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ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 4  |  Page : 1335-1340

Role of interleukin-6, interleukin-8, and β-2 microglobulin in assessment of severity of pancreatitis


1 Department of General Surgery, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of General Surgery, The Military Medical Complex in Kobry El-Koba Hospital, Armed Forces, Cairo, Egypt

Date of Submission29-May-2020
Date of Decision17-Jun-2020
Date of Acceptance26-Jun-2020
Date of Web Publication24-Dec-2020

Correspondence Address:
Ahmed M Maarek
MBBCH, Fisha, El.Bagour, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_166_20

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  Abstract 


Objective
The aim was to evaluate the role of interleukin-6 (IL-6), IL-8, and β-2 microglobulin (B2M) in assessment of severity of pancreatitis.
Background
Acute pancreatitis is a potentially lethal disease, especially in its severe form, which accounts for ~20% of cases in patients hospitalized with acute pancreatitis.
Patients and methods
This prospective comparative study was conducted on 80 patients with acute pancreatitis who were divided into two groups: mild/moderate acute pancreatitis (MAP) group and severe acute pancreatitis (SAP group). All patients were subjected to full history taking; clinical examination; and laboratory investigation, which included complete blood count, renal function tests, prothrombin time, partial thromboplastin time, international normalized ratio, liver function tests, serum electrolytes, serum albumin, serum amylase and lipase, and pancreatic markers.
Results
The authors found a highly significant increase in total leukocyte count in SAP group when compared with MAP group (P < 0.001); a highly significant decrease in serum albumin in SAP group when compared with MAP group (P < 0.001); a highly significant increase in baseline IL-6, IL-8, and B2M in SAP group when compared with MAP group (P < 0.001); a significant increase in third day IL-6, IL-8, and B2M in SAP group when compared with MAP group (P < 0.001); and a highly significant increase in complications and mortality rate, in SAP group when compared with MAP group (P < 0.001).
Conclusion
Inflammatory markers, particularly ILs, are important tools in the prediction and follow-up of patients with AP.

Keywords: assessment, β-2 microglobulin, interleukin-6, interleukin-8, pancreatitis


How to cite this article:
El-Gamal AS, Osman NF, AlKhateap YM, Maarek AM. Role of interleukin-6, interleukin-8, and β-2 microglobulin in assessment of severity of pancreatitis. Menoufia Med J 2020;33:1335-40

How to cite this URL:
El-Gamal AS, Osman NF, AlKhateap YM, Maarek AM. Role of interleukin-6, interleukin-8, and β-2 microglobulin in assessment of severity of pancreatitis. Menoufia Med J [serial online] 2020 [cited 2021 Apr 18];33:1335-40. Available from: http://www.mmj.eg.net/text.asp?2020/33/4/1335/304487




