REVIEW

CURRENT
OPINION Interpretation of serum pancreatic enzymes in
pancreatic and nonpancreatic conditions
Nikhil Bush and Venkata S. Akshintala

Purpose of review
Serum levels of amylase and lipase can be elevated in nonpancreatic conditions that may or may not be
associated with abdominal pain. This leads to a large proportion of patients being falsely labeled as
having acute pancreatitis. In this review, we aim to summarize the existing evidence on pancreatic enzyme
elevation in various pancreatic and nonpancreatic conditions and its practical implications in clinical
practice and healthcare.
Recent findings
Serum amylase and lipase levels are not specific for pancreatitis. Attempts have been made to validate
newer biomarkers including pancreatic elastase, serum trypsin, urinary trypsinogen-activated peptide,
phospholipase A2, carboxypeptidase B, activated peptide of carboxypeptidase B, the trypsin 2 alpha 1
activation complex, and circulating cell-free DNA for the diagnosis of acute pancreatitis.
Summary
Serum lipase levels can be elevated in many intra-abdominal inflammatory conditions. Although more
sensitive and specific than amylase, serum lipase levels are not sufficient to diagnose acute
pancreatitis in patients with abdominal pain. There is a need to increase stress on radiological
evidence as well increase cut-off levels of enzyme elevation for a more accurate diagnosis of acute
pancreatitis.
Keywords
amylase, enzyme, lipase, nonpancreatic causes, pancreas

INTRODUCTION EPIDEMIOLOGY OF PANCREATITIS

The pancreas is a retroperitoneal intraabdominal
organ with a mixed endocrine and exocrine func-
tion [1]. Much of the pancreas is constituted of
acinar cells that produce various enzymes involved
in the digestion and assimilation of the macronu-
trient constituents of ingested food [2]. These
enzymes include trypsin and chymotrypsin to digest
proteins; amylase for the digestion of carbohydrates;
and lipase to break down fats [3]. The enzymes are
stored in precursor zymogen forms to prevent auto-
digestion of the pancreas. Premature activation of
these enzymes is the pathological triggering event in
pancreatitis [4]. Raised serum amylase and lipase
levels have been used in diagnosing acute pancrea-
titis. However, both these enzymes can be elevated
in several pancreatic and nonpancreatic conditions
apart from acute pancreatitis [5]. In this review, we
will discuss the interpretation of these enzyme ele-
vations in various pancreatic and nonpancreatic
medical conditions.
Abdominal pain is the leading cause of emergency
hospitalizations among gastrointestinal disorders in
the United States. The annual incidence of acute
pancreatitis ranges from 13 to 45 per 100 000 pop-
ulations [6,7] and the number of emergency depart-
ment visits in the United States because of acute
&&
pancreatitis was 381 741 persons in 2018 [8 ]. A
recent meta-analysis found that the incidence of
acute pancreatitis has increased from 1961 to
2016, particularly in North America and Europe.
The incidence has remained stable in Asia. It is
Division of Gastroenterology, Johns Hopkins Medical Institutions,
Baltimore, Maryland, USA
Correspondence to Venkata S. Akshintala, MD, Johns Hopkins University
School of Medicine, 600N. Wolfe Street, Blalock 411, Baltimore, MD
21205, USA. Tel: +1 410 614 6708; fax: +1 410 614 7631;
e-mail: vakshin1@jhmi.edu
Curr Opin Gastroenterol 2023, 39:000–000
DOI:10.1097/MOG.0000000000000961

0267-1379 Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved. www.co-gastroenterology.com

Copyright © 2023 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Pancreas
KEY POINTS
 Amylase and lipase levels can be elevated in many
nonpancreatic conditions.
 Radiological features of pancreatitis are more specific,
correlation with serum enzymes and clinical features is
important in avoiding overdiagnosis of
acute pancreatitis.
 There is a need to develop more specific biomarkers for
accurate diagnosis of acute pancreatitis.
characterized by acute inflammation of the pancreas.
The severity of acute pancreatitis can be mild, mod-
erate, or severe with a mortality rate ranging from 3%
in patients with mild pancreatitis to as high as 20%
in patients with severe pancreatitis characterized by
pancreatic necrosis and multiorgan failures [9]. Pop-
ulation distributions are mostly reported from the
United States, Europe, and Japan, with emerging
data from other regions across the globe [6]. There
is a wide variation in reported estimates from differ-
ent regions owing to the difference in study designs,
use of different diagnostic definitions and variable
local risk factors [10]. Alcohol and gallstone disease
are the most common causes, and the illness tends to
be slightly more prevalent in males [11].
HISTORY OF DEFINITIONS AND SEVERITY
ASSESSMENT OF ACUTE PANCREATITIS
The diagnosis of acute pancreatitis until the early
1900s was made either clinically or at autopsy. Julius
Wohlgemuth from the Royal University of Berlin
was the first to introduce a biochemical method for
quantification of the pancreatic enzyme amylase in
the serum [12]. Subsequently, Robert Elman found
a correlation between acute abdominal pain and
elevation of blood amylase and a corresponding
normalization of the serum amylase values with
improvement of abdominal pain [13]. This study
established the use of serum amylase as a marker for
pancreatitis. Initial assays of amylase were fraught
with low specificity owing to multiple nonpancre-
atic causes of hyperamylasemia and the short-lived
nature of amylase elevations in acute pancreatitis.
