Role of Biomarkers in Diagnosis and Prognostic Evaluation of Acute Pancreatitis

Abstract

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.

Full text

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  May ; Revised  July ; Accepted  July 
AcademicEditor:EugeneH.J.M.Jansen
Copyright ©  Susanta Meher et al. is 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. e 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 –% 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 inltration 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-. In this review we have discussed briey the pathogenesis and the
role of dierent biochemical markers in the diagnosis and severity evaluation in acute pancreatitis.
1. Introduction
Acute pancreatitis (AP) is a potentially life threatening
disease with varying severity of presentation [,]. Nearly
%–% of all cases of AP in developed countries are
attributable to either gallstone disease or alcohol abuse [,].
e incidence is similar in both sexes, although alcohol abuse
is the more common cause in men and gallstones is the
morecommoncauseinwomen[,]. ere is an upsurge
in the incidence of AP over the last few decades, although
the case fatality rate has remained unchanged []. is may
either be due to increased incidence of gallstone disease or
improvement in diagnostic modalities [].
e revised Atlanta classication system has classied
AP into mild, moderate, and severe [,]. More than
% of acute pancreatitis attacks are mild and self-limiting
and resolve without serious complications. In % of cases,
however,itcanbesevereandcomplicatedbymajormor-
bidity or mortality [,,]. Moderate acute pancreatitis is
characterized by the presence of transient organ failure or
local/systemic complications []. Persistent organ failure is
the feature of severe acute pancreatitis which is associated
with a high rate of mortality. e overall mortality of AP
is about –% but reaches up to %–% in patients
with severe disease [,]. Sepsis related multiorgan failure
and infected pancreatic necrosis account for about –%
of all mortality in acute pancreatitis [,,]. Mortality
in AP occurs in two peaks [–]. Nearly % of deaths
occur early within the rst week due to massive inammatory
responses leading to multiorgan failure. Septic complications
related to infected pancreatic necrosis leading to multiorgan
failurearetheprimecauseofdeath,lateinthedisease[–
]. e course and severity of AP can uctuate rapidly and
unpredictably [,].
Despite the advances in investigational modalities and
research techniques, the exact pathogenesis of AP is still
unclear [,–]. Recent studies have suggested the role of
inammatory mediators and oxidative stress in the pathogen-
esis of AP and its sequelae [,–]. e pathophysiology
of AP, role of various markers in establishing the diagnosis
and prediction of severity, and upcoming markers including
markers of oxidative stress are being discussed in this review.
Hindawi Publishing Corporation
Journal of Biomarkers
Volume 2015, Article ID 519534, 13 pages
http://dx.doi.org/10.1155/2015/519534

Journal of Biomarkers
2. Pathophysiology of Acute Pancreatitis
Despite intense research over centuries, the exact pathogen-
esis of AP remains elusive [,]. Although many theories
havebeenproposed,noneofthemappeartobecomplete[,
]. Some of the propositions include abnormal biliopancre-
atic duct common pathway theory, pancreatic autodigestion
theory, gallstone migration theory, enzyme activation theory,
kinin and complement activation theory, microcirculation
disturbance theory, and pancreatic acinar cell apoptosis and
necrosis theory, all of which are still controversial [,].
ey can only explain certain aspects of pathogenesis or suit
disease due to specic aetiologies.
e biggest obstacle in the study of pathogenesis of AP
is its rapid course and relative inaccessibility of pancreatic
tissue []. To overcome this problem, investigators have
now taken to animal models to study the molecular aspects
of pathogenesis of acute pancreatitis [,,]. Further
complicating the issue are the paradoxical results about the
pathogenesis, obtained from dierent animals exposed to
similar aetiology []. e premature activation of trypsin
in pancreatic parenchyma acting as the central step in the
initiation of autodigestion of pancreatic tissue and subse-
quent local and systemic inammation is presently the most
accepted theory [,,,]. Whatever is the initiating
event, the disease progression can be viewed as a three-
phase continuum: local inammation of the pancreas and a
generalizedinammatoryresponsefollowedbythenalstage
of multiorgan dysfunction [,,,]. Figure  illustrates
the schematic overview of pathogenesis of acute pancreatitis
[,].
