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In: Acute Pancreatitis ISBN: 978-1-63485-229-6
Editor: Shane Copeland © 2016 Nova Science Publishers, Inc.
Chapter 4
IMPACT OF OBESITY TO SEVERITY OF
ACUTE PANCREATITIS
Jana Katuchova*
First Department of Surgery, Medical Faculty of Safarik University and
University Hospital, Košice, Slovakia
ABSTRACT
Acute pancreatitis is an inflammatory condition with a variable
clinical course from the acute interstitial edematous pancreatitis to the
most severe with serious complications that attempt the life of a patient,
severe acute pancreatitis. According to the Atlanta classification severe
acute pancreatitis occurs approximately at 25% of all patients with acute
pancreatitis and it is associated with 10-20% of mortality. Interstitial
edematous pancreatitis usually resolves without major consequences,
whereas severe acute pancreatitis is associated with considerable
morbidity and mortality. With the increasing prevalence of obesity, there
is growing evidence that obese patients with severe acute pancreatitis
might have worse outcomes in comparison to the patients with normal
body mass index.
Keywords: acute pancreatitis, obesity, severe acute pancreatitis, body mass
index, waist measurements
*
Corresponding Author address: Email: jana.katuchova@upjs.sk.
Jana Katuchova
72
INTRODUCTION
Acute pancreatitis (AP) is an inflammatory condition with a variable
clinical course from the acute interstitial edematous pancreatitis (IEP) to the
most severe with serious complications that attempt the life of a patient, severe
acute pancreatitis (SAP). According to the Atlanta classification SAP occurs
approximately at 25% of all patients with AP and it is associated with 10-20%
of mortality [1, 2]. IEP usually resolves without major consequences, whereas
SAP is associated with considerable morbidity and mortality. SAP is defined
by the presence of persistent organ failure (organ failure that persists for more
than 2 days) and/or presence of pancreatic necrosis, pancreatic and
peripancreatic abscess, pseudocyst and intraabdominal bleeding. Death of the
acute pancreatitis patients is often connected with at least one organ [3, 4].
Diagnosis is based upon clinical presentation, laboratory indicates and
imaging studies, whilst the illness severity can be assessed by the clinical
scoring systems, such as the Ranson, Glasgow or Apache II criteria, or by the
radiological assessments such as the computer tomography severity index [5-
7]. Prediction of the clinical course of SAP at the time of diagnosis still
remains unclear.
ACUTE PANCREATITIS
There are two phases of the SAP relating to the mortality. The first phase,
two weeks after onset of syndrome, is characterized by hypovolemia or even
by the shock. It is accompanied by the systemic inflammatory responsive
syndrome with production of inflammatory mediators and cytokines, which
cause consecutive injury of lungs, livers and cardiovascular system. The
multiorgan failure is a very common appearance in the case of the severe acute
pancreatitis and it happens very often even when the infection is absent. The
second phase of this disease (third-forth week) is characterized by the
complications caused by the infection of pancreatic necrosis. About 40-70%
patients with necrotic acute pancreatitis is afflicted by the infection of the
pancreatic necrosis, which causes the deaths of acute pancreatitis patients [8].
The extent of the pancreatic necrosis and the duration of disease are the risk
factors of the local pancreatic infection. Its incidence tends to culminate in
third week of disease, though it may appear in whichever phase of the disease
[9].
Impact of Obesity to Severity of Acute Pancreatitis
73
OBESITY
With the increasing prevalence of obesity, there is growing evidence that
obese patients with SAP might have worse outcomes in comparison to the
patients with normal body mass index (BMI). BMI is the basic method used to
determine obesity. It is a measure obtained by dividing the patient’s weight (in
kilograms) with the square of his/her height (in meters); obesity is defined as
BMI larger than 30 kg/m2. The method is based on the presumption that a
person’s excess weight predominantly consists of fat. The advantage of this
method is its application simplicity, namely the lack of complicated
procedures needed to determine it as well as the fact that it has been globally
accepted [10, 11]. The waist measurements (WC) larger than 94cm for men or
80cm for women give an indication of visceral fat mass [11].
There have been investigated that obesity is associated with a low-grade
inflammatory status in normal circumstances by many scientists. The chronic
low-grade inflammatory status is characterized by high levels of IL-6, IL-10,
IL-1b, TNF-a, leptin, plasminogen activator inhibitor-1 and CRP [12, 13, 14].
In obese patients suffered by AP obesity increases the inflammatory response
to pancreatic injury by upregulating these proinflammatory mediators. The
cytokines produced in the adipose tissue are adipokines including visfatin,
leptin, resistin and adipsin [15, 16], which play evident roles in the
pathogenesis of multisystem organ failure [14]. Leptin is generally considered
to be a proinflammatory adipokine, whereas adiponectin functions as a potent
anti-inflammatory molecule [16, 17]. High levels of leptin contribute to the
inflammatory state of adipose tissue associated with obesity. The
dysregulation between inflammatory and anti-inflammatory mediators causes
a greater systemic inflammatory response and results in worse or even fatal
outcome in obese AP patients [14].
