.63 ± 18.37; specificity: 77.18 ± 10.36)and MIF (mean AUC: 0.785 ± 0.088; sensitivity:89.07 ± 15.05: specificity: 64.28 ± 9.34) seem to benew promising parameters for use in clinical routine.Interestingly, the need for the surgery or image-guidedintervention was the hardest to predict andmost of thescoring systems and single serum markers were notable to stratify these patients, except for the APACHEII and Imrie-Glasgow scores that showed a theoreticalcapacity to predict the need for interventional and/orsurgical treatment. It is very inconvenient to havemanydifferent parameters and cut-off values for predictingthe possible outcomes of the disease and undertakingclinical decisions in clinical practice. Therefore, westratified the patients into the mild and severe APgroups according to the developed cut-off values for

prediction of severity and grouped them based on theoccurrence of the complications (large volume pan-creatic necrosis, infectious complications, need forsurgery, and mortality). Once again, there was nosignificant difference between the various clinicalscores or single serum markers. None of the scoresor serum markers turned to be useful in prediction ofthe need for surgery or image-guided intervention.The POP score in this model was not useful for theprediction of earlymortality (Table III). Severity of thedisease, necrotizing AP, and possible fatal outcomewere the clinical conditions that could be predicted bydifferent single serum markers with variable accuracy.On the other hand, infectious complications, need forinterventional or surgical treatment, and early mortal-itywere hard to predict early in the course of the diseaseusing single biochemical parameter or blood test(Table IV).

Discussion

Given the high mortality and morbidity associatedwith severe AP, such patients should be treated inhigh-dependency environment with close attentionpaid to volume resuscitation, gas exchange, nutrition,and treatment of infection and other complications[11]. Thus, early prediction of the severity of an acuteattack has important implications for managementand timely intervention.

Table II. Differences in clinical course and outcome of patients with mild and severe disease.

Clinical severity scores and patient characteristicsMild AP (n = 60) Severe AP (n = 48)

Pmean ± SD mean ± SD

Apache II (score) 3.6 ± 1.9 11.6 ± 4.7 p < 0.01

Imrie-Glasgow (score) 2.2 ± 1.2 4.4 ± 1.5 p < 0.01

C-reactive protein (mg/l) 91.8 ± 18.7 152.9 ± 21.5 p < 0.01

ICU stay (days) 1 ± 1 9 ± 2 p < 0.05

Total hospital stay (days) 12 ± 1 19 ± 3 p < 0.05

Patient no. (%) Patient no. (%)

Necrotizing AP (count) 16 (26.7%) 36 (75%) p < 0.01

Necrosis volume > 30% (count) 8 (13.3%) 26 (54.2%) p < 0.01

Infectious complications (count)* 2 (3.3%) 12 (25%) p < 0.01

Presence of MOF (count) 0 (0%) 18 (37.5%) p < 0.01

Need for surgery (count)** 1 (1.7%) 5 (10.4%) p = 0.06

Number of early deaths (<2 weeks) 0 (0%) 9 (18.8%) p < 0.01

Number of late deaths (>2 weeks) 0 (0%) 5 (10.4%) p < 0.01

Abbreviations: APACHE II = acute physiology and chronic health evaluation II; AP = acute pancreatitis; ICU = intensive care unit;MOF = multiple organ failure; SD = standard deviation.*Infectious complications: proved sepsis, infected pancreatic necrosis, lung and urinary infection.**Need for surgery: fasciotomy for intraabdominal compartment syndrome and/or necrosectomy.

962 Z. Dambrauskas et al.

Scoring systems

Growing knowledge on factors associated with highmortality in AP has led to the use of multifactorialclinical scoring systems, each representing the knowl-edge on severe AP at the point of development.A score with good prognostic ability provides thepossibility of identifying those patients who are

more likely to benefit from new therapeutic interven-tions and management regimens. But the drawback ofthe multifactorial scoring systems in clinical use now-adays is that they are lagging behind the growingknowledge on factors predicting mortality insevere AP. Few of the established systems, for exam-ple, take into account obesity (e.g., APACHE-O), orone of the known markers of systemic inflammation

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Figure 1. The diagnostic performance of multifactorial scores in prediction of clinical outcomes.