In the early phase, inammation is usually localized to the
pancreas which clinically manifests as mild acute pancreatitis.
is usually resolves within a week without any local or sys-
temic complications []. However, if the disease progresses,
there occurs a phase of generalized inammation, also known
as systemic inammatory response syndrome (SIRS) [,
]. Subsequently, there is a phase of mixed inammatory
response, known as mixed antagonist response syndrome
(MARS), which clinically manifests as moderately severe
acute pancreatitis, associated with transient organ failure and
local complications [].Finallyaphaseofsuppressedinam-
matory response occurs which is known as compensatory
response syndrome (CARS) which manifests as severe acute
pancreatitis associated with persistent organ failure [,].
e immune system in this phase is downregulated, leading
to higher susceptibility of the pancreatic and peripancreatic
tissue to infection from bacteria translocated from the gut.
e ensuing sepsis and multiorgan failure are the major cause
of late morbidity and mortality in severe acute pancreatitis
[,]. Figure  illustrates the two phases of severe acute
pancreatitis.
3. Biomarkers in Establishing Diagnosis of AP
e diagnosis of acute pancreatitis is usually based on a
combination of clinical ndings, laboratory investigations,
and imaging techniques. ere is no gold standard test
available to diagnose acute pancreatitis at present [,].
According to revised Atlanta classication, diagnosis of acute
pancreatitis requires two of the following three criteria [,]:
() Abdominal pain characteristic of AP (acute onset of
a persistent, severe, epigastric pain oen radiating to
back).
() Serum lipase (or amylase) activity at least three times
greater than the upper limit of the reference interval.
() Characteristic imaging ndings of AP on contrast
enhanced computed tomography (CECT) and less
commonly magnetic resonance imaging (MRI) or
transabdominal ultrasonography.
e pancreatic enzymes derived from pancreatic acinar cells
[amylase, lipase, and the proenzyme trypsinogen] are the
cornerstone in the laboratory diagnosis of AP []. Serum
lipase is a more sensitive and specic biochemical marker of
AP than the more frequently used amylase. Moreover, serum
amylase level oers no additional advantage if simultaneously
measured with serum lipase [–].
Additional biomarkers under evaluation for diagnosis
of acute pancreatitis include pancreatic isoamylase, pancre-
atic elastase, serum trypsin, urinary trypsinogen activated
peptide (TAP), Phospholipase A, and Carboxypeptidase
B(CAPB)[,].Serumtrypsinandelastaseareof
particular interest because of their longer half-life which
makes them useful in diagnosis during delayed presentations
[]. ese tests, however, have not found much favor in
clinical application because of a variety of reasons including
inferior diagnostic accuracy compared to amylase and lipase,
cumbersome techniques, or availability [].
3.1. Amylase. Amylase is a glycoside hydrolase primarily
produced in the pancreas and salivary glands and in very
small quantities in other tissues. In acute pancreatitis, the
blood level of amylase rapidly increases within six hours of
onset of disease, exhibits a half-life of – hours, remains
elevated for – days, and nally is excreted by the kidney
[,,]. Aer reaching a peak level, subsequent return
of serum amylase to its normal level does not correlate
with resolution of clinical symptoms []. Furthermore, the
magnitude of the hyperamylasemia does not show signicant
statistical correlation with disease severity and ultimate
prognosis []. In –% of cases amylase activity may be
normal at the time of hospital admission due to delayed
presentation or exocrine pancreatic insuciency (chronic
alcoholism) [,]. Raised serum amylase can also be found
in many other intrabdominal inammatory conditions and
salivary disorders and in patients having decreased renal
clearance. Macroamylasemia is a condition in which amylase
remains bound to immunoglobulins or polysaccharides to
form large molecular weight complexes leading to raised
levels of serum amylase [,,]. Hypertriglyceridemia
competitively interferes with amylase assay, so a false low
level of serum amylase can be found in patients having
hypertriglyceridemia [,]. Sensitivity and specicity of
amylase as a diagnostic test for AP depend on its threshold
value. At a cut-o level of  IU/L, it has a sensitivity of
around –% and specicity up to % [,,,].

Journal of Biomarkers 
Impaired Cell Membrane Tracking
Acinar cell damage
(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
Proinammatory mediators
Adhesion molecules, PAF, NO
Oxygen free radicals
Anti-inammatory mediators Chemokines
SIRS
Acute phase response, pyrexia, tachycardia, tachypnoea
MODS
Gut ischemia, bacterial translocation Pulmonary/renal failure, shock
Infected necrosis Sepsis
Impaired cell membrane tracking
−
−
+
+
TNF𝛼, IL1𝛽, IL-18, IL-6, IL-2IL-10, IL-1a, IL-11 IL-8, RANTES, MCP-1,
ENA-78, GRO-𝛼
F : Schematic overview of pathogenesis of acute pancreatitis. Acinar cell damage leads to activation of trypsin following impairment of
cell membrane tracking with subsequent activation of zymogen cascade by trypsin. Attraction and activation of leukocyte occur with release
of many proinammatory and anti-inammatory cytokines and also chemokines. An overt and sustained activation of proinammatory
mediators leads to Systemic Inammatory Response Syndrome (SIRS) which may further proceed to multiorgan failure and infection of
pancreatic necrosis and sepsis with late complications of acute pancreatitis [,].