  Introduction Top


Acute pancreatitis varies in severity from mild interstitial or edematous pancreatitis to severe forms, which can lead to a systemic inflammatory response syndrome and progress to septic systemic complications with significant morbidity and mortality in 20% of patients[1]. Acute pancreatitis remains the most common complication of endoscopic retrograde cholangiopancreatography (ERCP). The incidence of post-ERCP pancreatitis (PEP) varies from 1 to 40%[2]. Acute pancreatitis is caused by an inappropriate intracellular activation of proteolytic enzymes and cleavage of trypsinogen to trypsin. These enzymes initiate a cascade of phospholipases, elastases, and other mediators, with associated neutrophil migration into the pancreas. Subsequent autodigestion of pancreatic parenchyma results in destruction of the acini and pancreatic islet cells with interstitial fat necrosis and necrotizing vasculitis[3]. These pathological changes in the pancreas result in the release of active pancreatic enzymes into the bloodstream and stimulate the production of inflammatory cytokines, such as interleukin (IL)-1, IL-6 and IL-8, platelet activating factor, and tumor necrosis factor-α[4]. The release of these cytokines from macrophages triggers inflammatory cascade, which leads to mortality in 20% of patient. Diagnosis of acute pancreatitis is based on acute attacks of abdominal pain mainly in epigastric region radiating to the back and flanks, as well as signs such as pyrexia, abdominal distension, and peritonism. The classical signs of discoloration of the flanks (Grey-Turner's sign) and periumbilicus (Cullen's sign) are not always seen and are a result of retroperitoneal hemorrhage tracking along tissue planes. In addition, symptoms and signs of end-organ involvement may be evident, including respiratory distress, shock, oliguria, jaundice, and delirium[5]. Elevated blood levels of pancreatic enzymes such as amylase, lipase, and trypsinogen, which are derived from pancreatic acinar cells, have an important role in diagnosis of acute pancreatitis. Serum amylase is most commonly used in clinical practice. A level of greater than three times the normal upper range (the normal upper range: 300 IU/l) supports the diagnosis of pancreatitis. Lipase concentrations are increased for up to 14 days after onset of pancreatitis and appear to be more sensitive and specific than serum amylase[6]. Imaging tests such as transabdominal ultrasound, endoscopic ultrasound, computed tomography (CT) scanning, MRI, and magnetic resonance cholangiopancreatography play an important role in detection of gallstone, detection of biliary obstruction, diagnosis of pancreatitis when the clinical situation is unclear, identification of patients with high-risk pancreatitis, and detection of complications of pancreatitis[7]. Treatment of patients with acute pancreatitis is based on the initial assessment of severity. Fluid therapy is considered a cornerstone of the early treatment of patient with acute pancreatitis particularly in the initial 24 h. Underresuscitation during the early phase of acute pancreatitis has been associated with increased risk of necrosis and mortality[8]. Most patients with infected necrotizing pancreatitis require necrosectomy. Endoscopic transgastric necrosectomy, a form of natural orifice transluminal endoscopic surgery, reduces the proinflammatory response and complication[9]. The aim of this study was to evaluate and demonstrate the role of IL-6, IL-8, and β-2 microglobulin (B2M) in the assessment of severity of pancreatitis.


  Patients and methods Top


The Ethical Committee of Faculty of Medicine, Menoufia University, approved the study. A prospective comparative study was conducted on 80 patients with acute pancreatitis who were admitted to the General Surgery Department in Menoufia University Hospital and Kobri El Qobba Armed Force Hospitals. They were enrolled in the study from April 2018 to April 2019. Diagnosis was based on prolonged upper abdominal pain associated with a two-fold increase serum lipase, and it was confirmed by imaging techniques. Inclusion criteria included all patients above18 years old of either sex, diagnosed with acute pancreatitis. First, the diagnosis of acute pancreatitis was established by the criteria set by the Atlanta guidelines[10] as follows: clinical features suggestive of acute pancreatitis; ultrasonography (USG) or CT showing features of acute pancreatitis; and increase of serum lipase two-fold. Second, onset of pain should be within 24 h before admission to the hospital. Exclusion criteria were patients with known immunodeficient status; patients with progressive weight loss or mass may suspect cancer; severe cardiac disease; preexisting hepatic disorders (total bilirubin >1.5 times the upper limit of normal); psychiatric disorders; preexisting renal compromise (serum creatinine >2.0 mg/dl); all patients younger than 18 years; and patients with autoimmune disease such as rheumatoid arthritis. All patients were subjected to full history taking and clinical examination. Laboratory investigation included complete blood picture (complete blood count) to assess white blood cell, renal function tests, prothrombin time, partial thromboplastin time, international normalized ratio, liver function tests, serum electrolytes, serum albumin, serum amylase and lipase, and pancreatic markers (IL-6, IL-8, and B2M). Chest radiography, ECG, ultrasound (US), and contrast-enhanced CT abdomen were done. For pancreatic markers, we used ELISA kits (Sinogeneclon Co. Ltd, Hangzhou, China, in 2007).

Interleukin-6

IL-6 was assessed using electrochemiluminescence. Specimen type was plasma EDTA. Collection container/tube was Lavender-top (EDTA). Specimen volume was 0.5 ml. Collection instructions included the following: immediately after specimen collection, place the tube on wet ice; centrifuge at 1500g for 10 min and aliquot plasma; and freeze the specimen within 30 min (reference values: <or = 1.8 pg/ml). Interpretation was as follows: elevated concentrations of iIL-6 may indicate an ongoing inflammatory response, and could be consistent with a systemic infection, localized infection, or chronic inflammatory disease. Caution should be taken with respect to interpretation, as iIL-6 is a nonspecific marker associated with an inflammatory response and is not diagnostic for any specific disease or disease process. Elevated concentrations of IL-6 must be interpreted within the clinical context of the patient. Normal concentrations of IL-6 do not exclude the possibility of an ongoing inflammatory process. IL-6 has limited stability. Following centrifugation, plasma must be either immediately frozen or refrigerated. Samples can only be stored at refrigerated temperatures for 24 h, after which time, samples must be frozen. Storage of plasma for any length of time at room temperature is not acceptable.