This shortcoming was overcome by measurement of
macroamylase and isoamylase forms that increased
its specificity for diagnosis of acute pancreatitis
[14,15]. A few years later, Crandall et al. reported
blood lipase elevation in patients with acute pan-
creatitis that was subsequently refined to be more a
specific marker in diagnosing acute pancreatitis
[16]. In addition to amylase and lipase, there were
studies on trypsin, elastase, and carboxypeptidase as
2 www.co-gastroenterology.com
Copyright © 2023 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
diagnostic markers of acute pancreatitis [17]. None
of these, however, could outreach the validation
as achieved for amylase and lipase as none of
these markers could significantly predict the disease
severity, and physicians continued to rely on their
clinical prowess in diagnosing and managing
this disease.
To overcome the inability to make an accurate
prognostication of the severity of acute pancreatitis
based on biochemical assays of pancreatic enzymes,
further attempts aimed to classify disease severity
based on clinical pathophysiological parameters.
Fitz classified pancreatitis into acute, hemorrhagic,
and suppurative pancreatitis. Ranson et al. [18,19]
proposed the Ranson criteria based on clinical and
biochemical variables at the presentation and 48 h
later in 1974. This was the first comprehensive
prognostic system, but its primary shortcomings
were a 48 h delay for assessment and the need for
various laboratory tests that made it less user-
friendly. To stratify patients at the highest risk for
developing severe acute pancreatitis and organ fail-
ure, various scoring systems including the Glasgow
Score, Acute Physiology and Chronic Health Evalu-
ation (APACHE) II system, Marshall Score, and
Sequential Organ Failure Assessment (SOFA) scores
were developed [20]. These systems had limited
applicability owing to complicated calculations
making them cumbersome to use. A breakthrough
in severity assessment and disease classification was
the Atlanta classification proposed at an interna-
tional symposium in 1992 [21]. The guidelines ema-
nating from this landmark meeting also defined
interstitial pancreatitis, necrotizing pancreatitis,
pseudocyst, and infected pancreatic necrosis. This
was subsequently revised to distinguish between
transient and persistent organ failure and to
improve on the definitions of pancreatic pseudocyst
and pancreatic necrosis [22]. In 1985, Balthazar et al.
[23] proposed a severity classification based on
morphology of pancreatic necrosis powered by rapid
advances in CT-based imaging that remains the only
widely applied radiologic grading system to date.
Therefore, despite more than a century having passed
since Fitz’s initial attempt at classifying pancreatitis,
our ability to determine the severity of acute pan-
creatitis at the time of presentation or early in the
course of the disease and forecast the clinical course
of a patient remains markedly limited.
QUANTIFICATION TECHNIQUES FOR
AMYLASE AND LIPASE
The most common method of amylase quantifica-
tion in urine, plasma, serum, and other biological
samples is the enzymatic colorimetric method using
Volume 39  Number 00  Month 2023
 Interpretation of serum pancreatic enzymes Bush and Akshintala
the Amylase Activity Assay Kit (MAK009) (Sigma-
Aldrich, Burlington, Massachusetts, United States).
Other kits that have been used include Amylo-
chrome, Phadebas, DyAmyl-L, and Amylotube
[24]. The colorimetric method is a quick, conven-
ient, and sensitive method of amylase quantifica-
tion. Amylase activity is determined using a coupled
enzymatic assay, which results in a colorimetric
(405 nm) product that is proportional to the amount
of substrate, ethylidene-pNP-G7, that is cleaved by
the amylase. Similarly, various methods have been
described for the measurement of lipase activity.
These are broadly classified into volumetry, color-
imetry, chromatography, enzymatic assays, or
radioactive assays [25,26]. The widely described
titrimetric method uses olive oil as a substrate, in
which the fatty acid released from the triglyceride is
determined by titration with potassium hydroxide.
However, the method has several disadvantages,
including a restricted pH range, low sensitivity,
and the need to add emulsifiers such as Arabic
gum or surfactant to maintain the homogeneity
of the reaction medium [27]. The colorimetric
method of lipase detection uses p-nitrophenyl pal-
mitate as substrate, and p-nitrophenol released as a
yellow chromophore is calorimetrically quantified
to reflect the lipase concentration. The main
advantage of this method is its simplicity, although
it does have some disadvantages such as the turbid-
ity generated when the palmitate is released to the
aqueous medium, or the need to add emulsifiers or
organic solvents (ethanol or propanol) to maintain
the homogeneity of the reaction medium [28].
AMYLASE VS. LIPASE FOR THE
DIAGNOSIS OF ACUTE PANCREATITIS
A large proportion of serum amylase is derived from
the pancreatic acini and salivary glands. Other minor
sources include adipose tissue, the gonads, fallopian
tubes and intestinal tract, and skeletal muscles [29].
The a-amylase is an isoenzyme form that is specific
to humans, with different isoforms based on pancre-
atic and salivary origins. The measurement of pan-
creatic a-amylase has improved the sensitivity and
specificity in the diagnosis of acute pancreatitis. It is
possible to detect the specific a-amylase isoform,
however, because of high costs associated with meas-
uring pancreatic a-amylase, the measurement of
pancreatic a-amylase has been largely disregarded
whereas the measurement of total amylase continues
to be widely used [30]. The serum amylase levels rise
to at least three times the upper limit of normal and
reach their peak levels at 3–6 h following symptom
onset in acute pancreatitis with a half-life of 10–12 h
and persistent elevation for 3–5 days [31].
0267-1379 Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2023 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Serum lipase is also produced by pancreatic
acinar cells and is predominant bodily lipase and
is present at 100 times greater concentration than
other isoforms of hepatic, endothelial, and lipopro-
tein lipases [32]. The increased permeability of
acinar cells in acute pancreatitis results in high
circulating levels of lipase being released into the
circulatory system. The serum lipase levels increase
within 3–6 h of onset symptoms, peak within 24 h,
and have a persistent elevation of up to 2 weeks.