3.2. Lipase. Lipase assay has a sensitivity and specicity of
% and %, respectively [,]. e serum concentration
of lipase increases within – hours of onset of disease and
peaks within  hours []. e increased serum level stays
for around – days before it comes down to the normal
level [,]. In contrast to amylase, lipase is reabsorbed
in renal tubules and stays for long at higher concentration,
thereby giving greater sensitivity in patients with delayed
presentation [,]. Pancreatic lipase is four times more
active than amylase and it is less aected by exocrine pancre-
atic deciency occurring in patients of chronic pancreatitis
[,]. Hypertriglyceridemia does not inuence the serum
lipase assay as happens in the case of serum amylase.
Patients taking frusemide can show increased lipase activity
[]. Increased serum level of lipase can also be seen in
many intra-abdominal pathologies including acute chole-
cystitis, appendicitits, inammatory bowel disease, intestinal
ischemia, obstruction, perforation, and renal insuciency
[,]. According to recent guidelines from UK, serum
lipase should be preferred for diagnosis of AP over serum
amylase wherever available [–]. At a cut-o level of
 IU/L, most studies have reported specicity above %;

Journal of Biomarkers
Early phase Late phase
SIRS MARS CARS
Severity of disease
SAP
Mild AP
s MMMMMMILM
1–10 days >10 days
Time
F : Two phases of severe acute pancreatitis (SAP). CARS:
compensatory response syndrome; MARS: mixed antagonist
response syndrome; SIRS: systemic inammatory response syn-
drome; Mild AP: mild acute pancreatitis [].
however, serum lipase level’s sensitivity is limited between
–% [,]. Like that of amylase, most studies suggest a
poor correlation between lipase activity and disease severity
[].
3.3. Trypsinogen. Trypsinogen is the zymogen of the pancre-
atic enzyme trypsin which is cleaved by duodenal enteroki-
nase to produce the active enzyme trypsin and trypsinogen
activated peptide (TAP) [,]. Normally trypsinogen
(trypsinogen- and trypsinogen-) is secreted into the pan-
creatic uid by the acinar cells, of which a small amount
enters into the circulation and is excreted in urine. In
pancreatitis large amounts of this enzyme enter the systemic
circulation due to increased vascular permeability and there
is a consequent increased clearance in urine. is forms the
basis of the use of trypsinogen in the diagnosis and severity
assessment of AP []. Both serum and urine concentrations
rise within few hours of onset of disease and decline to normal
level within  to  days [,,]. A dipstick method using
urinary trysinogen- has been devised for rapid detection of
AP [,]. Because of its low sensitivity and less availability,
this test is less frequently used in routine clinical practice [].
e greatest demerit of trypsinogen as a diagnostic test is its
rapid clearance, which means it can only be used for early
cases. It can be a useful test for screening of ERCP induced
pancreatitis [,].
4. Rationale of Severity Stratification and
Its Assessment
Acute pancreatitis is self-limiting in %–% of cases and
does not require any treatment other than parenteral intra-
venousuid,analgesics,andsupportivecare[,,]. e
remaining may suer from severe attacks, with the mortality
reaching up to %–% []. is subgroup of patients
needs to be identied early in the course of the disease and
needs to be aggressively treated to prevent mortality. Proper
identication of the mild disease is also necessary to avoid
unnecessary over treatment, thereby reducing the nancial
implications.
5. Role of Biomarkers in Prediction of
Severe Acute Pancreatitis
Severity assessment in acute pancreatitis was rst started
in  by late Ranson et al. []. Since then a number of
multifactorial scoring systems using common clinical and
biochemical parameters have been described for prediction
of severity. Ranson, Glasgow, and APACHE II score are few of
thecommonlyusedscoringsystems[]. Limitations of these
scoring systems include delay in complete scoring where it
takes  hours to complete Ranson and Glasgow scoring
systems need a time of  hours to complete the assessment,
while APACHE II score is very cumbersome to calculate [].
e disadvantages of these prompt most of the researchers to
nd a single biochemical parameter which could accurately
predict the severity of AP early in the course of the disease.
5.1. Interleukins. Interleukin- (IL-) is produced by a wide
range of cells like monocytes, macrophage, endothelium, and
broblastinresponsetopotentproinammatorystimulus
like TNF-alpha and IL-𝛽[]. A large number of studies
have already conrmed the role of IL- in early and accurate
prediction of severity in acute pancreatitis [,,].
