Evaluación de-laboratorio-en-pancreatitis-2002

A Critical Evaluation of Laboratory Tests in Acute
Pancreatitis
Dhiraj Yadav, M.D., N. Agarwal, M.D., F.R.C.S., and C. S. Pitchumoni, M.D., M.A.C.G.
Division of Gastroenterology and Department of Surgery, Our Lady of Mercy University Medical Center,
New York Medical College, Bronx, New York
ABSTRACT
An ideal laboratory test in the evaluation of a patient with
acute pancreatitis (AP) should, in addition to accurately
establishing the diagnosis of AP, provide early assessment
of its severity and identify the etiology. None of the tests
available today meet all these criteria, and presently there is
no biochemical test that can be considered the “gold stan-
dard” for the diagnosis and assessment of severity of AP. In
the diagnosis of AP, serum amylase and lipase remain
important tests. Advantages of amylase estimation are its
technical simplicity, easy availability, and high sensitivity.
However, its greatest disadvantage is its low specificity. A
normal amylase would usually exclude the diagnosis of AP,
with the exception of AP secondary to hyperlipidemia, acute
exacerbation of chronic pancreatitis, and when the estima-
tion of amylase is delayed in the course of the disease. The
major advantage of lipase is an increased sensitivity in acute
alcoholic pancreatitis and in patients who initially present to
the emergency room days after the onset of the disease, as
lipase remains elevated longer than amylase. Although once
considered to be specific for AP, nonspecific elevations of
lipase have been reported in almost as many disorders as
amylase, thus decreasing its specificity. Simultaneous esti-
mation of amylase and lipase does not improve the accu-
racy. Other enzymes for the diagnosis of AP—pancreatic
isoamylase, immunoreactive trypsin, and elastase—are
more cumbersome and expensive and have no clear role in
the diagnosis of AP. No enzyme assay has a predictive role
in determining the severity or etiology of AP. Once the
diagnosis of AP is established, daily measurements of en-
zymes have no value in assessing the clinical progress of the
patient or ultimate prognosis and should be discouraged. A
host of new serological and urinary markers have been
investigated in the last few years. Their main use is in
predicting the severity of AP. At present, serum C-reactive
protein at 48 h is the best available laboratory marker of
severity. Urinary trypsinogen activation peptides within
12–24 h of onset of AP are able to predict the severity but
are not widely available. Serum interleukins 6 and 8 seem
promising but remain experimental. (Am J Gastroenterol
2002;97:1309–1318. © 2002 by Am. Coll. of Gastroenter-
ology)
INTRODUCTION
The diagnostic tests in the evaluation of a patient with
suspected acute pancreatitis (AP) must answer three ques-
tions sufficiently early in the course of the disease: first and
foremost, the tests should establish the diagnosis accurately,
excluding other conditions that mimic AP with or without
hyperamylasemia. Second, at the earliest they should pro-
vide an assessment of severity of AP to provide appropriate
treatment in the required setting: intensive care unit versus
a regular floor or by an internist alone versus a team of
medical specialists that includes a surgeon, radiologist, and
gastroenterologist trained in therapeutic endoscopy. Third,
tests should also help in establishing the etiology for AP, so
as to offer a definitive treatment such as cholecystectomy
and/or to prevent recurrences of AP, as in the case of a
patient with hyperlipidemic AP. The tests should be easily
available, cost-effective, and easily repeatable. Obviously,
every patient should not undergo all tests.
This article, an extension of a number of recent reviews
on the topic, including ours published in 1990 in this journal
(1), critically evaluates the standard serum and urine tests
and discusses the advances in laboratory technology that
may have new diagnostic possibilities. In addition to our
previous article on this topic (1), we have included relevant
articles after 1990, using a broad-based MEDLINE search
using the terms acute pancreatitis, diagnosis, laboratory
tests, and severity. Relevant articles as well as their refer-
ences were reviewed.
SERUM TESTS FOR DIAGNOSIS OF AP
A host of serum enzymes such as amylase, lipase, trypsino-
gen, elastase, phospholipase A2, ribonuclease, etc are avail-
able to diagnose AP and/or to assess the severity, but ele-
vated amylase levels continue to be the “gold standard”
among the serum markers.
Serum Amylase
In AP, serum amylase rises as a result of both increased
release and, to some extent, reduced catabolism. The most
familiar units of expression are the Somogyi unit (SU) and
the international unit (IU). One SU per 100 ml is equivalent
to 1.85 IU/L. The normal values are 60–160 SU/100 ml or
THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 97, No. 6, 2002
© 2002 by Am. Coll. of Gastroenterology ISSN 0002-9270/02/$22.00
Published by Elsevier Science Inc. PII S0002-9270(02)04122-9

110–300 IU/L in serum and 35–260 SU/h or 65–480 IU/L
in urine (2).