Therefore, lipase has a wider diagnostic window in
comparison to amylase as well as higher specificity,
as it is mainly produced by the pancreas. Initial
lipase testing techniques had low specificity because
of interferences by lipoprotein lipase, intestinal
lipase, hepatic lipase, and carboxyl esterase [33].
However, the use of reagent systems that are specific
for pancreatic lipase and addition of bile salts, col-
ipase, and calcium as cofactors has improved the
specificity and sensitivity of the lipase test.
There are situations when patients can have
normal amylase and lipase levels despite clinical
and radiological evidence of acute pancreatitis
[34]. These have been reported in cases of gallstone,
hypertriglyceridemia, alcohol-related, and some
cases of severe acute necrotizing pancreatitis
[35,36]. The timing of presentation also plays a
critical role in interpreting these results as the
enzyme levels are likely to be within normal range
with very early or very late presentations to
the emergency, especially when presenting within
4–5 h of the onset of pain [37]. Therefore, syncing
clinical suspicion and radiological evaluation is
essential in making a diagnosis of acute pancreatitis,
especially in conditions associated with normal lev-
els. There is no correlation between raised amylase
or lipase levels and the cause or determining severity
of acute pancreatitis. A lipase level higher than
seven times the upper limit of normal was shown
to be an early predictor of severe acute pancreatitis
[38]. The sensitivity of lipase in predicting severe
pediatric acute pancreatitis ranges between 72 and
85%, but the specificity is much lower at a range
between 41 and 56% [39]. A few studies have com-
bined the lipase levels with other biochemical tests
such as c-reactive protein, procalcitonin, and serum
calcium levels that have been shown to correlate
with disease severity [40–42]. But these are isolated
retrospective single-center studies and have not
been reproduced in subsequent studies. Based on
these findings, it does appear that lipase may be
superior in predicting acute pancreatitis, but there is
a definite lack of convincing evidence.
There is conflicting data with respect to the
utility of lipase-to-amylase ratio in determining
the cause of acute pancreatitis. A prospective study
www.co-gastroenterology.com 3
Pancreas
found an increased lipase-to-amylase ratio of greater
than two to be indicative of alcoholic pancreatitis,
however, many retrospective studies found a
ratio greater than five to be predictive of the same
[43–45]. Another study found the ratio to be sug-
gestive of biliary etiology [46]. Therefore, the role of
the ratio in determining etiology is controversial.
Nevertheless, elevated serum amylase or lipase with
high levels of aspartate aminotransferase, alanine
aminotransferase, and alkaline phosphatase has
been associated with acute biliary pancreatitis [47].
There are a number of guidelines by interna-
tional pancreas societies regarding the use of amy-
lase or lipase in diagnosing acute pancreatitis. Most
guidelines recommend using lipase as a diagnostic
biochemical test over amylase considering its supe-
rior specificity. The International Association of
Pancreatology recommends either amylase or lipase
with a preference for lipase for diagnosing acute
pancreatitis [48]. The United Kingdom working
group and the Japanese guidelines also recommend
use of lipase [49,50]. Similarly, the American College
of Gastroenterology and the Canadian Practice
Guidelines recommend the use of lipase over amy-
lase for the diagnosis of acute pancreatitis [51,52].
The Italian Society of Clinical Biochemistry and
Clinical Molecular Biology interestingly recom-
mends the use of pancreatic serum amylase over
total amylase or lipase levels [53].
Clinicians tend to prefer ordering lipase to amy-
lase. Beauregard et al. [54] did not find any signifi-
cant difference in the accuracy of lipase over
amylase. A study comparing amylase and lipase
for diagnostic accuracy found no difference in the
area under the receiver operating curve (ROC) [55].
A prospective study compared amylase and lipase
levels on the first and third days of acute pancreatitis
and found serum lipase to have better sensitivity
and specificity in diagnosing acute pancreatitis in
the early and later states of the illness [56]. Another
study found lipase to have 94% efficiency in detect-
ing acute pancreatitis compared with 91% efficiency
of amylase [57]. A cut-off of three times the upper
limit of the normal range for both amylase
and lipase has been shown to be more accurate in
detecting acute pancreatitis [58]. There have been
a number of studies comparing the sensitivity and
specificity of amylase and lipase in diagnosing acute
pancreatitis. The sensitivity and specificity of lipase
range from 64 to 100% and 87 to 99.4%. The same
for amylase was 35–93% and 87–99.1%, respec-
tively [31]. However, none of these studies used
radiologic imaging or histopathology as a gold
standard. Therefore, lipase fares slightly better than
amylase as a diagnostic biomarker in comparison to
amylase, which has a shorter half-life and may,
4 www.co-gastroenterology.com
Copyright © 2023 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
therefore, be falsely negative depending on the tim-
ing of testing [58,59]. Also, noted is a wide variation
in the reported sensitivity and specificity owing to
different study designs, laboratory techniques of
quantification, and heterogeneous patient popula-
tions. Delayed testing because of late presentation
may result in normal amylase levels in 19–32%
patients with acute pancreatitis [60]. Moreover,
the amylase levels can be normal in hypertriglycer-
idemia-induced acute pancreatitis or recurrent
alcoholic pancreatitis; in these cases, lipase has been
found to be a more accurate indicator of acute
pancreatitis [61,62].
NONPANCREATIC CAUSES OF AMYLASE
AND LIPASE ELEVATION
Raised serum amylase levels can be seen in other
pancreatic diseases such as pancreatic cancer and
pancreatic duct obstruction from other causes [63].