ValueofIL-issignicantlyelevatedinSAPontheday
of admission and tends to peak at hrs aer the clinical
onset of disease, which makes IL- an excellent marker
ofearlyseveritystratication[]. In terms of predicting
complications, IL- was found to be excellent in predicting
remote organ failure, which is an integral part of severe acute
pancreatitis []. Among various proinammatory and anti-
inammatory cytokines, IL- has the best sensitivity and
specicity for early assessment of SAP []. With a cut-
o value of  pg/mL, Jiang et al. have found a sensitivity
and specicity of % and .%, respectively []. With
a similar cut-o level, Khanna et al. found a sensitivity
of .% and specicity of .% in their study []. e
major drawback of IL- assay is that its serum concentration
decreases very rapidly. Use of Il- in routine clinical practice
is limited by its cost and the complexity of assay [].
IL- is the best characterized member of the chemokine
family studied in acute pancreatitis. It is a powerful secondary
chemoattractant of neutrophil in the inammatory process
[]. Many studies have shown promising results in early
prediction of SAP []. One study has shown its role in
monitoring life threatening complications in patients of
necrotizing pancreatitis with multiorgan failure [].
IL-, IL-, and IL- are proinammatory cytokines
which have been studied recently as potential biomarkers.
Similar results have been seen in various studies as single
biochemical markers on the day of admission. IL- and IL-
are better predictors of organ dysfunction and mortality [–
].
In a recent meta-analysis by Zhang et al., IL-, IL-,
andIL-haveshownpromisingresultsinpredictingsevere
acute pancreatitis. ey, however, found a lack of consensus
regarding the ideal cut-o value for assessing the same [].
5.2. C-Reactive Protein (CRP). CRP is an acute phase reactant
synthesized by the hepatocytes and is usually elevated in

Journal of Biomarkers 
inammatory conditions []. Cytokines like IL- are potent
inducers of CRP synthesis in liver. It takes nearly  hours for
the serum level of CRP to peak aer the onset of symptoms
[]. It is the most frequently used single biomarker for
assessment of severity in AP today. is is because it is
inexpensive, widely available, and easy to measure []. A
concentration of more than  mg/dL is oen accepted as
a predictor of severity in AP []. At this cut-o level, CRP
has a sensitivity of –% and specicity of –% for
diagnosing necrotizing pancreatitis within rst  hours of
onset of symptoms [,]. In their study, Khanna et al.
found a % sensitivity and .% specicity for detection
of pancreatic necrosis []. e demerit of CRP as marker
is its delayed peak (– hours) and its nonspecic nature
as inammatory marker. Before measurement of CRP, other
inammatory conditions such as cholangitis and pneumonia
should be ruled out [].
5.3. Procalcitonin (PCT). It is a  amino acid propeptide
of the hormone calcitonin which is released by hepatocytes
andG-cellsofthethyroidgland[]. It is an acute phase
reactant that has been extensively investigated as early marker
in systemic bacterial infection, sepsis, and multiorgan failure
[]. Because severe acute pancreatitis is associated with
sepsis, infected pancreatic necrosis, and multiorgan failure,
procalcitonin can be used as a useful marker in early pre-
diction of severity []. For faster result, PCT level can be
measured by a semiquantitative strip test with a cut-o level
of . ng/mL. For more accurate measurements however fully
automated assay should be opted []. An increased PCT
levelhasbeenfoundtobeanearlypredictorofseverity,
pancreatic necrosis, and organ failure in patients with AP
[–]. In a recent meta-analysis, a subgroup of  studies
using PCT cut-o values of . ng/mL as discriminator found
that the sensitivity and specicity of PCT for development
of SAP were % and %, respectively, and overall area
under curve (AUC) was .. However, there was signicant
heterogeneity among individuals in the study []. In their
study, Khanna et al. found % sensitivity of procalcitonin
for prediction of organ failure and mortality, with a sensitivity
of .% for prediction of SAP []. Like that of Interleukin-
, procalcitonin assay is expensive and that is the reason why
itisnotusedinroutineclinicalpractice.
5.4. Polymorphonuclear Elastase (PMN Elastase). PMN Elas-
tase is the protease released by activated neutrophil as a
rst line defense following tissue injury []. Granulocyte
inltration and activation occur in the early phase of AP [].
So PMN Elastase has been proved as an early marker of severe
acute pancreatitis within  hours of onset of symptoms.
