Admission Visfatin Levels Predict Pancreatic and
Peripancreatic Necrosis in Acute Pancreatitis and
Correlate With Clinical Severity
Andreas Schäffler, MD1, Okka-Wilkea Hamer, MD2, Judith Dickopf, MD1, Andrea Goetz, MD1, Karin Landfried, MD1, Markus Voelk, MD2,
Hans Herfarth, MD3, Andrea Kopp, PhD1, Christa Buechler, PhD1, Jürgen Schölmerich, MD1 and Tanja Brünnler, MD1
OBJECTIVES:
Adipocytes of peripancreatic and intrapancreatic adipose tissue secret adipocytokines such as leptin,
adiponectin, and resistin. For resistin, a role as an early predictor of peripancreatic necrosis and
clinical severity in acute pancreatitis has been reported. It was the aim of this study to investigate
whether the adipocytokine visfatin is able to serve as an early marker predicting peripancreatic
necrosis and clinical severity.
METHODS:
A total of 50 patients (20 females and 30 males) with acute pancreatitis were included in this
noninterventional, prospective, and monocentric cohort study on diagnostic accuracy. Clinical
severity was classified by the Ranson score and APACHE-II (Acute Physiology and Chronic Health
Evaluation II) score. Pancreatic and peripancreatic necrosis were quantified by the computed
tomography-based Balthazar score, the Schroeder score, and the pancreatic necrosis score. Visfatin
was measured at admission and daily for 10 days by enzyme-linked immunosorbent assay (ELISA).
RESULTS:
Visfatin values were significantly and positively correlated with clinical severity (APACHE-II score
and Ranson score) and with clinical end points such as death and need for interventions. Admission
visfatin levels were significantly elevated in patients with higher pancreatic and extrapancreatic
necrosis scores. It was shown by receiver operator characteristics that admission visfatin concentration provides a positive predictive value of 93.3% in predicting the extent of peripancreatic necrosis
(area under the curve (AUC): 0.89, P < 0.001, sensitivity: 93.3%, specificity: 81.8%, likelihood
ratio: 5.1, post-test probability: 93%) by using a cutoff value of 1.8 ng/ml.
CONCLUSIONS: Admission visfatin concentration serves as an early predictive marker of peripancreatic necrosis
and clinical severity in acute pancreatitis. Visfatin may have potential for clinical use as a new and
diagnostic serum marker.
Am J Gastroenterol 2011; 106:957–967; doi:10.1038/ajg.2010.503; published online 18 January 2011
INTRODUCTION
Systemic inflammatory response syndrome, multiorgan dysfunction syndrome, and sepsis represent the major causes of
morbidity and mortality in acute necrotizing pancreatitis (1–4).
These complications are caused by local complications such as
pancreatic necrosis, peripancreatic fat cell necrosis, local infection of necrosis or pseudocysts, abscess, and intraabdominal
bleeding. Local and systemic activation and release of a wide
variety of cytokines and chemokines promote systemic inflammatory response syndrome and also cause metabolic changes
such as hyperglycemia, insulin resistance, and elevated levels
of triglycerides and free fatty acids. Importantly, all major
complications of acute pancreatitis are more common and more
severe in obese patients (5). There is a considerable interest in
the early prediction of clinical severity and disease course, both
of them being influenced by the extent of necrosis (6,7). Scoring
systems including therapy-associated and patient-related factors
based on anthropometric, clinical, biochemical, and physiological
markers have been developed such as the APACHE-II (Acute
Physiology and Chronic Health Evaluation II) score (8,9), the
APACHE-O score (10), and the Ranson score (11). In order to
describe the extent of pancreatic and extrapancreatic necrosis
1
Department of Internal Medicine I, University Medical Center, Regensburg, Germany; 2Department of Radiology, University Medical Center, Regensburg,
Germany; 3Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA.
Correspondence: Andreas Schäffler, MD, Department of Internal Medicine I, University Medical Center, Regensburg, D-93042, Germany.
E-mail: [email protected]
Received 23 September 2010; accepted 7 December 2010
© 2011 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
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PANCREAS AND BILIARY TRACT
ORIGINAL CONTRIBUTIONS
nature publishing group
PANCREAS AND BILIARY TRACT
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Schäffler et al.
(peripancreatic fat cell necrosis), computed tomography (CT)based scoring systems such as the Schroeder score (12,13), the
pancreatic necrosis score (13), and the Balthazar score (13–16) have
been developed. Markers for trypsinogen activation (6,17–19),
proinflammatory cytokines (6,20) such as interleukin (IL)-10 (21),
IL-8 (22), or IL-6 (21,23), and standard biochemical parameters
such as glucose (21), calcium (21), C-reactive protein (CRP)
(24,25), or hematocrit (26) reflect disease activity and severity to
some degree along with the clinical time course. However, none
of them is suitable to predict both clinical severity and the extent
of peripancreatic and pancreatic necrosis by using only one single
serum sample at the time point of admission to the hospital. This
is obviously because of the fact that none of these parameters
specifically detects peripancreatic necrosis, which is the main
factor for mortality and morbidity (27). Based on these considerations, a marker specifically detecting peripancreatic inflammation and necrosis would bear a significant potential to serve as
an early prediction marker.
In acute necrotizing pancreatitis, release of pancreatic
lipase causes digestion of peripancreatic adipose tissue (28,29),
which becomes infiltrated by activated immune cells such as
lymphocytes, neutrophils, and monocytes (inflamed and necrotic
adipose tissue). Adipocytes synthesize and secrete adiposespecific proteins, the so-called adipocytokines (28,30–32). Several
of these adipocytokines are discussed to have an important role
in gastrointestinal diseases (28,29). Importantly, adipocytokines
(28) such as adiponectin (33), leptin (34), and resistin (35) have
potent immunomodulatory (30,36,37) and metabolic activities,
and the metabolic and proinflammatory changes seen in acute
pancreatitis might be—at least in part—caused by local release of
these proteins (29). A preliminary pilot study on 23 patients published in 2007 (38,39) and a subsequent follow-up study on a total
of 50 patients published in 2010 (40) demonstrated for the first
time that the adipocytokine resistin has the potential to serve as
an early predictor of peripancreatic necrosis, clinical severity, and
clinical end points. In contrast, the adipocytokines leptin and adiponectin failed to serve as reliable and early clinical predictors.
