Hindawi Publishing Corporation

Journal of Biomarkers
Volume 2015, Article ID 519534, 13 pages
http://dx.doi.org/10.1155/2015/519534

Review Article
Role of Biomarkers in Diagnosis and Prognostic
Evaluation of Acute Pancreatitis

Susanta Meher, Tushar Subhadarshan Mishra, Prakash Kumar Sasmal,

Satyajit Rath, Rakesh Sharma, Bikram Rout, and Manoj Kumar Sahu
Department of General Surgery, All India Institute of Medical Sciences, Bhubaneswar 751 019, India

Correspondence should be addressed to Susanta Meher; chikusus@gmail.com

Received 31 May 2015; Revised 14 July 2015; Accepted 15 July 2015

Academic Editor: Eugene H. J. M. Jansen

Copyright © 2015 Susanta Meher et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Acute pancreatitis is a potentially life threatening disease. The spectrum of severity of the illness ranges from mild self-limiting
disease to a highly fatal severe necrotizing pancreatitis. Despite intensive research and improved patient care, overall mortality
still remains high, reaching up to 30–40% in cases with infected pancreatic necrosis. Although little is known about the exact
pathogenesis, it has been widely accepted that premature activation of digestive enzymes within the pancreatic acinar cell is the
trigger that leads to autodigestion of pancreatic tissue which is followed by infiltration and activation of leukocytes. Extensive
research has been done over the past few decades regarding their role in diagnosis and prognostic evaluation of severe acute
pancreatitis. Although many standalone biochemical markers have been studied for early assessment of severity, C-reactive protein
still remains the most frequently used along with Interleukin-6. In this review we have discussed briefly the pathogenesis and the
role of different biochemical markers in the diagnosis and severity evaluation in acute pancreatitis.

1. Introduction the feature of severe acute pancreatitis which is associated

with a high rate of mortality. The overall mortality of AP
Acute pancreatitis (AP) is a potentially life threatening is about 10–15% but reaches up to 30%–40% in patients
disease with varying severity of presentation [1, 2]. Nearly with severe disease [13, 14]. Sepsis related multiorgan failure
60%–80% of all cases of AP in developed countries are and infected pancreatic necrosis account for about 40–50%
attributable to either gallstone disease or alcohol abuse [3, 4]. of all mortality in acute pancreatitis [13, 15, 16]. Mortality
The incidence is similar in both sexes, although alcohol abuse in AP occurs in two peaks [17–21]. Nearly 50% of deaths
is the more common cause in men and gallstones is the occur early within the first week due to massive inflammatory
more common cause in women [5, 6]. There is an upsurge responses leading to multiorgan failure. Septic complications
in the incidence of AP over the last few decades, although related to infected pancreatic necrosis leading to multiorgan
the case fatality rate has remained unchanged [7]. This may failure are the prime cause of death, late in the disease [17–
either be due to increased incidence of gallstone disease or 21]. The course and severity of AP can fluctuate rapidly and
improvement in diagnostic modalities [8]. unpredictably [1, 22].
The revised Atlanta classification system has classified Despite the advances in investigational modalities and
AP into mild, moderate, and severe [9, 10]. More than research techniques, the exact pathogenesis of AP is still
80% of acute pancreatitis attacks are mild and self-limiting unclear [18, 23–25]. Recent studies have suggested the role of
and resolve without serious complications. In 20% of cases, inflammatory mediators and oxidative stress in the pathogen-
however, it can be severe and complicated by major mor- esis of AP and its sequelae [18, 23–25]. The pathophysiology
bidity or mortality [3, 11, 12]. Moderate acute pancreatitis is of AP, role of various markers in establishing the diagnosis
characterized by the presence of transient organ failure or and prediction of severity, and upcoming markers including
local/systemic complications [10]. Persistent organ failure is markers of oxidative stress are being discussed in this review.
2 Journal of Biomarkers