SENSITIVITY. The sensitivity of any test is dependent on
the criteria used for diagnosis. If the test itself is taken as a
criterion for diagnosis, as is often the case for serum amy-
lase in AP, its sensitivity will be artificially raised to 100%
(3). In one cohort (4), a 99.6% sensitivity for serum amylase
reflected such subjective inclusion criteria. However, the
sensitivity decreases to 81–95% when CT scan or ultra-
sound is used to ascertain the clinical diagnosis of AP (5, 6).
Normoamylasemia is reported in 19–32% of patients
with AP (6, 7). Diagnosis of AP is questioned if the amylase
level is normal. However, there are three major factors that
lower the sensitivity:
1. Time interval since onset of attack. A major confounding
factor is the variable time elapsed between the onset of
the symptoms and the first blood analysis in a given
patient. Within 24 h of the onset of symptoms, all en-
zymes are elevated; thus, serum amylase is as sensitive as
serum lipase, pancreatic isoamylase (P-isoamylase), im-
munoreactive trypsin, or elastase (8). Amylase is the first
one to return toward normal values, and as such, after the
first hospital day it is the least sensitive of the enzymatic
tests for pancreatitis. Normalization can sometimes occur
very rapidly, indicating early resolution of the disease,
increased urinary clearance, or, less frequently, extensive
destruction of the pancreas with cessation of pancreatic
amylase production (6).
2. Alcoholic pancreatitis. Spechler et al. (7) noted that
patients with acute alcoholic pancreatitis frequently
(32%) have normal serum amylase levels. Furthermore,
in patients with alcoholic AP, normoamylasemia was
significantly associated with number of previous attacks
(0.7 vs 0.4, p Ͻ 0.01), indicating a parenchyma that is no
longer able to produce sufficient amounts of enzymes
(6).
3. Hypertriglyceridemia. Serum or urinary amylase levels
may be normal in as many as 50% of patients with
abdominal pain and hypertriglyceridemia, in whom a
clinical diagnosis of AP is considered and when CT
shows pancreatic inflammation (9). The hyperlipidemia
interferes with the amylase assay, leading to a spuriously
normal result. A circulatory inhibitor of serum amylase
exists, as suggested by demonstration of elevated amy-
lase by dilution of the serum (10), but is probably not
triglyceride itself (11). In all situations where AP is
suspected with a normal serum amylase, triglyceride
estimations must be done, and if lactescent plasma is
present, serial dilution techniques should be employed to
circumvent false negative amylase results.
SPECIFICITY. The greatest limitation of serum amylase is
its lack of specificity. Besides AP, conditions that increase
serum amylase levels include many diseases and derange-
ments of the biliary tract, liver, intestines, genitourinary
tract, lungs, breast, prostate, central nervous system, and, of
course, salivary glands (12). Abnormal serum levels also
occur in the presence of metabolic disturbances such as
renal failure, liver dysfunction, diabetic ketoacidosis, hypo-
perfusion, eating disorders like anorexia nervosa and bu-
limia (13), and abdominal and nonabdominal trauma includ-
ing head injury, as well as with the use of various drugs (2,
14). Interestingly, hyperamylasemia, seen commonly in
HIV-infected persons and in up to 40% of intoxicated al-
coholics, often does not signify AP, as predominantly S-
type amylase levels alone go up (15, 16). An important
observation is that, after ERCP, hyperamylasemia is noted
in 25–43% of patients but only 1–4% have evidence of
pancreatitis (17). Furthermore, persistent hyperamylasemia
may be a normal variant (18) and has been recently de-
scribed as a benign abnormality in many members of certain
families (19) (Table 1).