A majority of the amylase is reabsorbed by the renal
proximal tubules and gets degraded in the liver.
Fractional renal excretion of amylase refers to the
proportion of renal amylase clearance that refers to
the rate of glomerular filtration and tubular reab-
sorption of amylase and is usually elevated in acute
pancreatitis. An imbalance between the synthesis,
excretion, reabsorption, and metabolism of amylase
results in an increase in serum levels [64]. In addi-
tion to pancreatitis, hyperamylasemia could occur
because of several malignant conditions, such as
breast, colon, lung, and ovarian cancers. Conditions
such as gastric ulcers, intestinal perforation, mesen-
teric ischemia, and appendicitis, could lead to
hyperamylasemia because of the reabsorption of
amylase from the intestinal lumen [65]. Amylase
excretion is hampered in renal failure leading to
falsely raised serum amylase levels. This can also
occur in conditions associated with reduced meta-
bolic clearance of amylase, such as cirrhosis and
acute hepatic dysfunction [66]. Macroamylasemia
is a rare condition characterized by the formation of
large complexes between amylase and immunoglo-
bulins (usually IgA), which usually leads to a
decrease in renal function and prolong the presence
of amylase in serum and subsequently an abnormal
increase in the level of serum amylase [15]. Other
nonpancreatic conditions causing elevated amylase
include cystic fibrosis, burns, acidosis, pregnancy,
gynecological disorder, peritonitis, chronic alcohol-
ism, acute aortic dissection, head injury, and various
drugs and infectious diseases [32]. Salivary diseases
involving salivary glands could also increase the level
of total amylase in serum by more than three-folds,
causing the need for more specific pancreas enzymes
to determine the diagnosis of acute pancreatitis.
Volume 39  Number 00  Month 2023
 Interpretation of serum pancreatic enzymes Bush and Akshintala
Although purported to be more specific than
amylase, lipase levels can be falsely elevated in other
conditions associated with abdominal discomfort
such as trauma, appendicitis, diabetic ketoacidosis,
inflammatory bowel disease, intestinal obstruction
or infraction, fat embolism, hepatic failure, renal
failure, and hypertriglyceridemia. A landmark sys-
tematic review by Hameed et al. that screened 2990
studies identified a plethora of nonpancreatic causes
for lipase elevation more than three times [5]. They
identified impaired renal clearance to be a cause of
raised lipase levels in patients of acute and chronic
renal failure and macrolipase [67]. Like macroamy-
lasemia, macrolipase is characterized by reduced
renal lipase clearance because of formation of
lipase–immunoglobin complexes [68]. Lipase levels
were also found to be elevated in conditions with
intraabdominal hemorrhage because of various
causes, abdominal aortic aneurysms, and peritoni-
tis. Interestingly, lipase levels were also elevated in
conditions associated with raised intracranial pres-
sure, including intracerebral hemorrhage, traumatic
brain injury, and polytrauma [57]. Morphine-pros-
tigmine, sorafenib, nilotinib, and DDP-4 inhibitors
were the major incriminatory drugs associated with
lipase elevations. Grimmelmann et al. [69] found
lipase levels to be elevated among 9% of patients
receiving nivolumab and ipilimumab and 2% of
patients receiving ipilimumab monotherapy.
Reports from the LEADER 3 study found elevated
lipase levels to be prevalent in almost 25% of the
patients with type 2 diabetes mellitus [70]. Other
causes of false-positive lipase elevations that have
been described include acute cholecystitis, esopha-
gitis, sarcoidosis, renal transplant rejection, and
viral infections such as hepatitis C, HIV, and Cyto-
megalovirus (CMV) [5] (Table 1).
The exact pathogenesis for the lipase elevations
in these conditions is unclear. The various hypoth-
esis that has been proposed include reduced renal
clearance of lipase secondary to acute or chronic
renal disease, decreased hepatic metabolism of
lipase, decreased renal perfusion, the release of
lipase from extra-pancreatic sources such as stom-
ach, small bowel, liver, gall bladder, and formation
of macrolipase complexes [5]. ‘Troponin leak’
implying the release of cardiac troponin into the
bloodstream can be observed in noncardiac condi-
tions such as pulmonary embolism, pulmonary
hypertension, and chest trauma secondary to endo-
cardial stress or subclinical myocardial injury [71].
Similarly, we hypothesize that as observed in the
various nonpancreatic conditions of lipase eleva-
tion, the pancreas can be stimulated from inflam-
mation of surrounding structures such as the
stomach, small bowel, the biliary system, or the
0267-1379 Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2023 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Table 1. Nonpancreatic causes of significant lipase
elevation
Intra-abdominal Reduced clearance
Cholecystitis Renal impairment
Cholangitis Macrolipase
Post ERCP
Peptic ulcer disease
Bowel obstruction
Bowel ischemia/perforation
Gastroenteritis
Peritonitis
IBD
Critical illness
Intracranial hemorrhage
Traumatic brain injury
Others
Diabetes
Drugs
Diabetic ketoacidosis
Reproduced with permission from Hameed et al. [5].
peritoneum resulting in a lipase leak phenomenon
without clinically perceptible acute pancreatitis
(Fig. 1).