2. Pathophysiology of Acute Pancreatitis According to revised Atlanta classification, diagnosis of acute

pancreatitis requires two of the following three criteria [1, 22]:
Despite intense research over centuries, the exact pathogen-
esis of AP remains elusive [3, 26]. Although many theories (1) Abdominal pain characteristic of AP (acute onset of
have been proposed, none of them appear to be complete [3, a persistent, severe, epigastric pain often radiating to
27]. Some of the propositions include abnormal biliopancre- back).
atic duct common pathway theory, pancreatic autodigestion (2) Serum lipase (or amylase) activity at least three times
theory, gallstone migration theory, enzyme activation theory, greater than the upper limit of the reference interval.
kinin and complement activation theory, microcirculation
disturbance theory, and pancreatic acinar cell apoptosis and (3) Characteristic imaging findings of AP on contrast
necrosis theory, all of which are still controversial [3, 8]. enhanced computed tomography (CECT) and less
They can only explain certain aspects of pathogenesis or suit commonly magnetic resonance imaging (MRI) or
disease due to specific aetiologies. transabdominal ultrasonography.
The biggest obstacle in the study of pathogenesis of AP The pancreatic enzymes derived from pancreatic acinar cells
is its rapid course and relative inaccessibility of pancreatic [amylase, lipase, and the proenzyme trypsinogen] are the
tissue [3]. To overcome this problem, investigators have cornerstone in the laboratory diagnosis of AP [36]. Serum
now taken to animal models to study the molecular aspects lipase is a more sensitive and specific biochemical marker of
of pathogenesis of acute pancreatitis [3, 28, 29]. Further AP than the more frequently used amylase. Moreover, serum
complicating the issue are the paradoxical results about the amylase level offers no additional advantage if simultaneously
pathogenesis, obtained from different animals exposed to measured with serum lipase [36–38].
similar aetiology [5]. The premature activation of trypsin Additional biomarkers under evaluation for diagnosis
in pancreatic parenchyma acting as the central step in the of acute pancreatitis include pancreatic isoamylase, pancre-
initiation of autodigestion of pancreatic tissue and subse- atic elastase, serum trypsin, urinary trypsinogen activated
quent local and systemic inflammation is presently the most peptide (TAP), Phospholipase A2, and Carboxypeptidase
accepted theory [17, 18, 30, 31]. Whatever is the initiating B (CAPB) [39, 40]. Serum trypsin and elastase are of
event, the disease progression can be viewed as a three- particular interest because of their longer half-life which
phase continuum: local inflammation of the pancreas and a makes them useful in diagnosis during delayed presentations
generalized inflammatory response followed by the final stage [41]. These tests, however, have not found much favor in
of multiorgan dysfunction [17, 18, 30, 31]. Figure 1 illustrates clinical application because of a variety of reasons including
the schematic overview of pathogenesis of acute pancreatitis inferior diagnostic accuracy compared to amylase and lipase,
[32, 33]. cumbersome techniques, or availability [33].
In the early phase, inflammation is usually localized to the
pancreas which clinically manifests as mild acute pancreatitis. 3.1. Amylase. Amylase is a glycoside hydrolase primarily
This usually resolves within a week without any local or sys- produced in the pancreas and salivary glands and in very
temic complications [5]. However, if the disease progresses, small quantities in other tissues. In acute pancreatitis, the
there occurs a phase of generalized inflammation, also known blood level of amylase rapidly increases within six hours of
as systemic inflammatory response syndrome (SIRS) [1, onset of disease, exhibits a half-life of 10–12 hours, remains
3]. Subsequently, there is a phase of mixed inflammatory elevated for 3–5 days, and finally is excreted by the kidney
response, known as mixed antagonist response syndrome [33, 36, 42]. After reaching a peak level, subsequent return
(MARS), which clinically manifests as moderately severe of serum amylase to its normal level does not correlate
acute pancreatitis, associated with transient organ failure and with resolution of clinical symptoms [43]. Furthermore, the
local complications [1]. Finally a phase of suppressed inflam- magnitude of the hyperamylasemia does not show significant
matory response occurs which is known as compensatory statistical correlation with disease severity and ultimate
response syndrome (CARS) which manifests as severe acute prognosis [44]. In 19–32% of cases amylase activity may be
pancreatitis associated with persistent organ failure [1, 3]. normal at the time of hospital admission due to delayed
The immune system in this phase is downregulated, leading presentation or exocrine pancreatic insufficiency (chronic
to higher susceptibility of the pancreatic and peripancreatic alcoholism) [36, 43]. Raised serum amylase can also be found
tissue to infection from bacteria translocated from the gut. in many other intrabdominal inflammatory conditions and
The ensuing sepsis and multiorgan failure are the major cause salivary disorders and in patients having decreased renal
of late morbidity and mortality in severe acute pancreatitis clearance. Macroamylasemia is a condition in which amylase
[1, 33]. Figure 2 illustrates the two phases of severe acute remains bound to immunoglobulins or polysaccharides to
pancreatitis. form large molecular weight complexes leading to raised
levels of serum amylase [36, 45, 46]. Hypertriglyceridemia
3. Biomarkers in Establishing Diagnosis of AP competitively interferes with amylase assay, so a false low
level of serum amylase can be found in patients having
The diagnosis of acute pancreatitis is usually based on a hypertriglyceridemia [36, 46]. Sensitivity and specificity of
combination of clinical findings, laboratory investigations, amylase as a diagnostic test for AP depend on its threshold
and imaging techniques. There is no gold standard test value. At a cut-off level of 1000 IU/L, it has a sensitivity of
available to diagnose acute pancreatitis at present [34, 35]. around 55–84% and specificity up to 95% [36, 38, 46, 47].
Journal of Biomarkers 3