Interleukin-8

IL-8 was assessed using electrochemiluminescence. Specimen type was serum. Specimen required was the draw blood in a plain red-top tube(s). Serum gel tube(s) is acceptable. Spin down the blood, and send 1 ml of serum frozen in a plastic vial. Specimen minimum volume was 1 ml, and reference value was less than 57.8 pg/ml.

β-2 microglobulin

B2M was assessed using nephelometry. Specimen type was serum. Container/tube was serum gel. Specimen volume was 1 ml, and reference values were 1.21–2.70 μg/ml.

Statistical analysis

Data entry, processing, and statistical analysis were carried out using MedCalc ver. 18.2.1 (MedCalc, Ostend, Belgium). Tests of significance [Mann–Whitney's, χ2 tests, logistic regression analysis, and receiver operating characteristic (ROC) curve analysis] were used. Data were presented, and suitable analysis was done according to the type of data (parametric and nonparametric) obtained for each variable. P values less than 0.05% were considered to be statistically significant. Descriptive statistics were mean ± SD, and range for parametric numerical data, whereas median and interquartile range for nonparametric numerical data. Frequency and percentage were used for non-numerical data. Analytical statistics included the following: Mann–Whitney test (U test) was used to assess the statistical significance of the difference of a nonparametric variable between two study groups. χ2-test was used to examine the relationship between two qualitative variables. Logistic regression was useful in the prediction of the presence or absence of an outcome based on a set of independent variables. It is similar to a linear regression model but is suited when the dependent variable is qualitative (categorical). The ROC curve provides a useful way to evaluate the sensitivity and specificity for quantitative diagnostic measures that categorize cases into one of two groups. Excellent accuracy = 0.90–1%; good accuracy = 0.80–0.90%; fair accuracy = 0.70–0.80%; poor accuracy = 0.60–0.70%, and failed accuracy = 0.50–0.60%.


  Results Top


A total of 80 patients (60 males and 20 females) were enrolled at this study. The mean age was 36.5–50 years in patients in the mild/moderate acute pancreatitis (MAP) group and 37–54 years in patients of the severe acute pancreatitis (SAP) group. When comparing the two groups, we found a nonsignificant difference regarding age, sex, BMI, and etiology of AP (P = 0.3658, 0.5755, 0.4982, and 0.0929, respectively). Regarding etiology, we found that 16.3% of acute pancreatitis (AP) cases were caused by alcohol, 31.2% caused by ERCP, and 52.5% caused by gall bladder stones [Table 1]. When compare the two groups regarding laboratory results, there was a highly significant increase in total leukocyte count in the SAP group when compared with MAP group (P < 0.01). A highly significant decrease was seen in serum albumin in SAP group compared with MAP group (P < 0.001). Nonsignificant differences regarding all the remaining routine laboratory variables (P > 0.05) were found in our results [Table 2]. Regarding baseline markers, a comparative study between the two groups revealed a highly significant increase in baseline IL-6, IL-8, and B2M in SAP group when compared with MAP group (P < 0.01). Regarding third day markers, a comparative study between the two groups revealed a highly significant increase in third day IL-6, IL-8, and B2M in SAP group when compared with MAP group (P < 0.01) [Table 3]. Regarding outcome data, a comparative study between the two groups revealed a highly significant increase in complications and mortality rate in SAP group when compared with MAP group (P < 0.01) [Table 4]. Regarding baseline markers, by using ROC curve analysis, baseline IL-6 level at a cutoff point more than 47.8 predicted patients with SAP, with excellent accuracy (92%), sensitivity (91%), and specificity (96%) (P < 0.01); baseline IL-8 level at a cutoff point more than 40.3 predicted patients with SAP, with excellent accuracy (95%), sensitivity (91%), and specificity (96%) (P < 0.01); and baseline B2M level at a cutoff point >8.4 predicted patients with SAP, with good accuracy (87%), sensitivity (75%), and specificity (94%) (P < 0.01) [Table 5] and [Figure 1].
Table 1: Comparison between the two groups regarding demographic data