During the last 5 years, novel adipocytokines such as visfatin
(41) have been identified and partially characterized. Visfatin
is also named PBEF-1 (pre-B-cell colony-enhancing factor-1)
or NAMPT (nicotinamide phosphoribosyltransferase) and it is
expressed in not only adipocytes and visceral adipose tissue (42),
but also in activated lymphocytes (43) and neutrophils (44).
Visfatin is also expressed in neutrophils of patients with sepsis and
acts as an inflammatory cytokine (45) having a role in the delayed
neutrophil apoptosis of sepsis (44).
As visfatin can be regarded as a proinflammatory and immunomodulating adipocytokine (46), it could potentially serve as a
marker for adipocyte necrosis and local activation of immune
cells within the necrotic viseral adipose tissue. Thus, visfatin might
be promising in detecting early inflammation and necrosis of
peripancreatic adipose tissue.
It is the primary hypothesis that serum visfatin measured on the
day of admission is able to predict the occurrence of peripancreatic necrosis by identifying patients who will develop a CT-based
The American Journal of GASTROENTEROLOGY
Schroeder score > 3 with a sensitivity of at least 80% and a positive
predictive value (PPV) of at least 85%. A noninterventional, diagnostic, prospective, and monocentric cohort study design was used.
Furthermore, it was our aim
•
•
•
to evaluate the potential of visfatin as an early (admission)
and specific marker for predicting the extent of peripancreatic
necrosis (Schroeder score and Balthazar score) and pancreatic
necrosis (pancreatic necrosis score);
to investigate the potential of visfatin as an early (admission)
marker for predicting clinical severity (Ranson score and
APACHE-II score) and clinical end points (death, need for
interventions); and
to analyze by receiver operator characteristics whether
visfatin is suitable to serve as predictive markers for clinical
use, that is, calculating cutoff values, area under the curve
(AUC), PPV, likelihood ratio, post-test probability, sensitivity,
and specificity (diagnostic accuracy/feasibility study).
Study design, setting, and patients
In order to test the hypothesis, a noninterventional, prospective,
and monocentric cohort study design was chosen (diagnostic
accuracy study). The design and conduction of this study on diagnostic accuracy were based on the STARD (standards for reporting
of diagnostic accuracy) recommendations published in 2003 (47).
A total of 50 patients with acute pancreatitis, who were admitted
to the University Hospital of Regensburg, Germany, over a 5-year
period from August 2002 until August 2007 were prospectively
enrolled in the study. The University Hospital of Regensburg is the
only tertiary referral center for a large geographic region. Thus,
relatively more patients with a severe disease course might be
admitted. All patients gave informed consent. The study was conducted according to the Declaration of Helsinki and was approved
by the local ethics committee. In total, 309 patients suffering from
acute pancreatitis were treated during the study period and were
screened for meeting the inclusion/exclusion criteria (Figure 1).
Patients with an acute episode of pancreatitis at the time of enrollment but a history of chronic pancreatitis (n = 59) were excluded.
Moreover, patients with former episodes of idiopathic pancreatitis
were excluded. Patients admitted from other hospitals suffering
from acute pancreatitis with a history of abdominal pain for more
than 3 days were excluded (n = 105). However, because of the
fact that the present study center represents a university hospital
center, many patients were treated in community-based hospitals
before admission. These patients usually had symptoms for longer
than 3 days. As it was the aim of this study to evaluate the potential role of adipokines as very early prediction markers, patients
with a longer history of acute pancreatitis were not suitable candidates for proving or discharging our hypothesis. Additional
exclusion criteria were: unknown cause of pancreatitis (n = 8), not
consenting to participate in the study (n = 82), and age < 18 or
> 85 years (n = 5). The number of patients not consenting seems
to be high; however, most of them refused to undergo daily blood
sampling over 10 days. Moreover, severely ill patients could only
be included if informed consent was given by relatives.
VOLUME 106 | MAY 2011 www.amjgastro.com
The diagnosis of acute pancreatitis was based on clinical, laboratory, and radiological findings during CT and/or ultrasound examination. In all, 41 patients suffering from severe pancreatitis had a
CT scan, whereas 9 patients with clinically mild pancreatitis underwent ultrasound examination instead. The etiology of acute pancreatitis was biliary in 40%, alcohol-induced in 26%, metabolic in 12%,
post-endoscopic retrograde cholangio-pancreaticography (ERCP)
in 14%, and toxic in 8% of all cases. All post-ERCP patients had a
CT scan and their mean scores were 1.9 points for the pancreatic
necrosis score and 3.7 points for the Schroeder score. The relatively
high rate of necrosis in post-ERCP patients might be caused by a
“referral bias,” as mild courses of post-ERCP pancreatitis were usually treated in community-based hospitals. The high incidence of
biliary pancreatitis (40%) might be because of a relatively old (mean
age: 57.9 years, range 23–83 years) and obese (mean body mass
index: 29.9 kg/m2, range 17.4–58.8 kg/m2) study cohort (Table 1a).
METHODS
Radiological and CT-based scoring systems
A total of 41 patients underwent contrast-enhanced CT examination (multislice helical CT; Siemens Sensation 16, Erlangen,
Germany) within 48–72 h of admission. CT scans were interpreted
retrospectively regarding the extent of extra- and intrapancreatic
disease and the presence of pancreatic and extrapancreatic necrosis. If patients underwent multiple CT examinations, all CTs were
evaluated and the most severe score was used for statistical analysis.
These evaluations were performed by one of two teams (M.V., H.H.
or O.H., A.S., respectively), each of them consisting of a radiologist
(M.V. and O.H.) and an internal medicine specialist. The investigators classified the CT examinations in consensus and they were
blinded to the patients’ history, clinical and laboratory findings,
and clinical outcome. The following scores were determined (17):
Balthazar score:
A to E (scores A to E were
classified as 1–5 points, max.
score: 5).