Acinar cell damage

Impaired Cell
Impaired Membrane
cell Trafficking
membrane trafficking

(1) Fusion of lysosomal and zymogen grannule

Trypsinogen Trypsin (2) Trypsin activates zymogen cascade

(3) Secretory vesicles move to basolateral

membrane and act as chemoattractants

Attraction and activation of releasing cells

PMN leukocytes Macrophages Lymphocytes Endothelium

Proinflammatory mediators
Anti-inflammatory mediators +
+ − Chemokines
TNF𝛼, IL1𝛽, IL-18, IL-6, IL-2 − IL-10, IL-1a, IL-11 IL-8, RANTES, MCP-1,
Adhesion molecules, PAF, NO
ENA-78, GRO-𝛼
Oxygen free radicals

SIRS
Acute phase response, pyrexia, tachycardia, tachypnoea

MODS
Gut ischemia, bacterial translocation Pulmonary/renal failure, shock

Infected necrosis Sepsis

Figure 1: Schematic overview of pathogenesis of acute pancreatitis. Acinar cell damage leads to activation of trypsin following impairment of
cell membrane trafficking with subsequent activation of zymogen cascade by trypsin. Attraction and activation of leukocyte occur with release
of many proinflammatory and anti-inflammatory cytokines and also chemokines. An overt and sustained activation of proinflammatory
mediators leads to Systemic Inflammatory Response Syndrome (SIRS) which may further proceed to multiorgan failure and infection of
pancreatic necrosis and sepsis with late complications of acute pancreatitis [32, 33].

3.2. Lipase. Lipase assay has a sensitivity and specificity of [36, 49]. Hypertriglyceridemia does not influence the serum
80% and 60%, respectively [35, 48]. The serum concentration lipase assay as happens in the case of serum amylase.
of lipase increases within 3–6 hours of onset of disease and Patients taking frusemide can show increased lipase activity
peaks within 24 hours [32]. The increased serum level stays [36]. Increased serum level of lipase can also be seen in
for around 7–14 days before it comes down to the normal many intra-abdominal pathologies including acute chole-
level [32, 36]. In contrast to amylase, lipase is reabsorbed cystitis, appendicitits, inflammatory bowel disease, intestinal
in renal tubules and stays for long at higher concentration, ischemia, obstruction, perforation, and renal insufficiency
thereby giving greater sensitivity in patients with delayed [32, 36]. According to recent guidelines from UK, serum
presentation [32, 36]. Pancreatic lipase is four times more lipase should be preferred for diagnosis of AP over serum
active than amylase and it is less affected by exocrine pancre- amylase wherever available [36–50]. At a cut-off level of
atic deficiency occurring in patients of chronic pancreatitis 600 IU/L, most studies have reported specificity above 95%;
4 Journal of Biomarkers