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Table 2: Comparison between the two groups regarding routine laboratory data

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Table 3: Comparison between the two groups regarding pancreatic markers

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Table 4: Comparison between the two groups regarding outcome data

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Table 5: Receiver operating characteristics -curve of each pancreatic marker to predict patients with severe acute pancreatitis

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Figure 1: Receiver operating characteristics curve of baseline IL-6 (SAP), IL-8 (SAP), and B2M (SAP)- B2M, β-2 microglobulin; IL, interleukin; SAP, severe acute pancreatitis

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  Discussion Top


Acute pancreatitis is a potentially lethal disease especially in its severe form, which accounts for ~20% of cases in patients hospitalized with acute pancreatitis. Mortality in severe diseases varies from 10 to 20%. It has been reported that serum IL-6 and IL-8 are useful markers in the assessment of severity of pancreatitis and reported that the sensitivity of serum IL-6 and IL-8 for predicting the severity of acute pancreatitis was higher than that of serum c- reactive protein and β-2 microglobulin during the first 24 h of the onset of clinical symptoms[11]. In our study, the age range of patients was 36.5–50 years in the MAP group and 37–54 years in the SAP group. When comparing the two groups, we found a nonsignificant difference regarding age, sex, BMI, and etiology of AP. This came in agreement with Ceranic et al.[12] who reported the analyzed data of 96 patients. There were 59 (61.5%) male and 37 (38.5%) female patients, with the mean age of 62.5 ± 16.8 years, ranging from 22 to 91 years, with a nonsignificant difference regarding age, sex, BMI, and etiology of AP. Regarding etiology, we found that 16.3% of AP cases were caused by alcohol, 31.2% by ERCP, and 52.5% by gall bladder stones, which came in agreement with Sternby et al.[13], where the etiology was divided into biliary (56.5%), alcohol (16.8%), other (i.e., post-ERCP pancreatitis, tumors, and other strictures) (15.5%), and idiopathic (11.2%). Kohla et al.[14] reported that acute pancreatitis is the most common complication of diagnostic and therapeutic ERCP. In our study, when comparing the two groups regarding laboratory results, a highly significant increase was seen in total leukocyte count in SAP group when compared with MAP group, a highly significant decrease was seen in serum albumin in SAP group when compared with MAP group, and a nonsignificant difference was seen regarding all the remaining routine laboratory variables. This is in agreement with Gunjaca et al.[15], who reported that white blood cells (WBC) at day 1 (mean) was 12.4 ± 4.8 in mild pancreatitis and 16.4 ± 7,6 in severe pancreatitis, which provide increase in total leukocytic count in severe group. Mehta et al.[16] reported that compared with patients without POF, patients with POF showed significantly elevated values of LDH, whereas the levels of albumin were statistically lower, and albumin (gl) was 37.9 in mild pancreatitis and 29.1 in severe group. Alameldeen et al.[17] reported that in two (10%) patients, alanine aminotransferase (ALT), aspartate aminotransferase (AST), Albumin (ALP), total bilirubin, direct bilirubin, WBC count, serum amylase, and lipase were elevated. The mean value for ALP was 189.5 ± 111.92 U/l, total bilirubin was 2.33 ± 1.97 mg/dl, direct bilirubin was 1.46 ± 1.79 mg/dl, AST was 209.7 ± 252.41 U/l, ALT was 118.1 ± 175.25 U/l, WBC count was11.21 + 4.48 cells/cm3, serum amylase was 790.4 + 897.5 U/l, and serum lipase was 1059.5 + 1629.46 U/l. ALP was elevated in 70% cases. Total bilirubin was elevated in 60% cases, and levels higher than 4 mg were found in 40% cases. Direct bilirubin was elevated in 50% cases. AST was elevated in 70% cases, ALT in 40% cases, WBC count in 70% cases, serum amylase in 90% cases, and serum lipase in 80% cases. In our study, regarding baseline markers, a comparative study between the two groups revealed a highly significant increase in baseline IL-6, IL-8, and B2M in SAP group compared with MAP group. Regarding third day markers, a comparative study between the two groups revealed a highly significant increase in third day IL-6, IL-8, and B2M in SAP group when compared with MAP group. Sternby et al.[13] reported that upon admission significant differences between median values of the groups with MAP and SAP were found for IL-1β, IL-6, IL-10, and IL-8. In our study, regarding outcome data, a comparative study between the two groups revealed a highly significant increase in complications and mortality rate in SAP group when compared with MAP group. This is in agreement with Dambrauskas et al.[18], who reported that SAP (APACHE-II >7) comprised 44.4% of all cases. Necrotizing AP was detected by contrast-enhanced CT in 52 patients (48.1%), and high volume (>30%) necrosis was present in 34 cases (31.3%). Multiple organ failure (>2 systems) developed in 18 (16.7%) cases. Overall mortality in follow-up group was 12.9%; nine (8.3%) patients died within first 2 weeks of the disease and five (4.6%) patients later in the course of the disease, and mortality rate was highly significant increase in SAP group. In our study, regarding baseline markers, by using ROC curve analysis, baseline IL-6 level at a cutoff point more than 47.8 predicted patients with SAP with excellent accuracy (92%), sensitivity (91%), and specificity (96%); baseline IL-8 level at a cutoff point (>40.3) predicted patients with SAP, with excellent (95%) accuracy, sensitivity (91%), and specificity (96%); and baseline B2M level at a cutoff point more than 8.4 predicted patients with SAP, with good accuracy (87%), sensitivity (75%), and specificity (94%). Ceranic et al.,[12] reported the predictive values of IL-6, IL-8, and IL-10 at admission in the prediction of severity of AP. The values of IL-6 at admission had the highest predictive value (area under curve = 0.782). At a value of IL-6 = 70.05 pg/ml, the sensitivity was 0.80, specificity was 0.701, positive predictive value was 0.40, and negative predictive value was 0.96 (P < 0.001). However, IL-8, with area under curve = 0.672, at a value of 21.7 pg/ml, had sensitivity of 0.80, specificity of 0.610, and positive predictive value of 0.40.