Extrapancreatic Schroeder score:
1–7 points, max. score: 7.
Pancreatic necrosis score:
(modified Balthazar score) 1–4
points, max. score: 4 (no necrosis: 0 points, necrosis < 30%:
1 point, necrosis 30–50%:
2 points, necrosis > 50%: 3
points, total necrosis: 4 points).
Table 1a. Overall characteristics of the study population
n (%)
50 (100%)
Females, n (%)
20 (40%)
Males, n (%)
30 (60%)
Age, years (mean±s.d.; range)
57.9 ± 16.2; 23 – 83
BMI, kg/m2 (mean±s.d.; range)
29.9±7.8; 17.4 – 58.8
Visfatin, ng/ml
309 Patients were screened
between 2002 and 2007
Day 1 of admission: mean±s.d.; range
4.9 ± 7.1; 0.2 – 46.7
Day 10 mean±s.d.; range
4.3 ± 6.1; 0.1 – 92.0
Pathogenesis (n=50)
259 Patients were excluded:
105 Patients with symptoms > 3 days
82 Patients refused to participate
59 Patients with a history of chronic pancreatitis
8 Patients with unknown cause of pancreatitis
5 Patients with age < 18 or > 85 years
50 Patients were included
(20 females, 30 males)
Clinical scoring:
- APACHE-II score
- Ranson score
- interventions
- time until discharge
- 3-month survival
Gallstones, n (%)
20 (40%)
Alcohol, n (%)
13 (26%)
Metabolic, n (%)
6 (12%)
ERCP, n (%)
7 (14%)
Toxic, n (%)
4 (8%)
CT scoring (n = 41)
Balthazar score (median; range)
4.0 (1–5)
Schroeder score (median; range)
4.5 (1–7)
Necrosis score (median; range)
1.5 (1–4)
Clinical scoring (n = 50)
Measurement of serum visfatin:
Lethality, n (%)
6 (12%)
APACHE-II score (median; range)
12; 0–45
ELISA
Ranson score (median; range)
41 Patients received CT
9 Patients received no CT
(mild course)
3; 0–8
Interventions (n=50)
Laparotomy and/or CT-guided drainage, n (%)
8 (16%)
Dialysis, n (%)
3 (6%)
Mechanical ventilation, n (%)
8 (16%)
CT-based radiological scoring:
- Schroeder score
- Balthazar score
- Pancreatic necrosis score
Figure 1. Study design and inclusion of patients. APACHE-II, Acute
Physiology and Chronic Health Evaluation II; CT, computed tomography;
ELISA, enzyme-linked immunosorbent assay.
© 2011 by the American College of Gastroenterology
Time until discharge/death: days (mean + s.d.; range)
25.7±29.6; (2–176)
APACHE-II, Acute Physiology and Chronic Health Evaluation II; BMI, body mass
index; CT, computed tomography.
The American Journal of GASTROENTEROLOGY
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Visfatin Predicts Peripancreatic Necrosis
960
Schäffler et al.
Table 1b. Clinical and radiological characteristics of the study population
PANCREAS AND BILIARY TRACT
Number
Age
Sex
BMI
CT
Balthazar
Schroeder
Necrosis
Ranson
APACHE-II
Pathogenesis
1
69
Male
24.8
Yes
1
1
1
3
16
ERCP
2
23
Male
20.8
Yes
5
4
2
1
8
Toxic
3
34
Male
32.7
Yes
5
6
4
7
37
Alcohol
4
77
Female
25.6
Yes
5
6
4
4
13
Toxic
5
70
Female
30.9
Yes
5
5
3
3
10
Gallstones
6
41
Female
33.1
Yes
3
6
1
5
15
ERCP
7
69
Female
27.5
Yes
4
5
2
4
12
Gallstones
8
68
Female
25.7
Yes
5
7
4
3
14
Gallstones
9
77
Male
29.4
Yes
4
3
1
5
8
Gallstones
10
74
Male
25.6
Yes
5
4
3
2
17
Metabolic
11
43
Female
25.0
Yes
5
5
3
2
9
Alcohol
Alcohol
12
29
Male
24.5
Yes
3
2
1
0
4
13
28
Female
34.2
Yes
5
6
4
4
10
Metabolic
14
64
Male
33.3
Yes
3
4
3
3
10
Alcohol
15
56
Female
58.8
Yes
3
5
1
6
20
Gallstones
16
72
Female
42.5
Yes
3
2
1
3
21
Gallstones
17
62
Female
28.3
Yes
3
6
1
4
10
Gallstones
18
31
Male
40.2
Yes
4
3
2
4
12
Metabolic
19
79
Male
37.4
Yes
3
4
1
3
21
Gallstones
20
64
Female
35.4
Yes
5
6
4
5
13
ERCP
21
82
Male
25.9
No
—
—
—
4
5
Gallstones
22
53
Male
25.4
No
—
—
—
1
5
Gallstones
23
63
Male
25.6
No
—
—
—
1
7
Gallstones
24
52
Male
23.6
Yes
1
2
1
0
12
Gallstones
25
37
Male
26.2
Yes
5
6
4
3
25
Alcohol
26
50
Male
51.7
Yes
5
6
4
8
43
Metabolic
27
39
Male
29.4
Yes
5
0
3
0
3
28
83
Female
32.1
Yes
1
0
1
2
15
29
50
Male
30.9
No
—
—
—
1
4
Death
+
+
+
Alcohol
Gallstones
Alcohol
30
67
Male
27.1
No
—
—
—
2
13
Gallstones
31
65
Male
19.4
Yes
5
7
2
2
12
Toxic
32
78
Male
27.8
Yes
5
6
2
4
8
+
Metabolic
33
69
Male
25.9
No
—
—
—
4
10
34
67
Female
17.4
Yes
1
0
1
1
7
ERCP
Gallstones
35
30
Female
31.9
No
—
—
—
0
0
Toxic
36
38
Male
22.1
Yes
5
5
2
2
4
Metabolic
37
63
Female
28.3
Yes
4
4
3
3
14
Gallstones
38
48
Female
24.4
Yes
5
6
1
2
28
Gallstones
39
74
Female
41.6
Yes
5
6
4
7
45
40
56
Male
26.4
Yes
5
6
2
4
4
Alcohol
Gallstones
41
45
Male
28.1
Yes
1
0
1
0
9
Gallstones
42
75
Male
27.7
Yes
5
6
2
1
14
+
ERCP
Continued on following page
The American Journal of GASTROENTEROLOGY
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Visfatin Predicts Peripancreatic Necrosis
961
Number
Age
Sex
BMI
CT
Balthazar
Schroeder
Necrosis
Ranson
APACHE-II
Pathogenesis
43
51
Female
22.5
Yes
5
7
2
4
26
Alcohol
44
66
Male
46.0
No
—
—
—
1
13
Gallstones
45
53
Male
29.7
Yes
1
0
1
1
14
ERCP
46
75
Male
27.7
Yes
5
7
3
4
26
ERCP
47
60
Female
25.8
No
—
—
—
1
10
Alcohol
48
67
Male
34.7
Yes
4
5
1
1
5
Alcohol
49
68
Male
27.8
Yes
3
1
1
1
7
Alcohol
50
42
Male
27.7
Yes
5
7
4
8
37
Alcohol
Death
+
APACHE-II, Acute Physiology and Chronic Health Evaluation II; BMI, body mass index; CT, computed tomography.