Early phase Late phase 5. Role of Biomarkers in Prediction of

SIRS MARS CARS Severe Acute Pancreatitis
Severity assessment in acute pancreatitis was first started
in 1974 by late Ranson et al. [54]. Since then a number of
multifactorial scoring systems using common clinical and
Severity of disease
biochemical parameters have been described for prediction
SAP of severity. Ranson, Glasgow, and APACHE II score are few of
Mild AP the commonly used scoring systems [36]. Limitations of these
s MMMMMMILM
scoring systems include delay in complete scoring where it
1–10 days >10 days takes 48 hours to complete Ranson and Glasgow scoring
Time systems need a time of 48 hours to complete the assessment,
while APACHE II score is very cumbersome to calculate [36].
Figure 2: Two phases of severe acute pancreatitis (SAP). CARS: The disadvantages of these prompt most of the researchers to
compensatory response syndrome; MARS: mixed antagonist find a single biochemical parameter which could accurately
response syndrome; SIRS: systemic inflammatory response syn- predict the severity of AP early in the course of the disease.
drome; Mild AP: mild acute pancreatitis [1].
5.1. Interleukins. Interleukin-6 (IL-6) is produced by a wide
range of cells like monocytes, macrophage, endothelium, and
however, serum lipase level’s sensitivity is limited between fibroblast in response to potent proinflammatory stimulus
55–100% [36, 51]. Like that of amylase, most studies suggest a like TNF-alpha and IL-1𝛽 [33]. A large number of studies
poor correlation between lipase activity and disease severity have already confirmed the role of IL-6 in early and accurate
[44]. prediction of severity in acute pancreatitis [33, 36, 55].
Value of IL-6 is significantly elevated in SAP on the day
3.3. Trypsinogen. Trypsinogen is the zymogen of the pancre- of admission and tends to peak at 72 hrs after the clinical
atic enzyme trypsin which is cleaved by duodenal enteroki- onset of disease, which makes IL-6 an excellent marker
nase to produce the active enzyme trypsin and trypsinogen of early severity stratification [56]. In terms of predicting
activated peptide (TAP) [22, 36]. Normally trypsinogen complications, IL-6 was found to be excellent in predicting
(trypsinogen-1 and trypsinogen-2) is secreted into the pan- remote organ failure, which is an integral part of severe acute
creatic fluid by the acinar cells, of which a small amount pancreatitis [57]. Among various proinflammatory and anti-
enters into the circulation and is excreted in urine. In inflammatory cytokines, IL-6 has the best sensitivity and
pancreatitis large amounts of this enzyme enter the systemic specificity for early assessment of SAP [58]. With a cut-
circulation due to increased vascular permeability and there off value of 50 pg/mL, Jiang et al. have found a sensitivity
is a consequent increased clearance in urine. This forms the and specificity of 100% and 89.7%, respectively [59]. With
basis of the use of trypsinogen in the diagnosis and severity a similar cut-off level, Khanna et al. found a sensitivity
assessment of AP [32]. Both serum and urine concentrations of 93.1% and specificity of 96.8% in their study [56]. The
rise within few hours of onset of disease and decline to normal major drawback of IL-6 assay is that its serum concentration
level within 3 to 5 days [32, 36, 52]. A dipstick method using decreases very rapidly. Use of Il-6 in routine clinical practice
urinary trysinogen-2 has been devised for rapid detection of is limited by its cost and the complexity of assay [36].
AP [32, 53]. Because of its low sensitivity and less availability, IL-8 is the best characterized member of the chemokine
this test is less frequently used in routine clinical practice [32]. family studied in acute pancreatitis. It is a powerful secondary
The greatest demerit of trypsinogen as a diagnostic test is its chemoattractant of neutrophil in the inflammatory process
rapid clearance, which means it can only be used for early [60]. Many studies have shown promising results in early
cases. It can be a useful test for screening of ERCP induced prediction of SAP [60]. One study has shown its role in
pancreatitis [32, 36]. monitoring life threatening complications in patients of
necrotizing pancreatitis with multiorgan failure [61].
4. Rationale of Severity Stratification and IL-12, IL-15, and IL-17 are proinflammatory cytokines
Its Assessment which have been studied recently as potential biomarkers.
Similar results have been seen in various studies as single
Acute pancreatitis is self-limiting in 75%–80% of cases and biochemical markers on the day of admission. IL-15 and IL-17
does not require any treatment other than parenteral intra- are better predictors of organ dysfunction and mortality [62–
venous fluid, analgesics, and supportive care [4, 22, 23]. The 64].
remaining may suffer from severe attacks, with the mortality In a recent meta-analysis by Zhang et al., IL-6, IL-8,
reaching up to 30%–50% [18]. This subgroup of patients and IL-10 have shown promising results in predicting severe
needs to be identified early in the course of the disease and acute pancreatitis. They, however, found a lack of consensus
needs to be aggressively treated to prevent mortality. Proper regarding the ideal cut-off value for assessing the same [65].
identification of the mild disease is also necessary to avoid
unnecessary over treatment, thereby reducing the financial 5.2. C-Reactive Protein (CRP). CRP is an acute phase reactant
implications. synthesized by the hepatocytes and is usually elevated in
Journal of Biomarkers 5