NEWER BIOMARKERS FOR DIAGNOSIS
OF ACUTE PANCREATITIS
In addition to amylase and lipase, there have been
attempts to develop additional biomarkers in the
diagnostic evaluation of acute pancreatitis. These
include pancreatic elastase, serum trypsin, urinary
trypsinogen-activated peptide, phospholipase A2,
carboxypeptidase B, activated peptide of carboxy-
peptidase B, the trypsin 2 alpha 1 activation
complex, and circulating cell-free DNA [17]. Trypsi-
nogen is a pancreatic zymogen that occurs in two
isoforms – trypsinogen A and B, that gets secreted
into the pancreatic secretion and is activated to
trypsin in the duodenal lumen through the action
of enterokinase. Increased vascular permeability in
acute pancreatitis results in leakage of trypsinogen
into the circulation with subsequent excretion in
urine. Therefore, trypsinogen levels rise in a few
hours of onset and return to normal within 3–5 days
[72]. A urinary dipstick rapid diagnostic test to
detect trypsinogen B has been developed for the
detection of acute pancreatitis. Its main disadvan-
tages are rapid clearance and thereby tend to be only
useful in early cases, low sensitivity, and limited
availability [73]. The other newer markers have
restricted clinical applicability owing to isolated
studies with cumbersome techniques, limited avail-
ability, and inferior diagnostic accuracy in compar-
ison to established biomarkers such as amylase
and lipase.
www.co-gastroenterology.com 5
Pancreas
True Troponin Elevaon
Acute Coronary Syndrome /
Myocardial Infarcon
Troponin leak
Myocardial strain without ischemia,
systemic illness
Blunt Chest Trauma
Chronic Kidney Disease
Viral Illness
Diabetes
Hypothyroidism
Sepsis
Chemotherapy
Head Trauma
FIGURE 1. Schematic representation of causes of troponin leak vs. lipase leak.
IMPLICATIONS OF FALSE-POSITIVE
PANCREATIC ENZYME ELEVATION
It is important to account for other possible causes
of pancreatic enzyme elevation before labeling a
patient with a diagnosis of acute pancreatitis. As
mentioned above, there are a plethora of non-
pancreatic causes of abdominal pain that can be
associated with elevation of pancreatic enzymes.
Therefore, the diagnosis of acute pancreatitis must
not be based only on the presence of abdominal pain
and pancreatic enzyme elevation. This underlines
the importance of correlating radiological imaging
findings like peri-pancreatic fat stranding, pancre-
atic edema, necrosis (both pancreatic and extra-
pancreatic), and fluid collections that are more spe-
cific for the diagnosis of acute pancreatitis [74]. In
our unpublished data, we found serum lipase levels
greater than six times the upper limit of normal to
have 79% sensitivity, 52% specificity, and 67.4%
accuracy with an AUROC of 0.73 (P value <0.01)
in diagnosing acute pancreatitis. Whereas a lipase
cut-off of four times the upper limit had a higher
sensitivity of 91% but a very specificity of 26.6% in
accurately diagnosing acute pancreatitis. Therefore,
a more stringent diagnostic criterion is needed to
avoid a false-positive diagnosis of acute pancreatitis.
We commonly encounter patients labeled with
idiopathic acute recurrent pancreatitis based on
chronic recurrent abdominal pain and pancreatic
enzyme elevation with none or nonspecific radio-
logical features of acute pancreatitis. Most of these
6 www.co-gastroenterology.com
Copyright © 2023 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
True Lipase Elevaon
Acute Pancreas
Lipase Leak
Acinar cell strain without
inflammatory cascade
Abdominal trauma
Chronic Kidney Disease
Diabetes
Gastris
Cholecyss
Endotherapy
Chemotherapy
Head Trauma
patients are subjected to cholecystectomy as well as
multiple endoscopic procedures such as pancreatic
sphincterotomy or pancreatic duct stenting without
having many benefits. It is quite plausible that many
of these patients did not have acute pancreatitis and
the cause of abdominal pain and enzyme elevation
was an alternative cause such as acute gastritis,
enteritis, dysmotility secondary to drugs, autoim-
mune, metabolic causes such as diabetes and hypo-
thyroidism or functional abdominal pain. In fact, a
study by the Rome Foundation Global Study Group
found a 40.3% lifetime prevalence of functional
&&
abdominal pain [75 ]. Therefore, a false diagnosis
of acute pancreatitis could lead to unwarranted
surgeries and endoscopic procedures for conditions
with alternative effective treatment options thereby
not only increasing medical expenditure and use of
medical resources but also increasing morbidity
and mortality associated with these procedures that
could have been avoided.
Another important consideration during the
interpretation of pancreatic enzyme elevation is
the use of opioid analgesics. Opioid analgesics used
for any painful abdominal condition can cause
lipase elevation on its own accord because of sphinc-
ter of Oddi (SOD) spasm. A study by Lobo et al. [76]
described the Nardi test for SOD dysfunction, in
which they found that provocation with 10 mg of
intravenous morphine in healthy volunteers pro-
duced up to four times elevation of serum lipase
levels even among those without any reproducible
Volume 39  Number 00  Month 2023
 Interpretation of serum pancreatic enzymes Bush and Akshintala
abdominal pain. Opioid use disorder affects over 2.1
million people in the United States and a National
Health Interview survey estimated that 22.1% of
United States adults with chronic pain had used
&&
opioids in the past 3 months [77,78 ]. Therefore,
the use of opioids confuses the enzyme results, and
it is likely that many of the patients with chronic
abdominal pain have enzyme elevation because of
opioid use rather than an organic abdominal disor-
der. Most patients being admitted to an emergency
setting with abdominal pains are likely to receive
opioids for analgesia and this results in many cases
of being falsely diagnosed with acute pancreatitis.
This is an important point to be borne in mind
before making a diagnosis of acute pancreatitis.