Predicting the severity of acute pancreatitis 963

(e.g., CRP), or the results of imaging methods. How-ever, the use of standardized clinical scores allows forthe comparison between the severity of illness amongpatients on different ICU units and in different hos-pitals, and monitoring the course of the disease andthe response to therapy. It also considerably facilitatesprospective studies and comparisons of performance.

A variety of assessment tools have been used toidentify patients with AP at risk of developingcomplications and/or death. First, there are clinico-biochemical tools specific to AP, such as the Ransonand Imrie-Glasgow criteria and modifications thereof[22–28]. The presence of three or more criteria ineither the Ranson or Imrie-Glasgow scoring systems

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Figure 2. The diagnostic performance of serum markers in prediction of clinical outcomes.

964 Z. Dambrauskas et al.

Table III. The value of various multifactorial scores in prediction of clinical outcomes.

Scores and values Severity Necrosis Infection Intervention Early deaths All deaths

APACHE II

Cut-off (predicted) >7 >8 >11 >7 >9 >9

AUC 0.998 0.786 0.833 0.719 0.936 0.932

Sensitivity 97.50 63.64 69.23 75.00 88.89 92.31

Specificity 100 84.29 90 65.26 85.56 85.56

+LR/-LR - 0.025 4.05 0.43 6.92 0.34 2.16 0.38 6.15 0.13 6.39 0.09

Significance p < 0.01 p < 0.01 p < 0.01 p < 0.05 p < 0.01 p < 0.01

Cut-off (practical) ‡8 ‡8 ‡8 ‡8 ‡8 ‡8

c2 p < 0.01 p < 0.01 p < 0.01 n. s. p < 0.01 p < 0.01

Imrie-Glasgow score

Cut-off (predicted) >3 >3 >3 >3 >3 >3

AUC 0.844 0.824 0.853 0.782 0.809 0.844

Sensitivity 70 72.73 92.31 87.50 88.89 70

Specificity 82.54 78.57 70 66.32 70 82.54

+LR/-LR 4.01 0.36 3.39 0.35 3.08 0.11 2.60 0.19 2.96 0.16 4.01 0.36

Significance p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < 0.01 p < 0.01