The Schroeder score classifies seven characteristics such as
ascites, bowel distension, pleural effusion and edema of peripancreatic tissue, and of mesenteric and perirenal adipose tissue. Although the Schroeder score might be unfamiliar to the
US-based physicians, some of the parameters, such as edema of
peripancreatic tissue, reflect the involvement of peripancreatic
adipose tissue and thus is of interest in this pilot study on adipokines.
The pancreatic necrosis score classifies the extent of pancreatic necrosis, giving the percentage of the necrosis of the pancreas. The Balthazar score classifies the inflammatory changes of
pancreatic and peripancreatic soft tissue together with peritoneal
and mesenteric effusions. Thus, the Schroeder score and the
Balthazar score are the most suitable parameters for the evaluation of peripancreatic necrosis and inflammation, whereas the
pancreatic necrosis score strictly classifies necrosis of the pancreatic gland.
Subsequently, individual CT scores were subdivided in two
groups with either lower (Balthazar score A–C: 1–3 points;
Schroeder score: 1–3 points; pancreatic necrosis score: 1–2) or
higher scores (Balthazar score: D, E: 4–5 points; Schroeder score:
4–7 points; pancreatic necrosis score: 3–4 points), reflecting
moderate vs. extensive CT abnormalities. Of the patients, nine
had a mild clinical course and were examined by ultrasonography but not by CT scan. These nine patients were evaluated
separately.
Clinical scoring systems
In order to calculate clinical scores (Ranson score and
APACHE-II score), hospital records and relevant clinical and
laboratory data were documented daily. The highest score within
the period of hospitalization was chosen for further analysis, as
it was the aim to predict the most severe situation during the
course of the disease, even if clinical deterioration occurred late
after admission. The use of the Ranson score might be recognized
as outdated in normal clinical routine work. However, in pilot
studies, the analysis of multiple scores might be helpful in detecting single parameters that correlate with adipokine levels.
© 2011 by the American College of Gastroenterology
Measurement of visfatin serum concentrations
Serum samples were obtained at the day of admission from all
patients. Moreover, serum samples were obtained daily from
those patients with a stay shorter than 10 days or daily for the
first 10 days from those with a stay longer than 10 days. Visfatin
concentrations were measured in duplicate by enzyme-linked
immunosorbent assay (ELISA). Visfatin serum concentrations
were measured using the human visfatin ELISA kit (AdipoGen,
Seoul, Korea; sensitivity: 30 pg/ml; intra-assay coefficient of
variation: < 10%, and interassay coefficient of variation: < 8%).
Statistics
For statistical analysis, the SPSS/PC + statistical software package
was used (SPSS 15.0, Chicago, IL). Subjects were compared
regarding differences in anthropometric and biochemical data
using either Student’s t-test or Mann–Whitney U-test. The Mann–
Whitney U-test was used for nonparametric variables that underlie a non-Gaussian distribution, whereas the t-test was used for
variables characterized by a Gaussian normal distribution. For
correlation analysis, the two-tailed Spearman’s test was used.
The Pearson’s χ2 test was used for associations between classified variables. If necessary, Bonferroni correction was applied for
analysis of subgroups. Anthropometric and laboratory data were
expressed as means±s.d. Score-based classifications are given as
median and range. A P value < 0.05 (two tailed) was considered to
be statistically significant. For calculation of cutoff values, PPVs,
AUC, sensitivity, and specificity, receiver operator characteristics
analysis was performed.
RESULTS
Patient characteristics
The characteristics of the entire study population are summarized
in Tables 1a and b. In all, 20 females (40%) and 30 males (60%)
were included in the study.
The mean age was 57.9±16.2 years (range 23–83 years) and
the mean body mass index was 29.9±7.8 kg/m2 (range 17.4–
58.8 kg/m2). Mean visfatin concentrations showed a broad range
The American Journal of GASTROENTEROLOGY
PANCREAS AND BILIARY TRACT
Table 1b. Continued
Schäffler et al.
with significant interindividual variations and were 4.9±7.1 ng/ml
for the day of admittance (range 0.2–46.7 ng/ml) and 4.3±6.1 ng/ml
(range 0.1 + 92.0 ng/ml) for the mean value at day 10. Visfatin was
not correlated with body mass index, and CRP levels and mean
values were not different between females and males.
Classification of clinical severity by scoring systems, outcome
parameters, and need for interventions
Regarding clinical severity (Tables 1a and b), the median
APACHE-II score was 12 points and the median Ranson score
was 3 points. Six patients (12%) died. Eight patients (21.7%)
underwent laparotomy and/or CT-guided drainage, three patients
were on dialysis, and eight patients on mechanical ventilation.