Another critical limiting factor that significantly influ-
ences the specificity is the issue of what signifies an abnor-
mal value (3). More than 200 techniques of amylase deter-
mination are described in the literature, creating a host of
“normal” values that differ both quantitatively and in meth-
ods of expression (2, 20). Further, different studies have
arbitrarily used various cutoff values ranging from just the
upper limit of normal (300 IU/L) (3) to more than three
times the upper limit of normal (Ͼ1000 IU/L) (21). No
international reference method or cutoff value has yet been
adopted toward establishing a standardized tool. With a
cutoff value of 300 IU/L (upper limit of normal), total
amylase has a sensitivity of 91–100% but a specificity of
71–98%. Increasing the cutoff value to 1000 IU/L increases
the specificity to around 100% but decreases sensitivity to as
low as 61%. Ideally, sensitivity should be increased at the
Table 1. Conditions With Increased Amylase
Abdominal disorders
Pancreatic disorders: acute pancreatitis, chronic pancreatitis,
pseudocysts, pancreatic trauma, pancreatic cancer
Nonpancreatic intra-abdominal conditions: perforated bowel,
mesenteric infarction, intestinal obstruction, appendicitis,
peritonits, abdominal aortic aneurysm, ruptured ectopic
pregnancy, fallopian and ovarian cysts, salpingitis, hepatitis
Extra-abdominal conditions
Salivary diseases, renal failure, ketoacidosis, pneumonia,
cerebral trauma, burns, anorexia nervosa, bulimia,
nonabdominal surgery
Macroamylasemia
Idiopathic hyperamylasemia
Familial and nonfamilial
Drug induced
Definite association: azathioprine, L-asparginase,
sulfonamides, tetracycline, didanosine, methyldopa, estrogens,
furosemide, pentamidine, 5-aminosalicylic acid compounds,
valproic acid, salicylate, thiazide, calcium, vinca alkaloids
Probable association: glucocorticoids, nitrofurantoin,
phenformin, rifampin, FK-506 (tacrolimus), metronidazole,
6-mercaptopurine, procainamide, diphenoxylate,
chlorthalidone, cimetidine, cytosine arabinoside, cisplatin,
cyclosporin A
1310 Yadav et al. AJG – Vol. 97, No. 6, 2002

expense of specificity when the penalty associated with
missing the disease is high. On the other hand, specificity
should be increased relative to sensitivity when the costs or
risks associated with further diagnostic techniques are sub-
stantial. Because AP can be serious, it is wiser to increase
the sensitivity at the expense of specificity.
SEVERITY OF AP. Virtually all investigators agree that
the magnitude of increase in amylase activity does not
correlate with the severity of the disease. It is even possible
for patients with very severe necrotizing AP to have normal
or low values of amylase, indicating an inverse relationship
between the amylase level and the severity of the disease
(22, 23). Clinically, AP does not seem to behave differently
when serum amylase is normal or elevated (6, 24). Once the
diagnosis of AP is established, daily measurements of serum
amylase have little value in assessing the clinical progress of
the patient or ultimate prognosis (25). However, persistent
hyperamylasemia that does not return to normal within 5–10
days has been shown to correlate with complications such as
pseudocysts, necrosis, or abscess.
ETIOLOGY OF AP. In general, patients with biliary pan-
creatitis have markedly higher initial serum amylase levels
than those with alcoholic pancreatitis or pancreatitis from
other causes. Hiatt et al. (26) observed that only 11% of
patients with biliary disease had initial serum amylase val-
ues lower than 1000 IU/L, whereas only 6% with alcoholic
pancreatitis had initial amylase values higher than 1000
IU/L.
CLINICAL PRACTICE RECOMMENDATIONS. The ad-
vantage of serum amylase estimation lies in its technical
simplicity and ready availability in all hospitals. In contrast,
its greatest disadvantage is its overall low specificity. Be-
cause the presence of a raised serum amylase in the clinical
setting of abdominal pain is not entirely specific, it is de-
sirable to confirm it by imaging studies. A normal amylase
level would nearly exclude the diagnosis, with the excep-
tions of possible hyperlipidemic pancreatitis, acute exacer-
bation of chronic pancreatitis, and delayed estimation in the
course of the disease. Indeed, AP should not be dismissed in
the presence of an amylase level that is either normal or only
mildly elevated on initial evaluation if the clinical suspicion
for AP is high and it is prudent to seek additional tests.
Serum amylase has no value in assessment of severity or
etiology of AP.
Lipase
Lipase (triacylglycerol acylhydrolase) is mainly synthesized
and stored as granules in the pancreatic acinar cells. More
than 99% is subsequently excreted in the ductal systems,
and less than 1% diffuses via the lymphatics and capillaries
into the general circulation (27). The concentration gradient
between pancreatic tissue and serum is over 20,000-fold.
Other sources of lipase are the tongue, esophagus, stomach,
duodenum, leukocytes, adipose tissue, lung, and breast milk.
However, the lipase concentration in the pancreas is 100-
fold greater than in the liver, duodenum, and small bowels
(28). In AP, increased permeability in the basal pole of the
acinar cells accounts for the pronounced rise of the enzyme
in the serum. Usually, serum lipase increases within 4–8 h
after onset of symptoms, peaks at 24 h, and returns to
normal after 8–14 days (29). Lipase assay is fast, reliable,
practical, and almost as sensitive as an amylase assay. The
cost of the lipase assay compares favorably with amylase
assays, and the technique can be available 24 h a day, 7 days
a week in most hospitals.