Cut-off (practical) ‡3 ‡3 ‡3 ‡3 ‡3 ‡3

c2 p < 0.01 p < 0.01 p < 0.05 n. s. p < 0.05 p < 0.05

MODS

Cut-off (predicted) >2 >2 >3 >3 >4 >2

AUC 0.844 0.781 0.743 0.629 0.930 0.844

Sensitivity 72.50 69.70 69.23 50 88.89 72.50

Specificity 80.95 74.29 81.11 76.84 90 80.95

+LR/-LR 3.81 0.34 2.71 0.41 3.67 0.38 2.16 0.65 8.89 0.12 3.81 0.34

Significance p < 0.01 p < 0.01 p < 0.01 n. s. p < 0.01 p < 0.01

Cut-off (practical) ‡3 ‡3 ‡3 ‡3 ‡3 ‡3

c2 p < 0.01 p < 0.01 p < 0.05 n. s. p < 0.01 p < 0.01

Marshall score

Cut-off (predicted) >1 >2 >0 >0 >2 >2

AUC 0.819 0.711 0.774 0.682 0.933 0.819

Sensitivity 57.50 42.42 92.31 87.50 88.89 82.50

Specificity 95.24 92.86 51.11 48.42 90 63.49

+LR/-LR 12.07 0.45 5.94 0.62 1.89 0.15 1.70 0.26 8.89 0.12 2.26 0.28

Significance p < 0.01 p < 0.01 p < 0.01 n. s. p < 0.01 p < 0.01

Cut-off (practical) ‡3 ‡3 ‡3 ‡3 ‡3 ‡3

c2 p < 0.01 p < 0.01 p < 0.01 n. s. p < 0.01 p < 0.01

POP score

Cut-off (predicted) >5 >8 >8 >8 >8 >5

AUC 0.857 0.711 0.760 0.628 0.895 0.857

Sensitivity 82.50 51.52 69.23 50 77.78 82.50

Specificity 71.43 92.86 85.56 81.05 85.56 71.43

Predicting the severity of acute pancreatitis 965

indicates severe AP [16,29–31]. Sensitivity and spec-ificity for predicting mortality have been reported as63% and 76% for Ranson and 72% and 84% for themodified Glasgow criteria, respectively [32]. Thesescores were developed on outcome data collected insingle- or two-center specialist units rather than ageneral hospital population. As some may arguethat these pancreatitis specific scores are datingback several decades and do not necessarily reflectcontemporary patient management and outcomes,our study revealed that modified Imrie-Glasgow scoreis still a valuable prognostic tool with sensitivity andspecificity for predicting mortality of 70% and 83%,respectively. Similar sensitivity and specificity wereobserved for predicting severity of AP in our study.Some of the recently developed scoring systems arepromising, but need further assessment. We havechosen to evaluate the POP score, which was devel-oped after the analysis of 2462 patients admitted to159 UK ICUs with severe AP [33]. However, in ourstudy population, performance of the POP score wasinferior to that of APACHE II or Imrie-Glasgowscores. This could be related to the fact that thisprognostic system was based on the retrospectiveanalysis of the data, which were not collected forthe purpose of identifying patients with AP. It wastherefore not possible to validate the diagnosis ofpancreatitis (e.g., based on amylase levels or com-puted tomography scans) or to evaluate all potentialprognostic variables (e.g., serum lactate dehydroge-nase was included in the modified Glasgow criteria).The authors admit that other pertinent details, such asthe etiology of the pancreatitis, biochemical and clin-ical parameters at ICU admission, and comorbidities,such as diabetes and non-severe heart failure, are alsomissing in this study [33].Generic intensive care scoring systems, such as the

APACHE II and III scores and simplified acute phys-iology score (SAPS), have been applied to cohorts ofpancreatitis patients [16,34–40]. These scores havealso been modified by incorporating obesity [41].However, these modified scores have many of thesame drawbacks of the pancreatitis-specific scores,

being based on small data sets from single centers.An APACHE II score ‡8 has been used to indicatesevere AP [16,29–31]. It shows similar sensitivity andspecificity rates to those of Ranson and Imrie-Glasgowsystems using data collected over the first 24 h, but ismore cumbersome to perform [35,37]. Nevertheless,APACHE II score with the cut-off of ‡8 was superiorto all the other multifactorial clinical scores. It showedvery high sensitivity and specificity in predicting sever-ity (97% and 100%) and overall mortality (82% and86%) and had a strong correlation to other importantoutcomes, including development of necrosis, infec-tious complications, and need for surgical treatment.Venkatesan et al. also reported recently that a severeepisodewasunlikelywith scores<8(negativepredictivevalue of 89%). The score was shown to be superior tothe Ranson and Glasgow scores for the detection ofsevere AP in most other studies too (84–85). Somecould argue that both the APACHE II and the SAPSsystems are of limited clinical utility in the early prog-nostic evaluationofAP,but adeteriorating scoreat48htruly has a great prognostic value [35,37,42].After the definition of multiple organ dysfunction

syndrome as sequential vital system failure in 1973,different scoring systems have been developed, includ-ing the sepsis-related organ failure assessment score,MODS, and Marshall score. They were targeted todescribe multiple organ failure (pulmonary, coagula-tion, hepatic, renal, central nervous system, and car-diovascular dysfunction) in critically ill patients and toallow themonitoringof therapies [43]. Indeed, a recentinternational consensus conference redefined SAPfromacritical care perspective to represent pancreatitisin the context of systemic organ dysfunction, irrespec-tive of local complications (peripancreatic fluid collec-tions, necrosis, abscess, pseudocyst, etc.). Thus, theuse of these scores for the prediction of outcome ofseverely ill patients inAP seems to be justified, and theywere already proven to accurately predict hospitalmortality [44,45]. Our data support the use of theseprognostic systems, especially in ICU environmentwhere they could be employed for the assessment ofother severely ill patients.

Table III (Continued)

Scores and values Severity Necrosis Infection Intervention Early deaths All deaths

+LR/-LR 2.89 0.25 7.21 0.52 4.79 0.36 2.64 0.62 5.38 0.26 2.89 0.25

Significance p < 0.01 p < 0.01 p < 0.01 n. s. p < 0.01 p < 0.01

Cut-off (practical) ‡6 ‡6 ‡6 ‡6 ‡6 ‡6

c2 p < 0.01 p < 0.05 p < 0.01 n. s. n. s. p < 0.05

Abbreviations: APACHE II = acute physiology and chronic health evaluation II; AUC = area under the curve; MODS = multiple organdysfunction score; n.s. = not significant; POP = pancreatitis outcome prediction.