The mean time until discharge from hospital or until death was
25.7±29.6 days (range 2–176 days). In order to test for a possible
correlation of admission adipocytokine values with clinical scoring systems, regression analysis was performed (Figure 2a and b).
There was a positive (r = 0.52) and significant (P < 0.001)
correlation of admission visfatin levels with the Ranson score
(Figure 2a). Moreover, we found a positive and significant
(P < 0.001) correlation of admission visfatin levels with the
APACHE-II score (Figure 2b). However, this correlation was weak
with a correlation coefficient of r = 0.48.
In order to test for associations of mean visfatin levels with radiological scoring systems (Table 2a) in more detail, patients were
subdivided into two groups regarding each score: Schroeder score
≤3 and Schroeder score > 3 (Table 2a-I); necrosis score 1–2 and
necrosis score 3–4 (Table 2a-II); Balthazar score 1–3 and Balthazar score 4–5 (Table 2a-III). The patients with mild pancreatitis
who had no CT were evaluated as a separate group (Table 2a). This
subgroup analysis reflects the radiological severity and the extent
of pancreatic and peripancreatic necrosis in our patients and represents the basis for detailed statistical analysis in the search of a
predictive marker.
Admission visfatin values and Schroeder score
Mean admission visfatin values were significantly (P < 0.001)
higher in patients with a Schroeder score > 3 (6.7±8.6 ng/ml) when
compared with patients with a Schroeder score ≤3 (1.5±1.2 ng/ml)
(Table 2a-I). Patients with mild pancreatitis also had a trend
toward lower visfatin levels (3.3±1.5 ng/ml) when compared
with patients with a high Schroeder score; however, this trend
was statistically not significant. Admission CRP values were
not different in Schroeder score subgroups (Schroeder score
≤3 vs. > Schroeder score > 3: 127.6±29.3 vs. 176.4±16.1 mg/dl,
P = 0.1). CRP levels after 48 h of admission were not significantly
different in these subgroups.
Radiological classification of pancreatic and peripancreatic
necrosis by CT-based scoring systems
Admission visfatin values and pancreatic necrosis score
Patients receiving a CT scan (n = 41) had a median Balthazar score
of 4.0 points (stage D), a median Schroeder score of 4.5, and a
median pancreatic necrosis score of 1.5 (Table 1a). Also, nine
patients did not receive a CT scan because of a mild course of
pancreatitis. General correlation analysis (Pearson’s test) without
subgroup analysis demonstrated that day 1 visfatin values were
significantly and positively correlated with the Schroeder score
(P = 0.028; r = 0.31) and the pancreatic necrosis score (P = 0.002;
r = 0.43), whereas the positive correlation with the Balthazar score
was not significant (P = 0.054; r = 0.27).
Mean admission visfatin values were significantly (P = 0.003)
higher in patients with a pancreatic necrosis score of 3–4
(8.7±11.2 ng/ml) when compared with patients with a lower score
(3.1±3.0 ng/ml) (Table 2a-II). Similarly, patients suffering from
a mild pancreatitis also had lower visfatin levels (3.3±1.5 ng/ml)
when compared with patients with a higher necrosis score.
However, this trend was statistically not significant, probably
because of the size of the subgroup. Admission CRP values
were not different in pancreatic necrosis score subgroups (lower
score vs. higher score: 192.3±35.4 vs. 181.5±26.7 mg/dl, P = 0.1).
a
55
b
r = 0.52
P < 0.001
n = 50
50
45
55
r = 0.48
P < 0.001
n = 50
50
45
40
40
Visfatin (ng/ml)
Visfatin (ng/ml)
PANCREAS AND BILIARY TRACT
962
35
30
25
20
35
30
25
20
15
15
10
10
5
5
0
0
0
1
2
3
4
5
Ranson score
6
7
8
0
5
10 15 20 25 30 35 40 45 50
APACHE-II score
Figure 2. Visfatin levels and clinical severity scores. (a) Correlation of serum visfatin levels (day of admittance) with the Ranson score (n = 50).
(b) Correlation of serum visfatin levels (day of admittance) with the APACHE-II (Acute Physiology and Chronic Health Evaluation II) score (n = 50).
The American Journal of GASTROENTEROLOGY
VOLUME 106 | MAY 2011 www.amjgastro.com
Figure 3a and b and in Table 2b. As depicted in Figures 3a and
Figure 3b and summarized in Table 2b, visfatin is able to serve
as a positive predictive marker for the identification of patients
with a Schroeder score > 3. By plotting sensitivity against (1-specificity), an AUC of 0.89 (Figure 3a) was calculated, providing a
highly significant value (P < 0.001). In contrast, admission CRP
concentration had only an AUC of 0.7 in predicting a Schroeder
score > 3.
Furthermore, statistical analysis of admission visfatin concentrations demonstrated that a cutoff value of > 1.8 ng/ml can provide a PPV of 93.3% in predicting a Schroeder score > 3, with a
specificity of 81.8% and a sensitivity of 93.3% (Table 2b). These
results are depicted as a scattered plot in Figure 3b. The likelihood
ratio (sensitivity/1-specificity) was calculated to be 5.1 (Table 2b).
As 60% of our patients had a Schroeder score > 3, the pretest
probability for having a Schroeder score > 3 was 0.6. The post-test
probability was calculated to be 0.93.
Furthermore, when using the cutoff value of > 1.8 ng/ml,
admission visfatin concentration also served as a significant
positive predictor of a Balthazar score > 3 and a necrosis score > 2,
but with much lower AUCs, sensitivities, specificities, and PPVs
(Table 2b).
CRP levels after 48 h of admission were not significantly different
in these subgroups.
Admission visfatin values and Balthazar score
Patients having a higher Balthazar score of 4–5 had significantly
(P = 0.01) higher (6.9±9.1 ng/ml) visfatin values when compared
with patients with a lower score (2.3±1.5 ng/ml) (Table 2a-III).