SENSITIVITY. The sensitivity of lipase ranges from 85%
to 100% (3, 21), with some reporting it to be less sensitive
than serum amylase (3) and others believing it to be more
sensitive than amylase (21, 30). The major advantage of
lipase is an increased sensitivity in acute alcoholic pancre-
atitis and with late clinical presentation, as lipase remains
elevated longer than does amylase. Clavien et al. (6) found
that in patients with AP who had normal amylase, more than
two thirds had elevated lipase levels. Gumaste et al. have
shown in their study on patients with AP and nonpancreatic
abdominal pain (31) that the sensitivity of lipase levels of
greater than three times normal is much higher than amylase
levels (100% sensitivity and 99% specificity, vs 72% sen-
sitivity and 99% specificity for amylase levels). In a recent
study of ERCP-induced AP (32), mean lipase values were
four times higher than amylase levels 2 h after the procedure
in those who developed AP.
SPECIFICITY. Lipase elevation is not specific to AP, al-
though it may be slightly better than amylase. Apple and
associates (30) have shown that lipase activity is four times
greater than amylase activity in the pancreas. Second, pan-
creatic tissue in chronic pancreatitis demonstrates a substan-
tial decline in both amylase and lipase activity, with amylase
activity showing a greater decrease compared to lipase (91%
vs 26%). In conditions of extrapancreatic injury, lipase is
also elevated. Mumps, types I and IV hyperlipoproteine-
mias, peptic ulcer, acute cholecystitis, extrahepatic biliary
obstruction, liver diseases, small bowel obstruction, intesti-
nal infarction, perforated bowel, acute renal failure, fracture
of bone, crush injury, fat embolism, and the postcholecys-
tectomy syndrome are some examples (7, 33). In our study
of patients with diabetic ketoacidosis (34) we found non-
specific elevation of lipase to occur more frequently than
amylase elevation. Recently, inflammatory bowel disease
and familial pancreatic hyperenzymemia have been in-
cluded among causes of lipase elevation (19, 35).
The reference point determined in different laboratories
may differ even for identical methods (27, 36). Further,
different authors have arbitrarily used different cutoff val-
ues. Steinberg et al. (3) have shown that the upper limit of
normal itself provided the best cutoff value. Keim and
associates (5) suggest that 2-fold elevated lipase values
should be used as the cutoff, whereas Gumaste et al. (31)
1311AJG – June, 2002 Evaluation of Laboratory Tests in Acute Pancreatitis

advocate a cutoff level of three times normal. They observed
that when lipase elevation is not due to AP, the elevation is
usually less than three times normal. However, Frank and
Gottlieb (29) have reported patients with lipase greater than
three times normal secondary to renal insufficiency, malig-
nant tumors, cholecystitis, esophagitis, and hypertriglyceri-
demia. Other major disadvantages of lipase assay are a)
presence of as many as four fractions of lipase in serum of
patients with pancreatitis, b) the macroforms or macroli-
pasemia contribute to hyperlipasemia, and c) technical dif-
ficulties are more with lipase assays than amylase assays
(27, 36, 37).
CLINICAL PRACTICE RECOMMENDATIONS. The
major advantage of lipase is an increased sensitivity in acute
alcoholic pancreatitis and late clinical presentation, as lipase
remains elevated longer than amylase. Its specificity may be
slightly better than amylase; however, it is increasingly
being recognized that nonspecific elevations of lipase can be
seen in as many disorders as amylase. Serum lipase also has
no value in assessment of severity or etiology of AP.
Amylase, Lipase, or Both
Controversy exists whether amylase and lipase should be
used alone or in combination to avoid overlooking patients
with AP. Opinions vary on the preferential test (38). Al-
though amylase continues to be the screening test for AP (3,
6, 39), a number of studies have challenged the primary
diagnostic role of serum amylase, and a case has been made
for the use of serum lipase instead (31, 40, 41).
Within 24 h after onset of symptoms, both amylase and
lipase values have high sensitivity and specificity, with
lipase having a slightly higher diagnostic value. Amylase
appears to be a better test in gallstone pancreatitis and lipase
from alcoholic and other causes. The differences in perfor-
mance of the two tests, though small, are definite (42).
Simultaneous evaluation of amylase and lipase does not
improve the accuracy (5, 43).
Other Tests of Limited or No Value
Normal circulating amylase consists of P-isoamylase (40%
of total amylase) and a salivary-type isoamylase (60%) (18).
In AP, P-isoamylase is expected to rise; hence the estima-
tion of this fraction is theoretically attractive. Importantly,
some nonpancreatic abdominal emergencies such as acute
biliary tract disease, perforated duodenal ulcer, intestinal
obstruction, infarction, and ruptured abdominal aortic aneu-
rysm are also associated with an increase in P-isoamylase.
Thus, a major group of differential diagnoses is not elimi-
nated (44), and therefore, measurement of isoenzymes in the
serum has been largely abandoned (25).