966 Z. Dambrauskas et al.

Biochemical and biological markers

The ideal serum marker should fulfill the criteria ofappearing early, being reliable and accurate in stagingand predicting severity. Additionally, it should becheap and easy to measure. Many markers havebeen evaluated for their usefulness in severity

stratification in AP during recent decades, some ofthem measuring systemic inflammatory response(e.g., acute-phase proteins, cytokines, leukocyte-derived proteases, markers of oxidative stress), othersmeasuring pancreatic tissue damage itself (e.g., pan-creatic proteases), but the ideal marker is yet to befound.

Table IV. The value of various serum markers in prediction of clinical outcomes.

Scores and values Severity Necrosis Infection Intervention Early deaths All deaths

CRP

Cut-off (predicted) >45 mg/l >71 mg/l >206 mg/l >152 mg/l >84 mg/l >84 mg/l

AUC 0.671 0.766 0.727 0.651 0.640 0.671

Sensitivity 67.50 78.79 61.54 62.50 77.78 76.92

Specificity 65.08 71.43 82.22 71.58 63.33 63.33

+LR/-LR 1.93 0.50 2.76 0.30 3.46 0.47 2.20 0.52 2.12 0.35 2.10 0.36

Significance p < 0.01 p < 0.01 p < 0.01 n. s. n. s. p < 0.05

Cut-off (practical) >150 mg/l >150 mg/l >150 mg/l >150 mg/l >150 mg/l >150 mg/l

c2 p < 0.01 p < 0.05 p < 0.05 n. s. n. s. n. s.

Lymphocytes

Cut-off (predicted) <0.8 x 109/l <1.1 x 109/l <0.6 x 109/l <1 x 109/l <0.69 x 109/l <0.8 x 109/l

AUC 0.697 0.656 0.604 0.672 0.582 0.629

Sensitivity 67.50 87.88 46.15 87.50 66.67 76.92

Specificity 71.43 42.86 76.67 41.05 74.44 61.11

+LR/-LR 2.36 0.45 1.56 0.28 1.98 0.70 1.48 0.30 2.61 0.45 1.98 0.38

Significance p < 0.01 p < 0.01 n. s. n. s. n. s. n. s.

Cut-off (practical) <0.8 � 109/l <0.8 � 109/l <0.8 � 109/l <0.8 � 109/l <0.8 � 109/l <0.8 � 109/l

c2 p < 0.01 p < 0.05 n. s. n. s. n. s. p < 0.05

IL-6

Cut-off (predicted) >147 pg/ml >231 pg/ml >154 pg/ml >154 pg/ml >323 pg/ml >154 pg/ml

AUC 0.762 0.779 0.701 0.792 0.957 0.896

Sensitivity 70.37 60 71.43 100 100 100

Specificity 77.78 88.46 67.69 66.67 90.62 71.87

+LR/-LR 3.17 0.38 5.20 0.45 2.21 0.42 3 0 10.67 0 3.56 0

Significance p < 0.01 p < 0.01 n. s. n. s. p < 0.01 p < 0.01

Cut-off (practical) >150 pg/ml >150 pg/ml >150 pg/ml >150 pg/ml >150 pg/ml >150 pg/ml

c2 p < 0.01 p < 0.05 n. s. n. s. p < 0.05 p < 0.01

MIF

Cut-off (predicted) >633 pg/ml >574 pg/ml >633 pg/ml >633 pg/ml >1185 pg/ml >633 pg/ml

AUC 0.740 0.679 0.736 0.783 0.926 0.844

Sensitivity 70.37 75 85.71 100 100 100

Specificity 68.89 59.62 58.46 56.52 81.25 60.94

+LR/-LR 2.26 0.43 1.86 0.42 2.06 0.24 2.30 0 5.33 0 2.56 0

Significance p < 0.01 p < 0.05 p < 0.05 n. s. p < 0.01 p < 0.01

Cut-off (practical) >630 pg/ml >630 pg/ml >630 pg/ml >630 pg/ml >630 pg/ml >630 pg/ml

c2 p < 0.01 p < 0.05 p < 0.05 n. s. p < 0.01 p < 0.01

Abbreviations: AUC = area under the curve; CRP = C-reactive protein; IL = interleukin; MIF = macrophage migration inhibitory factor;n.s. = not significant.