Similarly, patients suffering from a mild pancreatitis had also
lower visfatin levels (3.2±1.5 ng/ml) when compared with patients
with a higher Balthazar score. However, this trend was statistically not significant, probably because of the size of the subgroup.
Admission CRP values were not different in Balthazar subgroups
(Balthazar score ≤3 vs. > Balthazar score 4–5: 148.2±26.2 vs.
169.6±17.3 mg/dl, P = 0.1). CRP levels after 48 h of admission were
not significantly different in these subgroups.
Calculation of cutoff values for visfatin in the prediction of
pancreatic and extrapancreatic necrosis
In order to test the hypothesis that admission visfatin has
the potential to serve as a marker in predicting the extent of
pancreatic and extrapancreatic necrosis, a receiver operator
characteristics analysis was performed. The results are given in
Table 2a. Admission visfatin levels (n=50) in 41 patients with acute necrotizing pancreatitis and 9 patients with mild pancreatitis
(no CT examination): (I) visfatin levels and Schroeder score subgroups; (II) visfatin levels and pancreatic necrosis score subgroups;
(III) visfatin levels and Balthazar score subgroups
(I)
Schroeder score: ≤3
(n=11)
Schroeder score: > 3
(n=30)
Significance
P
Mild pancreatitis
(n=9)
Significance
P
1.5 ± 1.2
6.7 ± 8.6
P < 0.001a
3.3 ±1.5
NS
Necrosis score: 1–2
(n =14)
Necrosis score: 3–4
(n =27)
Significance
P
Mild pancreatitis
(n =9)
Significance
P
3.1 ± 3.0
8.7 ± 11.2
P = 0.003a
3.3 ± 1.5
NS
Balthazar score: 1–3
(n =25)
Balthazar score: 4–5
(n =16)
Significance
P
Mild pancreatitis
(n =9)
Significance
P
2.3 ± 1.5
6.9 ± 9.1
P = 0.01a
3.2 ±1.5
NS
Visfatin, ng/ml (mean ± s.d.)
(II)
Visfatin, ng/ml (mean±s.d.)
(III)
Visfatin, ng/ml (mean±s.d.)
CT, computed tomography; NS, not significant.
Association with computed tomography-based scoring systems. For statistical analysis, the Mann–Whitney U-test was used.
a
Schroeder score ≤3 vs. Schroeder score > 3.
Table 2b. Sensitivity, specificity, AUC, PPV, likelihood ratio, post-test probability, cutoff levels, and asymptotic significance of visfatin
levels at the day of admission in the prediction of a Schroeder score > 3, a Balthazar score > 3, and a pancreatic necrosis score > 2
Visfatin (at day of
admission)
Sensitivity
Specificity
AUC
Asymptotic
significance
Likelihood
ratio
PPV
Post-test
probability
Cutoff
Schroeder score > 3
93.3%
81.8%
0.89
P < 0.001
5.1
93.3%
93.0%
1.8 ng/mla
Balthazar score > 3
88.9%
57.1%
0.74
P = 0.011
2.1
79.3%
55.0%
b
Necrosis score > 2
93.8%
40.0%
0.77
P = 0.004
1.5
48.3%
70.0%
b
AUC, area under the curve; PPV, positive predictive value.
a
The cutoff value was specifically calculated by receiver operator analysis (ROC).
b
Statistical parameters are also given for a Balthazar score > 3 and a pancreatic necrosis score > 2 when applying the cutoff value calculated specifically for the Schroeder
score (most suitable score for the prediction of extrapancreatic necrosis).
© 2011 by the American College of Gastroenterology
The American Journal of GASTROENTEROLOGY
963
PANCREAS AND BILIARY TRACT
Visfatin Predicts Peripancreatic Necrosis
964
Schäffler et al.
Visfatin values
(mean±s.d.)
Complications
No complications
Death (n =6)
3-month survival
(n =44)
Admission
visfatin (ng/ml)
15.7±16.2
3.5±2.8
P=0.001a
10-day mean
visfatin (ng/ml)
6.5±8.5
3.9±5.6
NS
Interventions
(n = 20)
No interventions
(n = 30)
Admission
visfatin (ng/ml)
6.9±10.5
3.7±3.4
NS (P=0.06)
10-day mean
visfatin (ng/ml)
5.3±5.5
3.6±6.5
P < 0.001b
1.0
0.8
0.6
Significance P
0.4
0.2
0.0
NS, not significant.
Mean values±s.e.m. are shown. Admission visfatin was measured at day 1
(admission to hospital) and repetitively over the first 10 days after admission
(10-day mean resistin). The need for interventions ( > 1 of either mechanical
ventilation, computed tomography (CT)-guided drainage, surgery, or dialysis).
a
Death vs. survival 3 months after onset of disease, calculated for admission
visfatin.
b
Need for interventions (≥1) vs. no need for intervention, calculated for mean
visfatin over 10 days of observation.
Association of visfatin levels with clinical end points
Table 2c summarizes the association of admission and 10-day
mean values of visfatin with 3-month survival and need for interventions. Patients with a lethal outcome within 3 months after
admission had significantly higher (P = 0.001) visfatin levels at
day 1 (admission) when compared with survivors (15.7±16.2 vs.
3.5±2.8 ng/ml). This association was not found when using the
mean level of visfatin at day 10. Patients with the need for ≥1 intervention (mechanical ventilation, dialysis, CT-guided drainage,
surgery) had higher admission values of visfatin when compared
with patients without interventions; however, this trend (P = 0.06)
was not significant. In contrast, when using the mean values
of visfatin at day 10, patients needing interventions had significantly (P < 0.001) higher visfatin levels (5.3±5.5 ng/ml) when compared with those with no need for interventions (3.6±6.5 ng/ml)
(Table 2c).
In contrast, admission CRP concentrations were not significantly different in these subgroups (death vs. 3 month survival:
CRP 203.7±32.6 vs. 133.8±13.7 mg/dl, P = 0.08; interventions vs. no
interventions: CRP 136.1±26.5 vs. 141.5±14.8 mg/dl, P = 0.8).