inflammatory conditions [66]. Cytokines like IL-6 are potent found quantification of plasma PMN elastase levels as a very
inducers of CRP synthesis in liver. It takes nearly 72 hours for accurate method for the early prognostic evaluation of AP
the serum level of CRP to peak after the onset of symptoms and found its applicability in the clinical setting [74].
[56]. It is the most frequently used single biomarker for
assessment of severity in AP today. This is because it is 5.5. Tumor Necrosis Factor-Alpha (TNF-Alpha). TNF-alpha is
inexpensive, widely available, and easy to measure [66]. A a macrophage derived pleotropic cytokine. It is thought to
concentration of more than 150 mg/dL is often accepted as play major roles in pathophysiologic responses of inflamma-
a predictor of severity in AP [56]. At this cut-off level, CRP tion following initial acinar cell injury. There are conflicting
has a sensitivity of 80–86% and specificity of 61–84% for results among various studies regarding its role in prediction
diagnosing necrotizing pancreatitis within first 48 hours of of severity in pancreatitis [79–81].
onset of symptoms [56, 67]. In their study, Khanna et al.
found a 100% sensitivity and 81.4% specificity for detection
of pancreatic necrosis [56]. The demerit of CRP as marker 5.6. Markers for Trypsinogen Activation
is its delayed peak (48–72 hours) and its nonspecific nature 5.6.1. Trypsin-Alpha-1-Protease Inhibitor Complex. Many
as inflammatory marker. Before measurement of CRP, other reports have shown its role in prediction of SAP. Its serum
inflammatory conditions such as cholangitis and pneumonia level is usually elevated early within 48 hours of the disease.
should be ruled out [56]. It is, however, a nonspecific marker as its level can also be
elevated in other gastrointestinal diseases like perforated
5.3. Procalcitonin (PCT). It is a 116 amino acid propeptide ulcers [82–84].
of the hormone calcitonin which is released by hepatocytes
and G-cells of the thyroid gland [56]. It is an acute phase
reactant that has been extensively investigated as early marker 5.6.2. Trypsin Activation Peptide (TAP). This is a small
in systemic bacterial infection, sepsis, and multiorgan failure peptide released during the process of activation of trypsin
[68]. Because severe acute pancreatitis is associated with from trypsinogen. TAP has been shown to be an excellent
sepsis, infected pancreatic necrosis, and multiorgan failure, marker of severity in experimental models of AP. In humans,
procalcitonin can be used as a useful marker in early pre- it is excreted in large amount in urine and peritoneal fluid.
diction of severity [69]. For faster result, PCT level can be TAP activity increases early in the course of the disease and
measured by a semiquantitative strip test with a cut-off level attains maximal value within 24–48 hours. Huang et al. did
of 0.5 ng/mL. For more accurate measurements however fully a meta-analysis on the role of urinary TAP in prediction of
automated assay should be opted [70]. An increased PCT severity [85]. They found a sensitivity of 71% and specificity
level has been found to be an early predictor of severity, of 75% with an area under curve of 0.83 with a cut-off value
pancreatic necrosis, and organ failure in patients with AP of 35 nmol/L. This was comparable to the sensitivity and
[70–72]. In a recent meta-analysis, a subgroup of 8 studies specificity of CRP and was better than that of APACHE II
using PCT cut-off values of 0.5 ng/mL as discriminator found score. They found urinary TAP may be used as a potential
that the sensitivity and specificity of PCT for development severity stratification marker for acute pancreatitis [67, 85].
of SAP were 73% and 87%, respectively, and overall area
under curve (AUC) was 0.88. However, there was significant 5.6.3. Carboxypeptidase B Activation Peptide (CAPAP). It is
heterogeneity among individuals in the study [73]. In their the largest activation peptide amongst the pancreatic proen-
study, Khanna et al. found 100% sensitivity of procalcitonin zymes [86]. This peptide is very stable in urine and serum.
for prediction of organ failure and mortality, with a sensitivity In a study of 85 patients with acute pancreatitis CAPAP
of 86.4% for prediction of SAP [56]. Like that of Interleukin- level correlated well, with an accuracy of 92%, in predicting
6, procalcitonin assay is expensive and that is the reason why development of pancreatic necrosis, whereas the level of its
it is not used in routine clinical practice. proenzyme did not show any correlation with pancreatic
necrosis [87]. Both CAPAP and urinary TAP are excellent
5.4. Polymorphonuclear Elastase (PMN Elastase). PMN Elas- prognostic markers, although TAP is a better marker on the
tase is the protease released by activated neutrophil as a day of admission [88].
first line defense following tissue injury [36]. Granulocyte
infiltration and activation occur in the early phase of AP [74]. 5.6.4. Trysinogen-2. In acute pancreatitis the level of trysin-
So PMN Elastase has been proved as an early marker of severe ogen-2 rises considerably more than that of trysinogen-1 [14].
acute pancreatitis within 48 hours of onset of symptoms. High level of trypsinogen-2 can be found in both serum and
With a cut-off level of 110 𝜇g/L, Domı́nguez-Muñoz et al. urine. High serum level correlates better with complications
found a sensitivity and specificity of 92 and 91%, respectively, and severity following ERCP induced pancreatitis [89–91].
for detection of SAP within 48 hours of onset of symptoms. High urinary trpsinogen-2 is used as a screening test for
The positive and negative predictive values were 78% and diagnosis of AP. A rapid dipstick method has been devised
96%, respectively, and the area under the receiver operator for rapid diagnosis of acute pancreatitis [92]. This test is
curve was 0.956 [74]. Similar result has been found by Gross particularly useful in rapid diagnosis of ERCP induced
et al. and Wilson et al. in their study [75, 76]. More recent pancreatitis. Overall trysinogen-2 appears to be more useful
studies, however, by a Swiss group and the Japanese have as a diagnostic marker than as a predictor of severity
yielded conflicting results [77, 78]. Domı́nguez-Muñoz et al. [93].
6 Journal of Biomarkers