Macroamylases are large molecules of amylase where
abnormal proteins—IgA, IgG, or IgM—produce a large
molecular weight complex that cannot be cleared through
the kidneys (45). It occurs in 0.1% of the population (46)
and in up to 2.7% of hospitalized patients (47). In a large
majority of individuals macroamylasemia is not clinically
significant. However, in an asymptomatic individual with
elevated serum amylase, which causes concern, an estima-
tion of urine amylase that shows low levels will settle the
issue.
Immunoreactive trypsinogen (IRT) has a sensitivity of
97–100%, a specificity of 83%, and a positive predictive
value of 46–74% (3, 8). However, the levels are also high
in malignant neoplasms of the pancreas, diabetes mellitus,
chronic renal failure, hypercalcemia, hypertriglyceridemia,
cirrhosis of the liver, chronic pancreatitis, and extrahepatic
obstructive jaundice (48). Therefore, many believe that IRT
helps to confirm the pancreatic origin of a raised serum
amylase, but does not much improve the diagnostic accu-
racy in patients with suspected AP with normal or only
mildly elevated amylase. IRT is a more difficult test to
perform and requires 24 h to complete.
Elastase-1, a proteolytic enzyme liberated in the course of
AP, has a specific elastolytic action that is responsible for
digestion of blood vessel walls and vascular complications.
By radiommunoassay, one can demonstrate elevated elas-
tase levels in the serum in all cases of AP. The test, however,
lacks specificity, as it is elevated in two thirds of pancreatic
cancer patients and less frequently in chronic pancreatitis
(17). Also, serum elastase levels did not correlate with
disease severity or development of complications. It is also
unable to discriminate between alcohol and gallstone pan-
creatitis (8). Elastase confers no benefit as a diagnostic test
nor does it provide any prognostic information. The only
strength of IRT and elastase assays is that they remain
elevated for 7–10 days after the onset of AP, and elastase is
the more sensitive of the two. Their determination may be
indicated in patients who present late and in whom the
diagnosis of pancreatitis is in doubt.
CLINICAL PRACTICE RECOMMENDATIONS. Pres-
ently, there is no role of isoamylases, IRT, macroamylases,
and elastase estimations in the routine management of pa-
tients with AP.
SERUM MARKERS OF SEVERITY OF AP
Hematocrit
Recently, hemoconcentration has been identified to be a
strong risk factor and early marker for necrotizing pancre-
atitis and organ failure (49, 50). An admission Hct of Ն47
and a failure of admission Hct to decrease at 24 h represent
a strong risk factor for the development of pancreatic ne-
crosis. Baillargeon et al. (49) compared 32 patients with
necrotizing pancreatitis to an equal number of patients with
mild pancreatitis. At 24 h, 81% (26/32) of patients met
either of the criteria (admission HCT Ն 47 or failure of HCT
to decrease), compared to 12.5% (4/32) of those with mild
AP (p Ͻ 0.01). The sensitivity and specificity using these
criteria on admission were 34% and 91% and, at 24 h, 81
and 88%, respectively.

C-Reactive Protein (CRP)
Serum CRP is an acute phase reactant that is elevated in
several inflammatory conditions and serves as a nonspecific
marker for inflammation. CRP levels peak on the 3rd or 4th
day, and values of Ͼ150 mg/L when done 48 h after the
onset of symptoms are now accepted as a proven predictor
of severity of AP (42). In a study by Wilson et al. (51), peak
CRP levels of Ն210 mg/L were able to differentiate severe
AP from the milder form with a sensitivity of 83–84% and
a specificity of 74–85%. Another recent study (52) has
shown CRP to be superior to interleukin 1B (IL-1B), IL-8,
and tumor necrosis factor ␣ (TNF-␣) and equivalent to IL-6
in predicting severe pancreatitis on day 2. CRP has also
been reported to have an overall accuracy of 93% in detect-
ing pancreatic necrosis. Serum CRP therefore is considered
to be the gold standard for predicting severity of AP (51–
55).
CRP is widely available, easy to measure, and cheap to
perform. The major drawback of CRP is that it takes 48–72
h to peak, a delay similar to other methods used for severity
assessment in AP.
Polymorphonuclear Elastase
In severe AP, neutrophils accumulate in the pancreas, pro-
ducing lysosomal proteases—mainly elastase—and a major
factor for pancreatic necrosis. It also causes activation of
complement, kinins, and fibrinolytic systems, leading to
multiple organ system failure. Obviously, estimation of
PMN elastase is not a diagnostic test for AP but may
indicate severity. Uhl et al. (56) have shown that elastase
levels differentiate edematous from necrotic pancreatitis.
The PMN elastase level is comparable to CRP in predicting
necrosis. Its advantage over CRP is that its peak levels are
reached on day 1 of onset and the levels fall rapidly in
patients with edematous pancreatitis, compared to CRP val-
ues, which remain elevated.