Detection and measurement of visfatin in intraabdominal fluid
In two patients with a high Schroeder score who underwent
emergency CT-guided drainage, we were able to obtain intraabdominal fluid directly after insertion of the drainage. The visfatin
concentration in these two samples was excessively high (8,918
and 594 ng/ml, respectively) and was only detectable by ELISA
after multiple dilution steps (1:500). These values exceed the
The American Journal of GASTROENTEROLOGY
AUC = 0.89
P < 0.001
0.0
b
Visfatin ng/ml
PANCREAS AND BILIARY TRACT
a
Table 2c. Association of admission values and 10-day
mean values of visfatin with complications (death, need for
interventions) in 50 patients with acute pancreatitis
22
21
20
19
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
Mild pancreatitis
(no CT scan)
0.2
0.4
0.6
0.8
1.0
Cutoff: 1.8 ng/ml
Schroeder score ≤ 3
Schroeder score > 3
Figure 3. Analysis of the predictive value of serum visfatin levels.
(a) Receiver-operator characteristics (ROC) and area under the curve
(AUC) of serum visfatin values (day of admission) in predicting a
Schroeder score > 3. Cutoff value, likelihood ratio, sensitivity, specificity,
positive predictive value (PPV), and post-test probability of visfatin are
given in Table 2. (b) Scattered plot analysis of admission visfatin levels
in three subgroups of patients with acute pancreatitis. Subgroup 1: mild
pancreatitis (no computed tomography (CT) scan available), subgroup 2:
Schroeder score ≤3, subgroup 3: Schroeder score > 3 (n = 49; 1 extreme
value (46.7 ng/ml) was excluded).
highest serum concentration measured in this cohort (92.0 ng/ml)
by a factor of ×97.
Evaluation of the mathematical product (visfatin (ng/ml) ×
resistin (ng/ml))
As we could demonstrate recently in the same study cohort that
the adipocytokine resistin is a highly significant predictive marker
of peripancreatic necrosis and clinical severity, we aimed to calculate whether the mathematical product (visfatin (ng/ml) × resistin (ng/ml)) on the day of admission is superior to visfatin alone
(Table 3). When compared with Table 2c, the visfatin × resistin
product is superior to visfatin alone regarding subgroup analysis for interventions vs. no interventions. Regarding death vs.
3-month survival, the visfatin × resistin product is as significant as
VOLUME 106 | MAY 2011 www.amjgastro.com
Table 3. Subgroup analysis and regression analysis for clinical
severity using the admission visfatin × resistin product
Visfatin × resistin
product
(mean ± s.d.)
Complications
No
complications
Death
(n = 6)
3-month
survival (n = 44)
2,135.1 ± 1,807.9
133.8±223.5
Interventions
(n=20)
No interventions
(n =30)
794.6 ±1,347.8
116.6 ± 228.4
P = 0.002b
Admission visfatin
× resistin product
(ng/ml) with:
Ranson score
r =0.66
P < 0.001
Admission visfatin
× resistin product
(ng/ml) with:
APACHE-II score
r = 0.72
P < 0.001
Subgroup analysis:
Admission visfatin
× resistin product
(ng/ml)
Subgroup analysis:
Admission visfatin
× resistin product
(ng/ml)
Significance
P
P = 0.005a
Regression analysis of
APACHE-II, Acute Physiology and Chronic Health Evaluation II; BMI, body mass
index; CT, computed tomography.
The mathematical product (visfatin (ng/ml) × resistin (ng/ml)) was calculated
for the day of admission. Mean values±s.d. were compared between subgroups
and results of the regression analysis regarding Ranson score and APACHE-II
score are shown.
a
Death vs. survival 3 months after onset of disease, calculated for admission
visfatin × resistin product.
b
Need for interventions (≥1) vs. no need for intervention, calculated for admission visfatin × resistin product.
visfatin alone. Moreover, the visfatin × resistin product is superior
to visfatin alone concerning the regression analysis for Ranson
score and APACHE-II score. Giving identical P values, the visfatin
× resistin product (Table 3 and Figure 2) provides better regression coefficients (r) than visfatin alone (Ranson score: r = 0.66 vs.
0.52; APACHE-II score: r = 0.72 vs. 0.48).
DISCUSSION
All major complications of acute pancreatitis are more common
and more severe in obese patients (5). This raises the question of
how adipocytes interact with the immune response (30,36,37)
to enhance the severity of acute pancreatitis. A recent review
addresses this point and discusses the potential role of adipocytokines in acute pancreatitis (5). Visfatin (41,46) is expressed not
only in adipocytes and in total visceral adipose tissue (42), but
also in activated immune cells such as neutrophils, macrophages,
and lymphocytes (43,44,46). Visfatin activates leukocytes and
induces the production of cytokines such as IL-1β, tumor necrosis factor, and IL-6 (46). Visfatin can therefore be regarded as a
proinflammatory, immunomodulating, and apoptosis-inhibiting
adipocytokine (46). These characteristics of visfatin suggest a
unique potential of this adipokine in detecting the combination
© 2011 by the American College of Gastroenterology
of adipocyte necrosis, adipose tissue inflammation, and adipose
tissue infiltration by activated immune cells. This triad is typical
for lipase-induced peripancreatic necrosis in pancreatitis.
The present data demonstrate
(i) that visfatin levels are highly elevated in patients with
severe pancreatitis when compared with patients with
moderate or mild pancreatitis;
(ii) that visfatin levels are positively correlated with clinical
severity (as determined by Ranson score and—to a lower
extent—by the APACHE-II score) and even with clinical
end points such as death and need for interventions (this
was not the case for admission CRP concentrations); and
(iii) that a single measurement of serum visfatin on the day of
admission is a highly significant and positive predictive
marker in predicting peripancreatic necrosis. A cutoff
value of admission resistin > 1.8 ng/ml predicts high
Schroeder scores ( > 3) during the hospitalization. This
predictive potential was also proved for patients whose
maximum extent of the necrosis developed relatively late
during the time course of the disease.