With a cut-o level of  𝜇g/L, Dom´
ınguez-Mu˜
noz et al.
found a sensitivity and specicity of  and %, respectively,
for detection of SAP within  hours of onset of symptoms.
e positive and negative predictive values were % and
%, respectively, and the area under the receiver operator
curve was . []. Similar result has been found by Gross
et al. and Wilson et al. in their study [,]. More recent
studies, however, by a Swiss group and the Japanese have
yielded conicting results [,]. Dom´
ınguez-Mu˜
noz et al.
found quantication of plasma PMN elastase levels as a very
accurate method for the early prognostic evaluation of AP
and found its applicability in the clinical setting [].
5.5. Tumor Necrosis Factor-Alpha (TNF-Alpha). TNF-alpha is
a macrophage derived pleotropic cytokine. It is thought to
play major roles in pathophysiologic responses of inamma-
tion following initial acinar cell injury. ere are conicting
results among various studies regarding its role in prediction
of severity in pancreatitis [–].
5.6. Markers for Trypsinogen Activation
5.6.1. Trypsin-Alpha-1-Protease Inhibitor Complex. Many
reportshaveshownitsroleinpredictionofSAP.Itsserum
level is usually elevated early within  hours of the disease.
Itis,however,anonspecicmarkerasitslevelcanalsobe
elevated in other gastrointestinal diseases like perforated
ulcers [–].
5.6.2. Trypsin Activation Peptide (TAP). isisasmall
peptide released during the process of activation of trypsin
from trypsinogen. TAP has been shown to be an excellent
marker of severity in experimental models of AP. In humans,
it is excreted in large amount in urine and peritoneal uid.
TAP activity increases early in the course of the disease and
attains maximal value within – hours. Huang et al. did
ameta-analysisontheroleofurinaryTAPinpredictionof
severity []. ey found a sensitivity of % and specicity
of % with an area under curve of . with a cut-o value
of  nmol/L. is was comparable to the sensitivity and
specicity of CRP and was better than that of APACHE II
score. ey found urinary TAP may be used as a potential
severity stratication marker for acute pancreatitis [,].
5.6.3. Carboxypeptidase B Activation Peptide (CAPAP). It is
the largest activation peptide amongst the pancreatic proen-
zymes []. is peptide is very stable in urine and serum.
In a study of  patients with acute pancreatitis CAPAP
level correlated well, with an accuracy of %, in predicting
development of pancreatic necrosis, whereas the level of its
proenzyme did not show any correlation with pancreatic
necrosis []. Both CAPAP and urinary TAP are excellent
prognostic markers, although TAP is a better marker on the
day of admission [].
5.6.4. Trysinogen-2. In acute pancreatitis the level of trysin-
ogen- rises considerably more than that of trysinogen- [].
High level of trypsinogen- can be found in both serum and
urine. High serum level correlates better with complications
and severity following ERCP induced pancreatitis [–].
Highurinarytrpsinogen-isusedasascreeningtestfor
diagnosis of AP. A rapid dipstick method has been devised
forrapiddiagnosisofacutepancreatitis[]. is test is
particularly useful in rapid diagnosis of ERCP induced
pancreatitis. Overall trysinogen- appears to be more useful
as a diagnostic marker than as a predictor of severity
[].

Journal of Biomarkers
6. Emerging Potential Biomarkers for
Prediction of Severity in AP
6.1. Tissue Factor. Tissue factor is a transmembrane glycopro-
tein involved in the initiation of coagulation cascade. Recent
studies have shown the usefulness of tissue factor as a marker
for severity assessment. Andersson et al. in their study found
that TF as a predictor of severity is not as good as IL- or
CRP. High serum level early in the course may suggest a role
in the pathogenesis of AP and give a window for therapeutic
interventions [].
6.2. Prealbumin to Fibrinogen Ratio. Prealbumin and Fib-
rinogen are acute phase reactants. Prealbumin is mostly used
for assessment of nutritional status, whereas brinogen is
used mostly for assessment of coagulation status in patients of
acute pancreatitis. Ratio of prealbumin to brinogen has been
studied recently as a severity marker in AP. According to Yue
et al., it has superior sensitivity, specicity, positive predictive
value (PPV), and NPV of .%, .%, .%, and .%,
respectively, at a cut-o level of . mg/g than other scoring
systems [].
6.3. Cytokeratin 18. isisanepithelialcellstructuralpro-
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
 level is found in patients with wide apoptotic cell death.
Koruk et al. found a signicantly high level of cytokeratin 
in patients with mild acute pancreatitis (. ±. versus
. ±. IU/L; 𝑝<.). M and M are newer ELISAs
used to detect dierent circulating forms of cytokeratin 
[].