6. Emerging Potential Biomarkers for damages the endothelium. Ida et al. studied these two mark-
Prediction of Severity in AP ers to find their significance in assessment of severe acute
pancreatitis [99]. They concluded that those high levels of
6.1. Tissue Factor. Tissue factor is a transmembrane glycopro- soluble ES can be found in all stages of the disease; therefore it
tein involved in the initiation of coagulation cascade. Recent can be used to monitor the disease severity. Soluble TM can be
studies have shown the usefulness of tissue factor as a marker used as a predictive parker of mortality in acute pancreatitis
for severity assessment. Andersson et al. in their study found on the first day of admission.
that TF as a predictor of severity is not as good as IL-6 or
CRP. High serum level early in the course may suggest a role 6.7. Endothelin 1. Elevated levels of endothelin have been
in the pathogenesis of AP and give a window for therapeutic found to be associated with acute pancreatitis with a strong
interventions [94]. correlation with the disease severity. High level of endothelin
1 can be used as a marker to monitor the disease progression
6.2. Prealbumin to Fibrinogen Ratio. Prealbumin and Fib- [100].
rinogen are acute phase reactants. Prealbumin is mostly used
for assessment of nutritional status, whereas fibrinogen is
used mostly for assessment of coagulation status in patients of 6.8. Melatonin Concentration. Melatonin plays a protective
acute pancreatitis. Ratio of prealbumin to fibrinogen has been role in the early phase of acute pancreatitis in the form of
studied recently as a severity marker in AP. According to Yue an antioxidant or scavengers of free radicals, inhibition of
et al., it has superior sensitivity, specificity, positive predictive nuclear factor kappa B which indirectly prevents production
value (PPV), and NPV of 76.5%, 94.1%, 89.6%, and 85.6%, of proinflammatory cytokines. It also modulates apoptosis
respectively, at a cut-off level of 31.70 mg/g than other scoring and necrosis in acute pancreatitis. Variation in the level of
systems [95]. melatonin can be used as a marker for prediction of SAP.
Melatonin concentration below 28.74 ng/L has been found to
be associated with severe acute pancreatitis as found by Jin et
6.3. Cytokeratin 18. This is an epithelial cell structural pro-
al. [101].
tein, associated with apoptotic cell death. Recent animal stud-
ies have shown that wide apoptotic cell death is associated
with a milder form of acute pancreatitis. High cytokeratin 6.9. Serum Intercellular Adhesion Molecule-1 (ICAM-1).
18 level is found in patients with wide apoptotic cell death. Many previous reports have shown that ICAM-1 level
Koruk et al. found a significantly high level of cytokeratin 18 increases significantly in acute pancreatitis. In a study of 36
in patients with mild acute pancreatitis (271.2 ± 45.5 versus patients, Zhu and Jiang found a sensitivity, specificity, positive
152.6 ± 38.2 IU/L; 𝑝 < 0.001). M30 and M65 are newer ELISAs predictive value, negative predictive value, positive likelihood
used to detect different circulating forms of cytokeratin 18 ratio, and negative likelihood ratio of 61.11%, 71.4%, 0.6111,
[96]. 0.7142, 2.1382, and 0.5445, respectively, at a cut-off level of
25 ng/mL [102]. The accuracy of detecting SAP was better
6.4. Hepcidin. Hepcidin is a protein which plays a key than IL-6 and similar to APACHE II. It can be used as a
role in iron absorption in mammals. Abnormally high level reliable early marker within the first 24 hours for prediction
of hepcidin can be found in acute inflammation. As it is of SAP in a rapid and simple manner.
primarily induced by IL-6, high level of hepcidin can be found
in patients with acute pancreatitis. Based on this theory, 6.10. Neutrophil Gelatinase-Associated Lipocalin (NGAL). It
Arabul et al. undertook a single centre prospective study to is also known as human neutrophil lipocalin, lipocalin 2,
assess its role in prediction of severity in AP. They found and siderocalin. Lipocalin 2 is secreted by activated neu-
hepcidin is a better predictive marker for SAP compared to trophil in inflammation in which it binds with bacterial
CRP with an AUC of 0.79 versus 0.69, respectively [97]. iron binding protein called siderophores, thus preventing
bacterial infections by acting as bacteriostatic agent. Recently,
6.5. Copeptin. Copeptin is a long amino acid peptide derived studies have shown that this can be used as an early marker.
from a preprohormone consisting of neurophysin II, vaso- Chakraborty et al. found a 100% sensitivity of detecting SAP
pressin, and copeptin. Its level rises during stress in critically within first 48 hours. It has also shown significant correlation
ill patients. Isman et al. studied its role in acute pancreatitis with fatal complications and mortality in acute pancreatitis
as a predictive marker of severity. They found a significantly [103].
high concentration of copeptin at the time of admission in
patients with SAP. Isman et al. also found that copeptin 6.11. Total Calcium and Albumin Corrected Calcium. Total
can be used as a novel prognostic marker for prediction calcium and corrected calcium have shown similar efficacy
of local complication, organ failure, and mortality in acute like that of Ranson and APACHE II score in prediction of
pancreatitis [98]. SAP. In a prospective study of 96 patients, Gutiérrez-Jiménez
et al. have found sensitivity, specificity, positive predictive
6.6. Soluble E-Selectin (sES) and Soluble Thrombomodulin value, and negative predictive value of 67%, 82%, 27%, and
(sTM). Soluble ES is an endothelial activation marker, 96% at a maximum cut-off level of 7.5 mg/dL for total calcium
whereas soluble TM is an endothelial injury marker. During and 67%, 90%, 40%, and 96% for corrected calcium with a
acute pancreatitis activated neutrophils release elastase which maximum cut-off level of 7.5 mg/dL [104].
Journal of Biomarkers 7

