How We Predict the Etiology of Acute Pancreatitis

Miguel Pérez-Mateo
Department of Internal Medicine, Gastroenterology Unit, Hospital General Universitario de
Alicante, Miguel Hernández University. Elche, Alicante, Spain
Although acute pancreatitis (AP) may be the
consequence of numerous etiologic factors,
more than 80% of the episodes are of biliary
or alcoholic origin. Although the clinical
picture is similar irrespective of the etiology,
patients with severe episodes of acute
pancreatitis require specific therapeutic
maneuvers when biliary-induced while, in the
case of alcoholic origin, they only need
general support. As a consequence, the early
estimation of the etiology is of particular
interest, and older age and female sex are
frequent characteristics of AP of biliary
origin. Together with these factors, abnormal
liver function tests have been classically used
to identify biliary etiology. Their intrinsic
value has grown in the era of new imaging
techniques. From another perspective, the
plasmatic level of carbohydrate-deficient
transferrin seems to be the most accurate
technique in differentiating cases of alcohol-
induced acute pancreatitis from other
Acute pancreatitis (AP) is a frequent disease
which represents 0.15-1.5% of all diagnoses
in the emergency room. Although its
prevalence varies in different countries and
even in different areas of a given country, it is
likely that its real prevalence ranges from
200-300 cases per million inhabitants a year
[1, 2, 3]. The list of etiologic factors related to
its development is shown in Table 1.
However, a biliary origin is by far the most
frequent cause, followed by an alcoholic
origin. Together these etiologies are
responsible for 80% of all episodes of AP [4].
In a published series, each one of the
remaining possible etiologic causes affected a
reduced number of patients with AP.
From a clinical perspective, the characteristics
of the episodes of AP having different
etiologies are similar and indistinguishable
from one another. Modern diagnostic tools
permit the identification of the etiology in
most cases, and the acronym “idiopathic” has
become rare [5]. However, many of these new
techniques may not be available in all
hospitals, and some of them are restricted to
academic hospitals. Furthermore, although the
basic clinical characteristics of all episodes
are similar, the suspicion of a biliary origin in
Table 1. Causes of acute pancreatitis.
Toxic and
Hyperlipidemia Iatrogenic injury
Pancreas divisum Hypercalcemia
Sphincter of Oddi
Scorpion venom Autoimmune
Cystic fibrosis

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JOP. Journal of the Pancreas - - Vol. 7, No. 3 - May 2006. [ISSN 1590-8577]
a patient with severe AP or associated
cholangitis may require an ERCP to confirm
choledocolithiasis and the removal of the
stone. This maneuver improves the clinical
evaluation of the patient [6]. Similarly, the
identification of the alcoholic origin of an
episode of AP, this being the second cause of
AP, is relevant in order to decrease expenses,
and avoid the use of non-necessary diagnostic
tools. In this regard, it is well-known that
information obtained by asking the patient or
his/her relatives is rarely accurate [7] and
questionnaires developed to estimate the
intake of alcohol have a low sensitivity and
specificity (60-95% and 40-95% respectively)
The association of certain abnormalities in
liver function tests in the first days of an
episode of AP and biliary etiology were
described more than 30 years ago [9]. Since
then, different studies intended to design an
easy-to-use, reliable and cheap method of
identifying the biliary origin of episodes of
AP confirmed that these episodes showed
levels of AST, ALT, alkaline phosphatase and
total bilirubin statistically significantly higher
than episodes of AP of a non-biliary origin
[10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20].
These studies were included in a meta-
analysis [21] which showed that
transaminsases are more useful in detecting
the biliary origin of AP than the other
parameters reported. According to this
research, values of transaminases 3 times the
upper normal limit show a positive predictive
value of 95% for the diagnosis of biliary-
induced AP. Similarly, in order to design a
multifactorial predictive system, we have
investigated the behavior of different
biochemical parameters in a series of 45 cases
of AP (33 of biliary origin and 12 of alcoholic
origin) [22]. The logistic regression analysis
performed based on 4 variables (age, sex, C-
reactive protein on day 1 and ALT on day 2)
accurately predicted the etiology in 97.7% of
all cases (44 out of 45 cases), and estimated
the likelihood of biliary origin by the
application of a mathematical formula.
Thereafter, the introduction of new diagnostic
tools raised doubt as to the usefulness of liver
function tests in predicting the biliary origin
of AP. A seminal study from Ros et al. [23] in
a series of 51 patients with “idiopathic” AP
reported that age, previous repetitive episodes
of AP and abnormal liver function tests were
significantly related to the presence of biliary
microlithiasis. Grau et al. [24] obtained
similar results by examining the bile from 91
patients with “idiopathic” AP. ALT analyzed
in the first 24 hours after admission (cut-off
equal to 1.2 times the upper normal limit)
showed a sensitivity of 73%, a specificity of
86% and a PPV of 92% in predicting the
presence of microlithiasis.
Recently, endoscopic ultrasound (EUS) has
become the most accurate technique for
detecting chole- and choledocolithiasis [25].
Hence, several authors have re-evaluated the
role of biochemical abnormalities for
predicting a biliary etiology in episodes of
AP. Ammori et al. [26] reported a sensitivity,
specificity, PPV and NPV for liver function
tests of 91, 100, 100 and 85%, respectively.
When combining this evaluation with EUS,
these values reached 98, 100, 100 and 96%
respectively. Two similar studies published
recently reached similar conclusions. Liu et
al. [27] (Hong Kong) performed EUS in a
series of 139 patients with AP in the first 24
hours after admission and identified the
etiology in all cases. Therefore, the sensitivity
of EUS for identifying the biliary origin of
AP was 100%. Multivariate analysis disclosed
that female sex, age over 58 years, and ALT
greater than 150 U/L became independent
predictors of biliary origin. With these three
factors, the sensitivity was 93% and overall
accuracy was 80%. Similar results were
obtained by Levy et al. [28] in a multicenter
study performed in France and Switzerland.
Patients who had a normal abdominal
ultrasound underwent EUS. Using this
diagnostic approach only 14 patients (7%)
remained in the group of “idiopathic” AP.
Again, female sex, increased age and
increased ALT levels at admission were
considered independent predictive variables
of biliary origin in the multivariate analysis.
The likelihood of biliary origin might be
estimated with the formula 1 / (1+exp(4.6967