6.4. Hepcidin. Hepcidin is a protein which plays a key
role in iron absorption in mammals. Abnormally high level
of hepcidin can be found in acute inammation. As it is
primarily induced by IL-, high level of hepcidin can be found
in patients with acute pancreatitis. Based on this theory,
Arabul et al. undertook a single centre prospective study to
assess its role in prediction of severity in AP. ey found
hepcidin is a better predictive marker for SAP compared to
CRP with an AUC of . versus ., respectively [].
6.5. Copeptin. Copeptin is a long amino acid peptide derived
from a preprohormone consisting of neurophysin II, vaso-
pressin, and copeptin. Its level rises during stress in critically
ill patients. Isman et al. studied its role in acute pancreatitis
as a predictive marker of severity. ey found a signicantly
high concentration of copeptin at the time of admission in
patients with SAP. Isman et al. also found that copeptin
can be used as a novel prognostic marker for prediction
of local complication, organ failure, and mortality in acute
pancreatitis [].
6.6. Soluble E-Selectin (sES) and Soluble rombomodulin
(sTM). Soluble ES is an endothelial activation marker,
whereas soluble TM is an endothelial injury marker. During
acute pancreatitis activated neutrophils release elastase which
damages the endothelium. Ida et al. studied these two mark-
ers to nd their signicance in assessment of severe acute
pancreatitis []. ey concluded that those high levels of
solubleEScanbefoundinallstagesofthedisease;thereforeit
can be used to monitor the disease severity. SolubleTM can be
usedasapredictiveparkerofmortalityinacutepancreatitis
on the rst day of admission.
6.7. Endothelin 1. Elevated levels of endothelin have been
found to be associated with acute pancreatitis with a strong
correlation with the disease severity. High level of endothelin
 can be used as a marker to monitor the disease progression
[].
6.8. Melatonin Concentration. Melatonin plays a protective
roleintheearlyphaseofacutepancreatitisintheformof
an antioxidant or scavengers of free radicals, inhibition of
nuclear factor kappa B which indirectly prevents production
of proinammatory cytokines. It also modulates apoptosis
and necrosis in acute pancreatitis. Variation in the level of
melatonin can be used as a marker for prediction of SAP.
Melatonin concentration below . ng/L has been found to
be associated with severe acute pancreatitis as found by Jin et
al. [].
6.9. Serum Intercellular Adhesion Molecule-1 (ICAM-1).
Many previous reports have shown that ICAM- level
increases signicantly in acute pancreatitis. In a study of 
patients, Zhu and Jiang found a sensitivity, specicity, positive
predictive value, negative predictive value, positive likelihood
ratio, and negative likelihood ratio of .%, .%, .,
., ., and ., respectively, at a cut-o level of
 ng/mL []. e accuracy of detecting SAP was better
than IL- and similar to APACHE II. It can be used as a
reliable early marker within the rst  hours for prediction
of SAP in a rapid and simple manner.
6.10. Neutrophil Gelatinase-Associated Lipocalin (NGAL). It
is also known as human neutrophil lipocalin, lipocalin ,
and siderocalin. Lipocalin  is secreted by activated neu-
trophil in inammation in which it binds with bacterial
iron binding protein called siderophores, thus preventing
bacterialinfectionsbyactingasbacteriostaticagent.Recently,
studies have shown that this can be used as an early marker.
Chakraborty et al. found a % sensitivity of detecting SAP
within rst  hours. It has also shown signicant correlation
with fatal complications and mortality in acute pancreatitis
[].
6.11. Total Calcium and Albumin Corrected Calcium. To t al
calcium and corrected calcium have shown similar ecacy
like that of Ranson and APACHE II score in prediction of
SAP. In a prospective study of  patients, Guti´
errez-Jim´
enez
et al. have found sensitivity, specicity, positive predictive
value, and negative predictive value of %, %, %, and
% at a maximum cut-o level of . mg/dL for total calcium
and%,%,%,and%forcorrectedcalciumwitha
maximum cut-o level of . mg/dL [].

Journal of Biomarkers 
6.12. Serum Proteomic Pattern. Serum proteomic prole has
features which can dierentiate mild from severe acute
pancreatitis. is has been shown by Papachristou et al. who
show  dierent signal intensities clusters out of  spectral
clusters. Classication and regression tree (CART) analysis
showed a primary splitter at ,Da. Aer analysis it was
found to have a sensitivity of % and specicity of % in
discriminating mild from severe acute pancreatitis [].