CONCLUSION
Serum levels of pancreatic amylase and lipase can be
elevated in a number of nonpancreatic conditions
that may or may not be associated with abdominal
pain. Lipase appears to be more specific than
amylase but is not the Holy Grail. Higher cut-offs
for enzyme elevation might help in improving the
specificity of these enzymes in diagnosing acute
pancreatitis. Specific radiological features could be
more representative of acute pancreatitis changes
and their presence must be considered essential for
the diagnosis of acute pancreatitis. There are a few
newer biomarkers that have shown promise; how-
ever, these require validation in large sample stud-
ies. Future studies should aim to develop novel
biochemical and radiological markers for accurate
diagnosis of acute pancreatitis, thereby reducing
misdiagnosis and avoiding mismanagement of
these patients.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. A-Kader HH, Ghishan FK. The pancreas. In: Textbook of clinical pediatrics.
Berlin, Heidelberg: Springer; 2012:; 1925–1936.
2. Logsdon CD, Ji B. The role of protein synthesis and digestive enzymes in
acinar cell injury. Nat Rev Gastroenterol Hepatol 2013; 10:362–370.
0267-1379 Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2023 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
3. Weisbeck A, Jansen RJ. Nutrients and the pancreas: an epigenetic perspec-
tive. Nutrients 2017; 9:283.
4. Hirota M, Ohmuraya M, Baba H. Genetic background of pancreatitis. Post-
grad Med J 2006; 82:775–778.
5. Hameed AM, Lam VWT, Pleass HC. Significant elevations of serum lipase not
caused by pancreatitis: a systematic review. HPB (Oxford) 2015;
17:99–112.
6. Chen HJ, Wang JJ, Tsay WI, et al. Epidemiology and outcome of acute
pancreatitis in end-stage renal disease dialysis patients: a 10-year national
cohort study. Nephrol Dial Transplant 2017; 32:1731–1736.
7. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic
cancer. Gastroenterology 2013; 144:1252–1261.
8. Peery AF, Crockett SD, Murphy CC, et al. Burden and cost of gastrointestinal,
&& liver, and pancreatic diseases in the United States: update 2021. Gastro-
enterology 2022; 162:621–644.
A recent study on epidemiology of gastrointestinal disorders in the United States.
9. Werge M, Novovic S, Schmidt PN, Gluud LL. Infection increases mortality in
necrotizing pancreatitis: a systematic review and meta-analysis. Pancreatol-
ogy 2016; 16:698–707.
10. Yadav D, Lowenfels AB. Trends in the epidemiology of the first attack of acute
pancreatitis: a systematic review. Pancreas 2006; 33:323–330.
11. Samanta J, Dhaka N, Gupta P, et al. Comparative study of the outcome
between alcohol and gallstone pancreatitis in a high-volume tertiary care
center. JGH Open 2019; 3:338–343.
12. Pannala R, Kidd M, Modlin IM. Acute pancreatitis: a historical perspective.
Pancreas 2009; 38:355–366.
13. Elman R, Arneson N, Graham EA. Value of blood amylase estimations in the
diagnosis of pancreatic disease: a clinical study. Arch Surg 1929;
19:943–967.
14. O’Donnell MD, FitzGerald O, McGeeney KF. Differential serum amylase
determination by use of an inhibitor, and design of a routine procedure. Clin
Chem 1977; 23:560–566.
15. Berk JE, Kizu H, Wilding P, Searcy RL. Macroamylasemia: a newly recognized
cause for elevated serum amylase activity. N Engl J Med 1967;
277:941–946.
16. Richman A. Seminar on Diseases of the Pancreas. Acute Pancreat 1956;
21:944–961.
17. Meher S, Mishra TS, Sasmal PK, et al. Role of biomarkers in diagnosis and
prognostic evaluation of acute pancreatitis. J Biomark 2015; 2015:519534.
18. Ranson JH, Rifkind KM, Roses DF, et al. Prognostic signs and the role of
operative management in acute pancreatitis. Surg Gynecol Obstet 1974;
139:69–81.
19. Ranson JH, Rifkind KM, Roses DF, et al. Objective early identification of
severe acute pancreatitis. Am J Gastroenterol 1974; 61:443–451.
20. Rau BM. Predicting severity of acute pancreatitis. Curr Gastroenterol Rep
2007; 9:107–115.
21. Bradley EL. A clinically based classification system for acute pancreatitis.
Summary of the International Symposium on Acute Pancreatitis, Atlanta, Ga,
September 11 through 13, 1992. Arch Surg 1993; 128:586–590.
22. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis–
2012: revision of the Atlanta classification and definitions by international
consensus. Gut 2013; 62:102–111.
23. Balthazar EJ, Ranson JH, Naidich DP, et al. Acute pancreatitis: prognostic
value of CT. Radiology 1985; 156:767–772.
24. Chua KS, Tan IK, Vengadiswaran R, Peiris JT. An assessment of four methods
for the assay of amylase activity. Ann Acad Med Singapore 1979;
8:187–192.
25. Ryes AL, Zlatev R, Stoytcheva M, et al. Conductometric method for rapid
lipase activity quantification. Int J Electrochem Sci 2019; 14:10508–10521.
26. Stoytcheva M, Montero G, Zlatev R, et al. Analytical methods for lipases
activity determination: a review. Curr Anal Chem 2012; 8:400–407.
27. Hasan F, Shah AA, Hameed A. Methods for detection and characterization of
lipases: a comprehensive review. Biotechnol Adv 2009; 27:782–798.
28. Guo J, Chen CP, Wang SG, Huang XJ. A convenient test for lipase activity in
aqueous-based solutions. Enzyme Microb Technol 2015; 71:8–12.