6.12. Serum Proteomic Pattern. Serum proteomic profile has as detected on contrast enhanced CT scan [110]. There was
features which can differentiate mild from severe acute no correlation however between MIF levels and multiorgan
pancreatitis. This has been shown by Papachristou et al. who failure in such patients. Macrophage Migration Inhibitory
show 18 different signal intensities clusters out of 72 spectral Factor is inexpensive and easily available. Efficacy of anti-MIF
clusters. Classification and regression tree (CART) analysis antibody has been proven in rodents by Calandra et al. and
showed a primary splitter at 11,720 Da. After analysis it was may act as target for future targeted therapy [111].
found to have a sensitivity of 100% and specificity of 81% in
discriminating mild from severe acute pancreatitis [105]. 7.4. Fibrinogen-Like Protein-2 (fgl-2). It is a new member of
fibrinogen related protein superfamily, with direct prothrom-
7. Biomarkers of Pancreatic Necrosis binase and serine protease activity. Its activation results in
fibrin deposition and microthrombosis lead to microvascular
Acute necrotizing pancreatitis is the deadliest form of AP changes. High levels of fgl-2 closely correlate with the severity
with a very high mortality rate. Identification of pancreatic of AP and PN as a result of aforesaid mechanism in rats and
necrosis and infection early in the course of the disease may serve as a useful biomarker of severe AP in humans in
is essential. A number of studies have been conducted times to come [112].
over the last few decades to find a novel biomarker which
can accurately predict pancreatic necrosis and infection in
7.5. Cortisol Binding Globulin (CBG). A recent study by
acute pancreatitis. However, there is a dearth of ideal and
Muller et al. has shown a significant difference in the
established biomarkers to indicate pancreatic necrosis (PN)
peak level of CBG in the first 48 hours in patients having
in AP, an area now mired by controversies requiring extensive
sterile (26.5 microg/mL) and infected pancreatic necrosis
research. Following are few biomarkers with high positive
(16.0 microg/mL) at a cut-off level of 16.8 microg/mL. A
predictive value in prediction of infected or sterile pancreatic
decreased CBG level in the first 48 hours has been found as
necrosis.
an early predictor of infected pancreatic necrosis in patients
with AP with PPV and NPV of 100% and 87.5%, respectively
7.1. Adipocytokines. Lipase mediated peripancreatic fat
[113].
necrosis is associated with release of high levels of adipocy-
tokines which can be used as marker for prediction of
severity and pancreatic necrosis in AP. Adiponectin, resistin, 7.6. Soluble Triggering Receptor Expressed on Myeloid Cells
leptin, and visfatin are the novel adipocytokines which (sTERM1). Lu et al. found sTERM1 as independent pre-
have been studied recently as potential biomarkers in dictor of infected pancreatic necrosis at a cut-off level of
AP. In a comprehensive review of adipocytokines in nine 285.6 pg/mL (AUC: 0.972) in patients of AP [114].
human and three experimental studies, Karpavicius et
al. found a significant correlation between high level of 7.7. IL-6 and PCT. These are established markers of infected
adipocytokines and SAP. Resistin and visfatin were found pancreatic necrosis. PCT at a cut-off level of >2.0 ng mL is an
to be good predictors of pancreatic necrosis with cut-off independent predictor of infected pancreatic necrosis [115].
levels of 11.9 ng/mL and 1.8 ng/mL, respectively. However, Many other studies including high serum creatinine level
Al-Maramhy et al. did not find resistin as a useful marker for at admission, ghrelin, and nesfatin-1 did not reveal significant
predicting severity [106, 107]. correlation as a predictive marker of pancreatic necrosis [116,
117].
7.2. Matrix Metalloproteinase-9 (MMP-9). MMP-9 is a Zn
containing endopeptidase whose main function is extracel- 8. Biomarkers of Organ Failure
lular matrix degradation. In the process of inflammation it
is thought to be involved in neutrophil trafficking through 8.1. Angiopoietin 2. Increased vascular permeability is the
the endothelial membrane. Recent studies on MMP-9 as major cause of third space fluid loss which leads to organ
potential biomarker in AP have shown a strong association of failure in acute pancreatitis. Angiopoietin 1 and Angiopoietin
MMP-9 concentration at admission with subsequent devel- 2 are modulators of vascular permeability which can be
opment of pancreatic necrosis with a high sensitivity (91.7%) used as marker of persistent organ failure. Angiopoietin 2
and positive predictive value (90.4%). It can also be used as has been recently evaluated as a marker of persistent organ
a marker of disease severity and assessment of course of the failure in patients of severe acute pancreatitis. Whitcomb
disease [108, 109]. et al. did a multicentre prospective study to assess the role
of angiopoietin 2 as an early marker of persistent organ
7.3. Macrophage Migration Inhibitory Factor (MIF). It is failure in patients of SAP from USA and Germany [118]. They
a cytokine of the innate immunity system secreted from found that angiopoietin 2 level on the day of admission was
monocytes and macrophages. It is released in response to significantly higher in patients with persistent organ failure
circulating lipopolysaccharides, gram positive exotoxins and with sensitivity, specificity, and area under curve of 90%,
proinflammatory cytokines. Rahman et al. observed that 67%, and 0.81, respectively. Buddingh et al. found a similar
serum MIF concentrations were considerably elevated in result in their randomized control trial. Angiopoietin 2 level
patients of severe AP. This is typically seen in patients was significantly higher in patients with SAP [6.4 versus
having PN involving more than 30% area of the pancreas 3.1 𝜇g/L (𝑝 < 0.001)]. In both studies angiopoietin 2 level was
8 Journal of Biomarkers