  Conclusion Top


Inflammatory markers, especially ILs, are considered as an important tool in the prediction of severity and follow-up of patients with AP. Unfortunately, low availability and high costs are limiting their use in everyday clinical practice. However, Ranson score, CRP, WBC, platelets, and blood urea nitrogen are simple and available markers for routine clinical work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Leser H, Gross V, Scheibenbogen C, Heinisch A, Salm R, Lausen M, et al. Elevation of serum interleukin-6 on centration precedes acute-phase response and reflects severity in acute pancreatitis. Gastroenterology 2010; 101:782–785.  Back to cited text no. 10
    
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Zaheer A, Vikesh K, Singh O, Qureshi A, Elliot K. The revised Atlanta classification for acute pancreatitis: updates in imaging terminology and guidelines. Abdom Imaging 2013; 38:125–136.  Back to cited text no. 11
    
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Ceranic DB, Zorman M, Skok P. Interleukins and inflammatory markers are useful in predicting the severity of acute pancreatitis. Bosnian Journal of Basic Medical Sciences. 2020;20:99.  Back to cited text no. 12
    
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Sternby H, Hannes H, Dorthe J, Henrik T, Sara R. Predictive capacity of biomarkers for severe acute pancreatitis. Eur Surg Res 2016; 56:154–163.  Back to cited text no. 13
    
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Kohla S, El-Dein A, Mahmoud F, Mukhtar H. Glyceryl trinitrate for prevention of pancreatitis after endoscopic retrograde cholangiopancreatography: meta-analysis of randomized, controlled trials. Menoufia Med J 2015; 28:793.  Back to cited text no. 14
    
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Gunjaca I, Josip Z, Mihaela G, Zdenko K. Circulating cytokine levels in acute pancreatitis–model of SIRS/CARS can help in the clinical assessment of disease severity. Inflammation 2012; 35:758–763.  Back to cited text no. 15
    
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Mehta S, Shuchi G, Rajendra T, Verma A. Serum albumin level in persistent organ failure in acute pancreatitis. Int J Med Biomed Stud 2019; 3:59.  Back to cited text no. 16
    
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Alameldeen M, Abouelnagah G, Rageh T, Ammar M. Laparoscopic cholecystectomy role in the management of acute biliary pancreatitis. Menoufia Med J 2018; 31:145.  Back to cited text no. 17
    
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