Pancreatitis-Associated Protein (PAP)
PAP, an acute phase protein, is secreted from pancreatic
acinar cells (57, 58), especially in AP. It induces extensive
bacterial aggregation and thus may play a role in the pre-
vention of bacterial infection in AP. PAP levels have been
correlated with severity of pancreatitis in rats (59) and
humans (60), suggesting a prognostic role.
Phospholipase A2 and Ribonuclease
Phospholipase A2 and ribonuclease are elevated in AP but
not in healthy individuals. Phospholipase A2 is produced in
the pancreas and also by neutrophil activation. Several stud-
ies have also shown it to be a good early marker of severe
pancreatitis (61–64). In a recent study by Mayer et al. (65),
levels of secretory synovial-type phospholipase were signif-
icantly higher in patients with infected necrosis than those
with sterile necrosis, and levels of Ͼ300 ng/ml on 2 suc-
cessive days within the first 4 days predicted infected ne-
crosis with a high sensitivity and specificity. Warshaw and
Lee (66) have reported a relationship between serum levels
of pancreatic ribonuclease and the need for operative treat-
ment of pancreatic necrosis or abscesses. They found that,
among 24 patients with normal ribonuclease levels, only one
required surgical treatment for abscesses. In contrast, 11 of
13 patients with elevated ribonuclease required surgical
intervention. These relationships need further evaluation in
a large group of patients. The assays are cumbersome and
not currently available for clinical use.
Interleukins
The activation of inflammatory cells that release cytokines
plays an important role in the pathogenesis of the disease.
Various studies have demonstrated that IL-6 and IL-8 peak
within the first 24 h after onset of symptoms and are sig-
nificantly higher in patients with severe AP (67–72). A
study of serum markers in ERCP-induced AP showed that
the earliest peak was of serum IL-8, 12 h after the procedure,
followed by IL-6’s peak at 24 h and CRP’s peak at 72 h.
Chen and associates (52) have observed that, when com-
pared to serum TNF-␣, IL-1B, IL-8, and CRP, IL-6 is the
best early predictor (day 1 after admission) of severe AP.
Using a cutoff value of Ͼ400 pg/ml, the sensitivity, speci-
ficity, and accuracy were 89%, 87%, and 88%, respectively,
on day 1. Furthermore, patients with fatal outcomes showed
the most markedly elevated IL-6 concentrations (2–5 times
the mean values in severe pancreatitis) on days 1 and 2, and
they remained elevated on day 7. The disadvantage is that
the routine determination of IL-6 is not yet widely available.
A rapid dipstick method for estimation of IL-8 is also under
investigation (72).
In contrast, IL-10 reduces the inflammatory response in
experimental pancreatitis. In humans, Pezzelli and associ-
ates (68) have also observed higher levels of IL-10 in the
sera of patients with mild disease.
Tumor Necrosis Factor
The prognostic significance of serum TNF in AP has not
been established, as its release is variable and phasic. de-
Beaux et al. (73) have shown that the concentration of
soluble TNF receptors is able to differentiate mild, severe,
and fatal attacks of AP. Banks et al. (74) observed no
significant difference between mild and severe AP, whereas
Chen and associates (52) found significantly elevated levels
in severe AP on days 1–3 but not on days 4 and 7. The role
of TNF assay as a prognostic marker remains unclear.
Other Serum Markers
Preliminary studies indicate serum procalcitonin to be a
valuable marker for the prediction of infected pancreatic
necrosis as well as septic multiorgan failure (75, 76). Sev-
eral other markers have been evaluated recently to assess the
severity of AP. These include plasma soluble intercellular
adhesion molecule 1 (76, 77), serum levels of extracellular
matrix (78), serum levels of the activation peptide of car-
boxypeptidase B (79), serum amyloid A (80), and serum
trypsinogen-2 and trypsinogen-2-␣-1-antitrypsin complex
(81). The use of these tests is currently restricted to research

settings, and further studies defining their clinical impor-
tance in assessment of severity of AP are awaited.
Clinical Practice Recommendations for Serum Tests of
Severity
Although a host of newer serum markers hold promise for
the future, they are still experimental, used in research
settings, and not widely available. Serum CRP is the best
available serum marker presently to assess the severity of
AP. A cutoff level of Ͼ150 mg/L is now accepted as a
proven predictor of severity.
CRITERIA UTILIZING MULTIPLE LABORATORY TESTS
Blood urea nitrogen with glucose levels have been shown to
be helpful in identifying patients with severe AP (82). The
most commonly used criteria for predicting severity are
Ranson’s criteria (83), which include 11 signs with prog-
nostic significance. The mortality is related to the number of
these signs present: 0.9% with less than three positive prog-
nostic signs, 16% with three or four, 40% with five or six,
and 100% with more than six signs (84). A modification of
Ranson’s signs as suggested by Osborne et al. (85) is used
in the United Kingdom. They have excluded Hct, base
deficit, and fluid sequestration, but included serum albumin
of Ͻ3.2 g/dl as an important criterion of severity.