29. Pieper-Bigelow C, Strocchi A, Levitt MD. Where does serum amylase come
from and where does it go? Gastroenterol Clin North Am 1990; 19:793–810.
30. Tietz NW, Burlina A, Gerhardt W, et al. Multicenter evaluation of a specific
pancreatic isoamylase assay based on a double monoclonal-antibody tech-
nique. Clin Chem 1988; 34:2096–2102.
31. Ismail OZ, Bhayana V. Lipase or amylase for the diagnosis of acute pancrea-
titis? Clin Biochem 2017; 50:1275–1280.
32. Lippi G, Valentino M, Cervellin G. Laboratory diagnosis of acute pancreatitis:
in search of the Holy Grail. Crit Rev Clin Lab Sci 2012; 49:18–31.
33. Tietz NW. Support of the diagnosis of pancreatitis by enzyme tests — old
problems, new techniques. Clin Chim Acta 1997; 257:85–98.
34. Shah AM, Eddi R, Kothari ST, et al. Acute pancreatitis with normal serum
lipase: a case series. JOP J 2010; 11:369–372.
35. Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet 2015;
386:85–96.
36. Limon O, Sahin E, Kantar FU, et al. A rare entity in ED: Normal lipase level in
acute pancreatitis. Turk J Emerg Med 2016; 16:32–34.
37. Singh A, Shrestha M, Anand C. Acute pancreatitis with normal amylase and
lipase–an ED dilemma. Am J Emerg Med 2016; 34:940.e5 –940.e7.
www.co-gastroenterology.com 7
CE: ; MOG/390509; Total nos of Pages: 8;
MOG 390509
Pancreas
38. Coffey MJ, Nightingale S, Ooi CY. Serum lipase as an early predictor of
severity in pediatric acute pancreatitis. J Pediatr Gastroenterol Nutr 2013;
56:602–608.
39. Fabre A, Boulogne O, Gaudart J, et al. Evaluation of serum lipase as predictor
of severity of acute pancreatitis in children. J Pediatr Gastroenterol Nutr 2014;
58:e41–e42.
40. Wilson C, Heads A, Shenkin A, Imrie CW. C-reactive protein, antiproteases
and complement factors as objective markers of severity in acute pancreatitis.
Br J Surg 1989; 76:177–181.
41. Rau BM, Kemppainen EA, Gumbs AA, et al. Early assessment of pancreatic
infections and overall prognosis in severe acute pancreatitis by procalcitonin
(PCT): a prospective international multicenter study. Ann Surg 2007;
245:745–754.
42. Bierma MJ, Coffey MJ, Nightingale S, et al. Predicting severe acute pancrea-
titis in children based on serum lipase and calcium: a multicentre retrospective
cohort study. Pancreatology 2016; 16:529–534.
43. Gumaste VV, Dave PB, Weissman D, Messer J. Lipase/amylase ratio. A new
index that distinguishes acute episodes of alcoholic from nonalcoholic acute
pancreatitis. Gastroenterology 1991; 101:1361–1366.
44. Tenner SM, Steinberg W. The admission serum lipase:amylase ratio differ-
entiates alcoholic from nonalcoholic acute pancreatitis. Am J Gastroenterol
1992; 87:1755–1758.
45. Pacheco RC, Oliveira LCM de. [Lipase/amylase ratio in biliary acute pan-
creatitis and alcoholic acute/acutized chronic pancreatitis]. Arq Gastroenterol
2007; 44:35–38.
46. Kazmierczak SC, Catrou PG, Van Lente F. Enzymatic markers of gallstone-
induced pancreatitis identified by ROC curve analysis, discriminant analysis,
logistic regression, likelihood ratios, and information theory. Clin Chem 1995;
41:523–531.
47. Tenner S, Dubner H, Steinberg W. Predicting gallstone pancreatitis with labora-
tory parameters: a meta-analysis. Am J Gastroenterol 1994; 89:1863–1866.
48. Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-
based guidelines for the management of acute pancreatitis. Pancreatology
2013; 13(4 Suppl 2):e1–e15.
49. Working Party of the British Society of Gastroenterology, Association of
Surgeons of Great Britain and Ireland, Pancreatic Society of Great Britain and
Ireland, Association of Upper GI Surgeons of Great Britain and Ireland. UK
guidelines for the management of acute pancreatitis. Gut 2005; 54 Suppl 3:
iii1–iii9.
50. Yokoe M, Takada T, Mayumi T, et al. Japanese guidelines for the management
of acute pancreatitis: Japanese Guidelines 2015. J Hepato-Biliary-Pancreat
Sci 2015; 22:405–432.
51. Tenner S, Baillie J, DeWitt J, Vege SS. American College of Gastroenterology.
American College of Gastroenterology guideline: management of acute
pancreatitis. Am J Gastroenterol 2013; 108:1400–1415; 1416.
52. Greenberg JA, Hsu J, Bawazeer M, et al. Clinical practice guideline: manage-
ment of acute pancreatitis. Can J Surg J Can Chir 2016; 59:128–140.
53. Panteghini M, Ceriotti F, Pagani F, et al., Italian Society of Clinical Biochem-
istry and Clinical Molecular Biology (SIBioC) Working Group on Enzymes.
Recommendations for the routine use of pancreatic amylase measurement
instead of total amylase for the diagnosis and monitoring of pancreatic
pathology. Clin Chem Lab Med 2002; 40:97–100.
54. Beauregard JM, Lyon JA, Slovis C. Using the literature to evaluate diagnostic
tests: amylase or lipase for diagnosing acute pancreatitis? J Med Libr Assoc
JMLA 2007; 95:121–126.