persistently high for initial 5–7 days which means that it can patients with acute pancreatitis has shown mixed results in
also be used to monitor the disease severity [119]. human studies. Future studies are necessary to understand
epigenetic modulation of proinflammatory genes in acute
8.2. D-Dimer. Activation of coagulation cascade has been pancreatitis for better management of these patients.
known to occur during the early phase of acute pancreatitis
[120]. D-dimer of fibrinogen can be used as potential severity 10. Conclusion
marker in AP. Studies have shown significantly different
levels of D-dimer in patients of pancreatitis with or without Acute pancreatitis has been intensively studied worldwide.
complications [121]. In a recent study, Radenkovic et al. found The overall mortality of the disease, however, has not
D-dimer as novel marker for prediction of organ failure with improved significantly. Early aggressive management has
a sensitivity of 90% and negative predictive value of 96% at been shown to reduce morbidity and mortality, for which
a cut-off level of 414.00 microg/L [121]. Furthermore, it has early diagnosis and assessment of severity are essential. An
been found that D-dimer level in pancreatitis correlates well ideal marker for early assessment of severity and predicting
with traditional markers like APACHE II and CRP levels worsening of disease is lacking. Although IL-6 has shown
[122]. According to Papachristou and Whitcomb D-dimer promising result in assessment of the disease severity, its
can be an easy, useful, and inexpensive early prognostic routine clinical use is limited by its cost and complexity of
marker of SAP [123]. assay. C-reactive protein continues to be the most frequently
used marker for severity assessment. Large population based
8.3. Soluble CD73. Many studies have shown that soluble multicentre studies of the available biomarkers need to be
CD73 can be used as a marker for early prediction of established which is ideal for predicting the disease severity
persistent organ failure. It has a low cost and it is simple to and monitoring disease progression and which can be used
do but it is not as good as other parameters used for severity routinely. Recently it has been found that oxidative stress
assessment [124]. plays an important role in the pathogenesis of AP. Further
research into the biomarkers of oxidative stress and the role
9. Biomarkers of Oxidative Stress of antioxidants in limiting the disease progression will benefit
the management of this otherwise unpredictable disease.
Although pathogenesis of acute pancreatitis is not fully
understood, there is evidence suggesting important role of Conflict of Interests
oxidative stress in early stages of the disease as well as during
disease progression. Sanfey et al. were the first to describe the The authors declare that there is no conflict of interests
involvement of oxygen free radicals in pathogenesis of acute regarding the publication of this paper.
pancreatitis [125]. Multiple clinical studies have shown higher
oxidative stress levels in patients of acute pancreatitis than Authors’ Contribution
in healthy individuals. The level of oxidative stress marker
increases with increase in disease severity [126–136]. Levels of Dr Susanta Meher and Dr Satyajit Rath prepared the paper. Dr
antioxidants, lipid peroxidation products, and end products Rakesh Sharma, Dr Bikram Rout, and Dr Manoj Kumar Sahu
of action of reactive oxygen species (ROS) on biological helped in data collection. Dr Prakash Kumar Sasmal and Dr
molecules can help in assessing the oxidative stress of the Tushar Subhadarshan Mishra critically revised the paper. All
patient with acute pancreatitis. After several studies, oxidative authors have read the final version of the paper and agreed
stress is now considered as key mediator of both local and for publication.
systemic events occurring in acute pancreatitis [137, 138].
Animal studies with experimental acute pancreatitis have
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