Acute Physiology and Chronic Health Evaluation
(APACHE-II) uses the worst values of 12 physiological
measurements, age, and previous health status to provide a
general measure of severity of disease (86). The physiolog-
ical variables considered are temperature, mean arterial
pressure, heart rate, respiratory rate, arterial oxygenation,
arterial pH, serum sodium, serum potassium, serum creati-
nine, Hct, white blood cell count, and Glasgow Coma Scale.
An APACHE-II score of Ͼ8 indicates severe AP. The
advantages of APACHE-II over other prognostic criteria are
objective determination of AP within hours of admission
and the ability to be recalculated daily so as to follow the
course of the disease and response to therapy.
LABORATORY TESTS TO PREDICT THE ETIOLOGY OF AP
The height of amylase or lipase does not predict the etiology
of AP. A reported benefit of estimating serum lipase is that
it might suggest the etiology of AP. Gumaste et al. (87)
found that a lipase/amylase ratio of Ͼ2 was suggestive of
acute alcoholic pancreatitis. Several other studies have tried
to determine the utility value of the lipase/amylase ratio
(88–91). Although all studies did not agree that a lipase/
amylase ratio is a precise indicator, most reveal a definite
trend—values of Ͼ3 are highly indicative of acute alcoholic
pancreatitis, whereas low values (Ͻ1–2) are more sugges-
tive of gallstone pancreatitis (90). Controversy still exists
with regard to the utility of the ratio in clinical practice. A
recent practice guideline article (25) did not recommend it.
Table 2 summarizes the laboratory tests in AP.
Several studies have looked at the utility of liver function
tests in predicting gallstone pancreatitis (92–94). According
to a recent meta-analysis (95), an ALT level of Ն150 U/L
(approximately a 3-fold elevation) has a positive predictive
value of 95% in diagnosing acute gallstone pancreatitis.
However, the sensitivity is only 50%. Bilirubin and ALP
were not found to be as useful as ALT (95).
URINE TESTS
Diagnosis
Although routine use of urinary amylase is not done widely
to evaluate a patient with AP, recently several studies have
reported the use of urinary dipstick tests for screening cases
of AP in the emergency room (96, 97). A dipstick test for
detecting pancreatic amylase in urine by an immunochro-
matography principle using the monoclonal antibodies spe-
cific for pancreatic amylase in initial studies has shown
promising results (97). The test has a high specificity of 97%
and is likely to become useful in the emergency room
setting. Other tests have reported the clinical utility of the
urine trypsinogen-2 dipstick test in AP for screening pa-
tients with suspected AP as well as predicting the severity
(98, 99). In a study of 525 consecutive patients presenting to
the emergency room with abdominal pain, the sensitivity
and specificity of diagnosing AP were 96% and 92%, re-
spectively. All nine patients with severe AP were detected
by the dipstick (98).
Severity
Trypsinogen activation peptides (TAPs) are the highly con-
served tetra-1-aspartyl-1-lysyl amino terminal peptides re-
Table 2. Laboratory Tests in AP
Tests for diagnosis
Serum tests
1. Amylase
2. Isoamylases
3. Macroamylases
4. Lipase
5. Immunoreactive trypsin
6. Elastase
Urine tests
1. Amylase
2. Lipase
Fluid amylase
Tests for severity
Serum tests
1. CRP
2. Interleukins (IL-6, IL-8, etc)
3. Polymorphonuclear elastase
4. PAP
5. Phospholipase
6. Procalcitonin
7. TNF-␣
8. Ribonuclease
9. Methalbumin
Urine tests
TAPs

leased during the activation of trypsinogen to trypsin.
Though normally produced in the intestinal lumen after
activation of trypsinogen by enterokinase, they are not ab-
sorbed, because of degradation by enteric oligopeptidases
(100–103). In AP, premature intrapancreatic activation of
trypsinogen leads to the release of TAPs into blood, lym-
phatics, and peripancreatic tissue, leading to increased con-
centrations in body fluids. TAPs are liberated within the first
few hours of the onset of AP, and they peak within 12–24
h of admission.
Experimental studies done in animals and humans have
found estimation of TAPs to be helpful as a prognostic
marker in differentiating severe from mild AP. Gudgeon et
al. in their study (103) found urinary TAP estimation to be
much better than serum CRP levels. When a urinary con-
centration of Ͼ2 nmol/L was used as a cutoff on admission,
the sensitivity and specificity for predicting severe AP were
80% and 90%. When the highest concentration of TAPs in
the first 24 h was used, the sensitivity and specificity of
urinary TAP levels of Ͼ10 ng/ml were 100% and 85% in
predicting severe AP (104).