Predicting the severity of acute pancreatitis 967

CRP is probably the most widely used non-specificmarker for inflammatory diseases. It belongs to thegroup of acute-phase proteins predominantly synthe-sized in the liver in answer to cytokine release and hasbeen studied in detail for its use in severity stratifi-cation of AP. It reaches its peak serum concentration72–96 h after symptom onset, stays at this level duringthe following days, and is significantly higher inpatients with necrotizing disease [46–49]. In accor-dance with the latest consensus conference dealingwith this topic, a cut-off level of 150 mg/l within thefirst 48 h of onset of symptoms indicates necrotizingAP with a sensitivity and specificity of >80% and anaccuracy of 86% [49,50]. As shown by the data fromother authors and our own study, CRP is also usefulin indicating infection of pancreatic necrosis [51].Our study has also revealed high sensitivity (rangingfrom 61% to 79%) and specificity (ranging from 65%to 82%) of CRP in predicting severity of the disease,development of pancreatic necrosis, and infectiouscomplications at even lower cut-off levels. Taking intoaccount its high prognostic value and its availability inthe routine clinical setting, it is still considered thereference parameter among the single indicators ofpancreatic necrosis.Cytokines (inflammatory mediators released by

activated leukocytes and other cell types) are inducersof hepatic synthesis of acute-phase proteins and med-iators of distant organ complications. As their con-centrations increase earlier than those of acute-phaseproteins, several clinical studies have addressed theirusefulness for the early prediction of severe AP, focus-ing on pro-inflammatory IL-6 and IL-8 [52]. IL-6 hasbeen proven to be significantly increased in severe APin comparison with mild disease already on the day ofadmission to hospital, with a peak concentration onday three after the clinical onset of the disease, andtherefore to be helpful for early severity stratification[47,53–56]. Sensitivities of 69–100%with specificitiesin the range 70–86% for the detection of severe AP arereported [53,55,57,58]. Our study also revealed thesensitivity in the range of 70–100% and specificity inthe range of 61–74% for predicting mortality andseverity of the disease. Recently, IL-6 has becomeavailable for routine clinical use and might thereforeplay an important role as early prognostic tool. How-ever, due to its rapid decrease it cannot be used as amarker of disease progression. Recently, data on therole and expression of IL-8 and IL-10 during AP werereported; however, these cytokines still cannot berecommended as diagnostic or prognostic tools. Wehave also assessed the value of MIF for early strati-fication of patients with SAP and it proved to be veryuseful in detecting patients who are likely to sufferearly death. The sensitivity and specificity for

predicting early mortality were 100% and 61%,respectively. Our findings also support the notionthat MIF is a sensitive marker of pancreatic necrosis,which was recently published by Rahman et al.; how-ever, this marker had only moderate sensitivity andspecificity (approx. 70%) comparable to that of otherwidely used predicting factors [59].Lymphopenia is a well-described phenomenon

associated with SIRS, sepsis, and other severe condi-tions, including SAP [60,61]. It is easy to assess onroutine basis and was reported to be associated withsevere AP; however, to our knowledge, its prognosticvalue has not yet been described. Much to our regret,we have to conclude that it is associated with thedevelopment of pancreatic necrosis and possible fataloutcome, and could be used for early prognosis ofsevere AP with a moderate sensitivity and specificitylagging behind that of the other well-establishedpredictors.

Conclusions

CRP remains the most useful among single biochem-ical markers; the most promising novel parameters,IL-6 and MIF, seem to be appropriate for introduc-tion into clinical routine. Among multifactorial scor-ing systems, the APACHE II score has been proven tobe an early and reliable tool. Simplified scoring sys-tems may be used as an alternative. Recently intro-duced scores (e.g., POP score) have their owndrawbacks and are not superior to the widely acceptedsystems.In conclusion, prediction of severity and progres-

sion of AP may be achieved with a series of accuratemethods. Indication, timing, and consequences of themethods applied need to be carefully considered andtaken into the clinical assessment to avoid additionalcosts and harm to the patient. The decision to under-take interventional or surgical treatment seems to bethe most complex task requiring both clinical judg-ment and meticulous monitoring of the patient.

Declaration of interest: The authors report noconflicts of interest. The authors alone are responsiblefor the content and writing of the paper.

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