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JOP. Journal of the Pancreas - - Vol. 7, No. 3 - May 2006. [ISSN 1590-8577]
- 0.0656 x age [years] - 0.6909 x ALT [times
of the upper limit of the reference range] +
1.1208 x sex [1 for men, 0 for women]).
Information obtained from recent studies
reinforces the idea that early determination of
liver function tests still constitutes a valid
method for predicting the biliary origin of AP.
Traditionally, certain biochemical parameters
such as GGT and MCV have been considered
in identifying alcoholic etiology of AP
episodes. However, it has been shown that
these parameters are not useful in
distinguishing AP episodes of alcoholic origin
from those of other origins [29]. Other studies
reported that an increased lipase/amylase ratio
is characteristic of AP episodes of alcoholic
origin. Gumaste et al. [30] reported that the
lipase/amylase ratio has a sensitivity of 91%
for detecting the alcoholic origin of AP. In the
study by Tenner and Steinberg [31], only
alcohol-induced AP showed a lipase/amylase
ratio higher than 5 (specificity of 100%,
although with a low sensitivity of 31%).
However, other investigations reported that
the ratio quoted was not useful in
differentiating alcoholic from non-alcoholic
AP [13, 29, 32, 33]. It has also been reported
that both an increase in the plasmatic activity
of trypsin [33] or a trypsin-2-alpha1-
antitrypsin/trypsinogen-1 ratio [34] correctly
identified an alcoholic origin. Our group
reported that levels of serum trypsin activity
are significantly higher in patients with
episodes of AP of alcoholic origin when
compared with episodes of other etiologies
The measurement of carbohydrate-deficient
transferrin (CDT) may detect an excessive
consumption of alcohol [36] and it has been
used to detect the alcoholic origin of AP.
Jaakola et al. [29] showed that levels of CDT
higher than 17 U/L show a 27% sensitivity
and 100% specificity in the detection of an
alcoholic origin. Our group reported similar
results in a group of 70 patients with AP [35].
Furthermore, multivariate analysis of all the
parameters evaluated in this investigation, age
less than 44 years, plasma CDT greater than
22.5 U/L and trypsin activity greater than 152
U/L correctly identified the alcoholic origin in
98% of the episodes; these results are similar
to data published elsewhere [37].
In summary, by means of simple biochemical
studies, it is possible to correctly predict the
biliary or alcoholic origin of AP episodes in
approximately 80% of cases when performed
in the first hours after admission. However, a
biliary origin needs to be confirmed with
imaging techniques before considering any
specific form of therapy. The negativity of
these markers should suggest investigating
other possible etiologic factors with specific
analytical or morphological tests.
Alcoholism; carbohydrate-
Diagnosis; Liver Function Tests; Pancreatitis,
Acute Necrotizing /etiology
Abbreviations AP: acute pancreatitis; CDT:
carbohydrate-deficient transferrin
Miguel Pérez-Mateo
Department of Internal Medicine
Hospital General Universitario de Alicante
c/ Pintor Baeza 12
03010 Alicante
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