Neoptolemus and associates (105) in a prospective study
compared levels of urinary TAPs with serum CRP and the
three currently used scoring systems in 172 patients with AP
(35 with severe disease) and 74 controls. Urinary TAP
concentrations differed significantly between mild and se-
vere AP at 24 h and 48 h after onset of symptoms and also
at 24 h and 48 h after admission. CRP concentrations dif-
fered significantly at 48 h but not at 24 h. TAPs at 24 h (Ͼ34
mmol/L) were similar to an APACHE-II score of Ͼ8 (0–12
h after admission) with respect to sensitivity (58% vs 58%),
specificity (73% vs 76%), positive predictive value (39% vs
40%), negative predictive value (86% vs 87%), and accu-
racy (70% vs 72%) (Table 3).
CLINICAL PRACTICE RECOMMENDATIONS. The as-
say of TAPs for determining severity of AP is appealing as
a single marker that is able to provide accurate severity
prediction within 24 h after onset of symptoms. These
encouraging results should be considered preliminary, and
further studies are needed to establish its role in the evalu-
ation of AP. Presently, TAP assays are not widely available.
ASCITIC FLUID ANALYSIS
Early appearance of ascites is seen in over 60% of cases of
severe AP (106). This peritoneal exudate is rich in activated
lipolytic and proteolytic enzymes, vasoactive substances,
and several other proinflammatory mediators. Ascites may
play a role in the transfer of toxic mediators into the sys-
temic circulation or may be a reflection of the locoregional
necrotizing process (106). A peritoneal tap can provide
corroborative evidence of AP by the presence of a high
amylase concentration, especially if sterile fluid is aspirated
(106). The biochemical composition of peritoneal fluid dur-
ing AP, however, reveals no major differences between the
principal etiological categories of AP (107, 108).
McMahon et al. (109) have shown that volume and color
of peritoneal fluid are indicators of the severity of an attack
of AP. Severe AP is indicated in the presence of one or more
of the following: greater than 20 ml of free peritoneal fluid,
dark-colored free intraperitoneal fluid, and lavage fluid
darker than a pale straw color obtained after peritoneal
lavage with a liter of normal saline. However, peritoneal
lavage is an invasive procedure that is not applicable for
patients with mild disease and contraindicated in patients
with previous scars, obesity, coagulopathy, or difficulty in
catheterization. It is associated with visceral puncture in
0.8% of patients. It is also a poor system for accurate
grading of patients with biliary pancreatitis (108).
CLINICAL PRACTICE RECOMMENDATIONS. Diag-
nostic peritoneal lavage is an invasive test and a poor system
for grading the severity of AP. It has never been accepted
widely into clinical practice.
RESULTS AND DISCUSSION
It is clear that there is no biochemical test that can be
considered to be a gold standard for the diagnosis or assess-
ment of severity of AP. Amylase and lipase remain impor-
tant tests in the diagnosis of AP. Lipase, which was initially
thought to be more specific than amylase, has recently been
shown to be almost as nonspecific as amylase. The use of
other tests like P-isoamylase, IRT, elastase, urinary amylase
Table 3. Comparison of Laboratory Tests for AP
Amylase Lipase Serum CRP Urinary TAPs Interleukins (IL-6, IL-8)
Sensitivity 67–100%* 82–100% Test for severity Test for severity Test for severity
Specificity 85–98% 82–100%† Test for severity Test for severity Test for severity
Prediction of severity None None Yes
(Ͼ150 mg/L at
48 h)
Yes
(peak within 12–24 h)
Yes
(peak within 12–24 h)
Comments Cheap, widely
available
Cheap, widely
available
Cheap, widely
available, best
available lab
test for severity
Not widely available,
expensive
Experimental
* Poor sensitivity in hyperlipidemic AP, acute or chronic AP due to alcohol, and delayed estimation.
† Better than amylase. Lipase is increasingly being recognized as nonspecific.

and lipase, and fluid amylase has no clear role in the eval-
uation of patients with AP. Urinary TAPs within 12–24 h
and serum CRP at 48 h are now considered by many to be
good markers for predicting severity of AP. A host of new
serological markers have been investigated in the last few
years to predict the severity of AP early. Some of them show
promise but have yet to prove their superiority.
Reprint requests and correspondence: C. S. Pitchumoni, M.D.,
M.A.C.G., M.P.H., Professor of Medicine and Preventive & Com-
munity Medicine, New York Medical College, Director, Depart-
ment of Medicine & Chief of GI, Our Lady of Mercy Medical
Center, 600 East 233rd Street, Bronx, NY 10466.
Received Feb. 6, 2001; accepted Jan. 15, 2002.
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