Admission visfatin levels were superior to admission CRP levels
regarding the correlation with clinical severity and end points. Of
course, it is known from the literature that CRP is more accurate at
48–72 h after admission (6,48). However, this study was conducted
to investigate the significance of early admission markers in acute
pancreatitis.
The present data on visfatin data are in accordance with a recent
Polish study (49) on 32 patients suffering from alcoholic acute
pancreatitis. In those patients, visfatin levels were higher on the day
of admission and on the third day after admission and decreased
on the fifth day after admission. However, no data on the role of
visfatin in clinical end point prediction and on peripancreatic
necrosis were available in this study (49).
Up to now, visfatin has never been measured in the peritoneal
fluid of infected necrosis. Peritoneal fluid visfatin concentrations (obtained directly after insertion of a CT-guided drainage)
were excessively high and ~97-fold higher than the highest serum
concentration. These data support our hypothesis that elevated
serum concentrations of visfatin in acute pancreatitis are caused
by a massive intra-abdominal release of this protein by necrotic
adipocytes and activated immune cells.
However, before introducing visfatin into clinical use, the present
data have to be approved by larger and multicentric clinical studies.
Moreover, there are several limitations of our study. Although the
prerequisite of an acute pancreatitis with a disease course shorter
than 3 days together with the required exclusion criteria severely
limits the number of patients suitable for enrollment, the sample
size is still relatively small. Thus, special care is necessary when
interpreting lack of significance in subgroups. In addition, repeated
analysis of data may increase the risk of type I error.
Although visfatin was measured over the first 10 days after
admission, the significance of day 1 visfatin values proved to be
sufficient and thus provides the practical feasibility necessary in
The American Journal of GASTROENTEROLOGY
965
PANCREAS AND BILIARY TRACT
Visfatin Predicts Peripancreatic Necrosis
PANCREAS AND BILIARY TRACT
966
Schäffler et al.
clinical use. The mean value of visfatin (calculated for each patient
by using the values of the first 10 days after admission) and single visfatin values obtained later than on day 1 were also tested
for their ability to serve as predictors (data not shown). However,
these calculations were not superior to the day 1 admission visfatin value. In contrast, the mathematical visfatin × resistin product calculated on the day of admission provides more statistical
power regarding clinical end points and clinical severity and
should be further evaluated in future studies. The role of resistin
as a suitable and early predictor of clinical end points (need of
interventions, death), clinical severity (determined by scoring
systems), and peripancreatic necrosis (determined by radiological scoring systems) has been reported recently by our group
(40) using the same cohort of patients who were prospectively
enrolled in this study on the role of adipokines. However, at that
time point, reliable and commercial visfatin ELISAs were not
available.
As ELISA-based measurement of serum visfatin concentrations
does only require a small serum sample, and as no complicated
preanalytical procedures are necessary, visfatin fulfils the basic
criteria for a future clinical use. The cost of measuring one single
visfatin serum sample by the ELISA used in this study is 8.7 Euro.
Pancreatic and peripancreatic necrosis is only present in 15–20%
of patients with acute pancreatitis (2,9,11,13), whereas in tertiary referral centers (such as the presenting university hospital)
the incidence rate is higher (60% of our patients had a Schroeder
score > 3). Considering the incidence of necrosis in ~15% of
patients in a community-based setting, a PPV of visfatin ~93.3%
in predicting peripancreatic necrosis would provide a valuable
clinical and prognostic advantage.
The single measurement of serum visfatin at the day of admission provides a positive predictive marker for the prediction of
extrapancreatic findings characteristic for peripancreatic necrosis. In contrast to admission CRP concentrations, high admission visfatin concentrations are positively correlated with clinical
severity and clinical end points. However, these data have to
be approved in larger cohorts and in a multicentric setting.
Moreover, the relevance of visfatin during a longer disease
course and the time between peak visfatin concentration and
clinical or radiological deterioration has to be investigated in
future studies.
ACKNOWLEDGMENTS
The technical work of K. Winkler and C. Lederer is highly appreciated.
CONFLICT OF INTEREST
Guarantor of the article: Andreas Schäffler, MD.
Specific author contributions: Study concept and design, revision,
and drafting the manuscript: Andreas Schäffler, Juergen Schölmerich,
Tanja Brünnler, and Christa Büchler; acquisition of data: Judith
Dickopf, Andrea Goetz, and Karin Landfried; analysis and interpretation of data, and statistical analysis: Hans Herfarth,
Okka Hamer Markus Voelk, Andrea Kopp, and Andreas Schäffler.
Financial support: None.
Potential competing interests: None.
The American Journal of GASTROENTEROLOGY
Study Highlights
WHAT IS CURRENT KNOWLEDGE
3There is no early (time of admission) and predictive marker
in acute pancreatitis predicting peripancreatic necrosis,
clinical severity, and clinical end points such as death and
need for interventions.
3Surrogate parameters such as calcium, C-reactive protein
(CRP), hematocrit, and others are able to resemble clinical
severity to some degree. However, they are not suitable
as early markers indicating the extent of peripancreatic
necrosis and predicting clinical end points.
3Recent studies reported on a potential role of fat cell
proteins (adipocytokines) such as resistin in the prediction
of peripancreatic necrosis and clinical severity, whereas
leptin and adiponectin failed to predict these parameters.
WHAT IS NEW HERE
3The adipocytokine visfatin has the potential to serve as
adipocyte-specific marker protein indicating extrapancreatic findings such as intra-abdominal and
peripancreatic fat cell necrosis.
3In contrast to admission CRP values, admission visfatin
values are significantly correlated with clinical severity and
clinical end points such as death and need for interventions.
3Admission serum visfatin concentrations are able to serve
as early and predictive markers of peripancreatic necrosis
and clinical severity in acute pancreatitis.
3Visfatin has a potential for clinical use as a new and
diagnostic serum marker in acute pancreatitis.
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PANCREAS AND BILIARY TRACT
Visfatin Predicts Peripancreatic Necrosis