7. Biomarkers of Pancreatic Necrosis
Acute necrotizing pancreatitis is the deadliest form of AP
with a very high mortality rate. Identication of pancreatic
necrosis and infection early in the course of the disease
is essential. A number of studies have been conducted
over the last few decades to nd a novel biomarker which
can accurately predict pancreatic necrosis and infection in
acute pancreatitis. However, there is a dearth of ideal and
establishedbiomarkerstoindicatepancreaticnecrosis(PN)
in AP, an area now mired by controversies requiring extensive
research. Following are few biomarkers with high positive
predictive value in prediction of infected or sterile pancreatic
necrosis.
7. 1 . A di p o c y t o k in e s . Lipase mediated peripancreatic fat
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,
leptin, and visfatin are the novel adipocytokines which
have been studied recently as potential biomarkers in
AP.Inacomprehensivereviewofadipocytokinesinnine
human and three experimental studies, Karpavicius et
al. found a signicant correlation between high level of
adipocytokines and SAP. Resistin and visfatin were found
to be good predictors of pancreatic necrosis with cut-o
levels of . ng/mL and . ng/mL, respectively. However,
Al-Maramhy et al. did not nd resistin as a useful marker for
predicting severity [,].
7.2. Matrix Metalloproteinase-9 (MMP-9). MMP- is a Zn
containing endopeptidase whose main function is extracel-
lular matrix degradation. In the process of inammation it
is thought to be involved in neutrophil tracking through
the endothelial membrane. Recent studies on MMP- as
potential biomarker in AP have shown a strong association of
MMP- concentration at admission with subsequent devel-
opment of pancreatic necrosis with a high sensitivity (.%)
andpositivepredictivevalue(.%).Itcanalsobeusedas
amarkerofdiseaseseverityandassessmentofcourseofthe
disease [,].
7.3. Macrophage Migration Inhibitory Factor (MIF). It is
a cytokine of the innate immunity system secreted from
monocytes and macrophages. It is released in response to
circulating lipopolysaccharides, gram positive exotoxins and
proinammatory cytokines. Rahman et al. observed that
serum MIF concentrations were considerably elevated in
patients of severe AP. is is typically seen in patients
having PN involving more than % area of the pancreas
as detected on contrast enhanced CT scan []. ere was
no correlation however between MIF levels and multiorgan
failure in such patients. Macrophage Migration Inhibitory
Factor is inexpensive and easily available. Ecacy of anti-MIF
antibody has been proven in rodents by Calandra et al. and
may act as target for future targeted therapy [].
7.4. Fibrinogen-Like Protein-2 (fgl-2). It is a new member of
brinogen related protein superfamily, with direct prothrom-
binase and serine protease activity. Its activation results in
brin deposition and microthrombosis lead to microvascular
changes. High levels of fgl- closely correlate with the severity
of AP and PN as a result of aforesaid mechanism in rats and
may serve as a useful biomarker of severe AP in humans in
times to come [].
7. 5 . C o r t i s o l B i n d in g Gl o b u l in (C B G ) . Arecentstudyby
Muller et al. has shown a signicant dierence in the
peak level of CBG in the rst  hours in patients having
sterile (. microg/mL) and infected pancreatic necrosis
(. microg/mL) at a cut-o level of . microg/mL. A
decreasedCBGlevelinthersthourshasbeenfoundas
an early predictor of infected pancreatic necrosis in patients
with AP with PPV and NPV of % and .%, respectively
[].
7.6. Soluble Triggering Receptor Expressed on Myeloid Cells
(sTERM1). Lu et al. found sTERM as independent pre-
dictor of infected pancreatic necrosis at a cut-o level of
. pg/mL (AUC: .) in patients of AP [].
7.7. I L -6 a n d PC T . ese are established markers of infected
pancreatic necrosis. PCT at a cut-o level of >. ng mL is an
independent predictor of infected pancreatic necrosis [].
Many other studies including high serum creatinine level
at admission, ghrelin, and nesfatin- did not reveal signicant
correlation as a predictive marker of pancreatic necrosis [,
].
8. Biomarkers of Organ Failure
8.1. Angiopoietin 2. Increased vascular permeability is the
major cause of third space uid loss which leads to organ
failure in acute pancreatitis. Angiopoietin  and Angiopoietin
 are modulators of vascular permeability which can be
used as marker of persistent organ failure. Angiopoietin 
has been recently evaluated as a marker of persistent organ
failure in patients of severe acute pancreatitis. Whitcomb
et al. did a multicentre prospective study to assess the role
of angiopoietin  as an early marker of persistent organ
failure in patients of SAP from USA and Germany []. ey
found that angiopoietin  level on the day of admission was
signicantly higher in patients with persistent organ failure
with sensitivity, specicity, and area under curve of %,
%, and ., respectively. Buddingh et al. found a similar
result in their randomized control trial. Angiopoietin  level
was signicantly higher in patients with SAP [. versus
. 𝜇g/L (𝑝<.)]. In both studies angiopoietin  level was

Journal of Biomarkers
persistentlyhighforinitial–dayswhichmeansthatitcan
also be used to monitor the disease severity [].