55. Clav e P, Guillaumes S, Blanco I, et al. Amylase, lipase, pancreatic isoamylase,
and phospholipase A in diagnosis of acute pancreatitis. Clin Chem 1995; 41
(8 Pt 1):1129–1134.
56. Treacy J, Williams A, Bais R, et al. Evaluation of amylase and lipase in the
diagnosis of acute pancreatitis. ANZ J Surg 2001; 71:577–582.
57. Chase CW, Barker DE, Russell WL, Burns RP. Serum amylase and lipase in
the evaluation of acute abdominal pain. Am Surg 1996; 62:1028–1033.
8 www.co-gastroenterology.com
Copyright © 2023 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
58. Hofmeyr S, Meyer C, Warren BL. Serum lipase should be the laboratory test of
choice for suspected acute pancreatitis. South Afr J Surg 2014; 52:72–75.
59. Batra H, Kumar A, Saha T, et al. Comparative study of serum amylase and lipase
in acute pancreatitis patients. Indian J Clin Biochem 2015; 30:230–233.
60. Matull WR, Pereira SP, O’Donohue JW. Biochemical markers of acute
pancreatitis. J Clin Pathol 2006; 59:340–344.
61. Kumar P, Ghosh A, Sinha N, Tonk RS. Secondary hypertriglyceridemia
causing recurrent acute pancreatitis with normal pancreatic enzymes. Indian
J Crit Care Med Peer-Rev 2018; 22:381–383.
62. Kim YS, Chang JH, Kim TH, et al. Prolonged hyperamylasemia in patients with
acute pancreatitis is associated with recurrence of acute pancreatitis. Med-
icine (Baltimore) 2020; 99:e18861.
63. He QB, Xu T, Wang J, et al. Risk factors for post-ERCP pancreatitis and
hyperamylasemia: a retrospective single-center study. J Dig Dis 2015;
16:471–478.
64. Pezzilli R, Andreone P, Morselli-Labate AM, et al. Serum pancreatic enzyme
concentrations in chronic viral liver diseases. Dig Dis Sci 1999; 44:350–355.
65. Yadav D, Agarwal N, Pitchumoni CS. A critical evaluation of laboratory tests in
acute pancreatitis. Am J Gastroenterol 2002; 97:1309–1318.
66. Banks PA, Sidi S, Gelman ML, et al. Amylase-creatinine clearance ratios and
serum amylase isoenzymes in moderate renal insufficiency. J Clin Gastro-
enterol 1979; 1:331–335.
67. Masoero G, Bruno M, Gallo L, et al. Increased serum pancreatic enzymes in
uremia: relation with treatment modality and pancreatic involvement. Pancreas
1996; 13:350–355.
68. Taes YE, Louagie H, Yvergneaux JP, et al. Prolonged hyperlipasemia attri-
butable to a novel type of macrolipase. Clin Chem 2000; 46:2008–2013.
69. Grimmelmann I, Momma M, Zimmer L, et al., German Dermatooncology
Group (DeCOG). Lipase elevation and type 1 diabetes mellitus related to
immune checkpoint inhibitor therapy - a multicentre study of 90 patients from
the German Dermatooncology Group. Eur J Cancer Oxf Engl 1990 2021;
149:1–10.
70. Steinberg WM, Nauck MA, Zinman B, et al. LEADER 3—lipase and amylase
activity in subjects with type 2 diabetes. Pancreas 2014; 43:1223–1231.
71. Tanindi A, Cemri M. Troponin elevation in conditions other than acute
coronary syndromes. Vasc Health Risk Manag 2011; 7:597–603.
72. Petersson U, Appelros S, Borgström A. Different patterns in immunoreactive
anionic and cationic trypsinogen in urine and serum in human acute pan-
creatitis. Int J Pancreatol 1999; 25:165–170.
73. Yasuda H, Kataoka K, Takeyama Y, et al. Usefulness of urinary trypsinogen-2
and trypsinogen activation peptide in acute pancreatitis: A multicenter study
in Japan. World J Gastroenterol 2019; 25:107–117.
74. Busireddy KK, AlObaidy M, Ramalho M, et al. Pancreatitis-imaging approach.
World J Gastrointest Pathophysiol 2014; 5:252–270.
75. Sperber AD, Bangdiwala SI, Drossman DA, et al. Worldwide prevalence and
&& burden of functional gastrointestinal disorders, results of Rome Foundation
Global Study. Gastroenterology 2021; 160:99.e3 –114.e3.
A study highlighting the burden of functional gastrointestinal disorders that can
often be misdiagnosed as acute pancreatitis because of false lipase elevation from
other causes.
76. Lobo DN, Takhar AS, Thaper A, et al. The morphine-prostigmine provocation
(Nardi) test for sphincter of Oddi dysfunction: results in healthy volunteers and
in patients before and after transduodenal sphincteroplasty and transampul-
lary septectomy. Gut 2007; 56:1472–1473.
77. Chang HY, Kharrazi H, Bodycombe D, et al. Healthcare costs and utilization
associated with high-risk prescription opioid use: a retrospective cohort
study. BMC Med 2018; 16:69.
78. Dahlhamer JM, Connor EM, Bose J, et al. Prescription opioid use among adults
&& with chronic pain: United States, 2019. Natl Health Stat Rep 2021; 1–9.
A study highlighting opioid use in United States, widespread use of opioid
medication for acute abdominal pain can result in increased serum lipase levels
and false diagnosis of acute pancreatitis in nonpancreatic conditions.
Volume 39  Number 00  Month 2023