8.2. D-Dimer. Activation of coagulation cascade has been
knowntooccurduringtheearlyphaseofacutepancreatitis
[]. D-dimer of brinogen can be used as potential severity
marker in AP. Studies have shown signicantly dierent
levelsofD-dimerinpatientsofpancreatitiswithorwithout
complications []. In a recent study, Radenkovic et al. found
D-dimer as novel marker for prediction of organ failure with
a sensitivity of % and negative predictive value of % at
a cut-o level of . microg/L []. Furthermore, it has
been found that D-dimer level in pancreatitis correlates well
with traditional markers like APACHE II and CRP levels
[]. According to Papachristou and Whitcomb D-dimer
can be an easy, useful, and inexpensive early prognostic
marker of SAP [].
8.3. Soluble CD73. Many studies have shown that soluble
CDcanbeusedasamarkerforearlypredictionof
persistent organ failure. It has a low cost and it is simple to
do but it is not as good as other parameters used for severity
assessment [].
9. Biomarkers of Oxidative Stress
Although pathogenesis of acute pancreatitis is not fully
understood, there is evidence suggesting important role of
oxidativestressinearlystagesofthediseaseaswellasduring
disease progression. Sanfey et al. were the rst to describe the
involvement of oxygen free radicals in pathogenesis of acute
pancreatitis []. Multiple clinical studies have shown higher
oxidative stress levels in patients of acute pancreatitis than
in healthy individuals. e level of oxidative stress marker
increases with increase in disease severity [–]. Levels of
antioxidants, lipid peroxidation products, and end products
of action of reactive oxygen species (ROS) on biological
molecules can help in assessing the oxidative stress of the
patient with acute pancreatitis. Aer several studies, oxidative
stress is now considered as key mediator of both local and
systemic events occurring in acute pancreatitis [,].
Animal studies with experimental acute pancreatitis have
shownmarkeddecreaseinthelevelsofreducedglutathione
in pancreas together with increase in lipid peroxidation
products in the tissue and plasma. is suggests the presence
ofoxidativestressattissueaswellassystemiclevelsin
acute pancreatitis []. Increased plasma levels of lipid
peroxidation products, myeloperoxidase activity, and protein
carbonyls are seen in patients with severe acute pancreatitis.
ese parameters correlate well with the severity of the
disease in both clinical and experimental studies [,,
]. us increase in levels of malondialdehyde (MDA),
one of the lipid peroxidation products, correlates directly
with tissue injury and has also been associated with organ
dysfunction in acute pancreatitis.
Multiple mechanisms are involved in triggering the
expression of inammatory genes and thus stimulating syn-
thesis of proinammatory molecules. Role of oxidative stress
is complex and is yet to be clear. Antioxidant therapy in
patients with acute pancreatitis has shown mixed results in
human studies. Future studies are necessary to understand
epigenetic modulation of proinammatory genes in acute
pancreatitis for better management of these patients.
10. Conclusion
Acute pancreatitis has been intensively studied worldwide.
e overall mortality of the disease, however, has not
improved signicantly. Early aggressive management has
been shown to reduce morbidity and mortality, for which
early diagnosis and assessment of severity are essential. An
ideal marker for early assessment of severity and predicting
worsening of disease is lacking. Although IL- has shown
promising result in assessment of the disease severity, its
routine clinical use is limited by its cost and complexity of
assay. C-reactive protein continues to be the most frequently
used marker for severity assessment. Large population based
multicentre studies of the available biomarkers need to be
established which is ideal for predicting the disease severity
and monitoring disease progression and which can be used
routinely. Recently it has been found that oxidative stress
plays an important role in the pathogenesis of AP. Further
research into the biomarkers of oxidative stress and the role
of antioxidants in limiting the disease progression will benet
the management of this otherwise unpredictable disease.
Conflict of Interests
e authors declare that there is no conict of interests
regarding the publication of this paper.
Authors’ Contribution
DrSusantaMeherandDrSatyajitRathpreparedthepaper.Dr
Rakesh Sharma, Dr Bikram Rout, and Dr Manoj Kumar Sahu
helped in data collection. Dr Prakash Kumar Sasmal and Dr
Tushar Subhadarshan Mishra critically revised the paper. All
authorshavereadthenalversionofthepaperandagreed
for publication.
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