Park and coworkers in their recent study investigated the profile of
inflammatory cytokines in AP to determine how they are related to obesity,
central fat distribution, and AP severity. IL-1ra and IL-6 were significantly
higher in overweight patients compared with non-overweight patients. IL-1ra,
IL-6, TNF-a, and sTNFR-I were significantly higher in patients with central fat
distribution compared with patients with non-central fat distribution. IL-6,
sTNFR-I, and sTNFR-II were significantly higher in patients with moderate
pancreatitis compared to those with mild pancreatitis. Among the six
cytokines, IL-6 was commonly elevated in patients with central fat
distribution, overweight, and moderate AP. The authors recommended IL-6 as
Jana Katuchova
74
a good marker for AP severity and is association with obesity and central fat
distribution in AP patients [18].
IMPACT OF OBESITY TO SEVERITY OF
ACUTE PANCREATITIS
In acute pancreatitis patients obesity supports to development of
complications with several mechanisms. The fat in obese patients occurs also
around the pancreas, in peripancreatic area. It is known that the risk of
infection of the pancreas is proportional to the amount of pancreatic necrosis
and obese patients display microcirculatory changes which may lead to
increased tissue ischemia which also tend to favor the development of
infection of the pancreas [19].
Patel and colleagues suggested that pancreatic fat lipolysis plays an
important role in severe acute pancreatitis. They evaluated the role of
pancreatic lipases in SAP-associated visceral fat necrosis, the inflammatory
response, local injury, and outcomes of AP. For this, cerulein pancreatitis was
induced in lean and obese mice, alone or with the lipase inhibitor or listat and
parameters of AP induction (serum amylase and lipase), fat necrosis,
pancreatic necrosis, and multisystem organ failure, and inflammatory response
were assessed. Pancreatic lipases were measured in fat necrosis. They found
obesity to convert mild cerulein AP to SAP with greater cytokines, unsaturated
fatty acids, and multisystem organ failure, and 100% mortality without
affecting AP induction or pancreatic necrosis. They confirmed increased
pancreatic lipase amounts and activity in the extensive visceral fat necrosis of
dying obese mice. Lipase inhibition reduced fat necrosis, unsaturated fatty
acids, organ failure, and mortality but not the parameters of AP induction.
They conclude that unsaturated fatty acids generated via lipolysis of visceral
fat by pancreatic lipases convert mild AP to SAP independent of pancreatic
necrosis and the inflammatory response [20].
Petrov has found that abdominal rather than whole-body fat is a key player
in AP. A biological interaction between abdominal adiposity and disturbance
in glucose and lipid metabolism is likely to increase the risk of developing AP
[21].
Achayra et coworkers have studied human pancreas autopsy samples of
obese and non-obese controls and compared them with obese and non-obese
patients with AP, and noted that the amount of intrapancreatic fat increased
Impact of Obesity to Severity of Acute Pancreatitis
75
with increasing BMI in both controls and patients with AP [22, 23]. They
explore the mechanism by which obesity may influence AP [24]. Fat adjacent
to acinar tissue has been shown to be associated with parenchymal damage in
AP [22, 23], and it has been shown that fat in the pancreas during acute
pancreatitis, has a direct toxic effect on the pancreatic parenchyma [22, 23,
24]. On human pancreatic samples authors noted that necrosed adipocytes
were surrounded by a zone of necrosed parenchyma, and the worst damage
was immediately around the fat - perifat acinar necrosis, with progressively
less necrosis noted with increasing distance from the necrosed fat. Perifat
acinar necrosis is an ante-mortem phenomenon since it is surrounded by CD68
positive macrophages and was significantly more in patients with pancreatitis
compared to controls. This perifat acinar necrosis was significantly higher in
SAP and was the predominant form of necrosis noted on the autopsy samples
[22, 24]. The other form of necrosis noted, was isolated acinar necrosis in
pancreatic parenchyma not adjacent to the necrosed fat. The authors
investigated that necrosis to be significantly lesser than perifat acinar necrosis
in SAP. On a molecular level it is important to recognize the predominant free
fatty acids contained in visceral fat impact the severity of AP It has been
shown on fluid analysis of necrosectomy samples, which were from obese
patients, that the predominant long chain fatty acids (up to 73%) were
unsaturated fatty acids, comprising primarily of oleic acid and linoleic acid.
This is similar to what other investigators have noted where unsaturated fatty
acids accumulate in the pancreas adipocytes and can be 6-11 fold higher in
necrosed pancreas samples as compared to a normal pancreas [24, 25, 26].
In previous study from the Department of Surgery University Hospital in
Kosice, the authors found obesity as a risk factor for SAP. The severe acute
pancreatitis was confirmed in 91 (23.7%) patients. Local and systemic
complications were recorded in 64 (16.7%) and 51 (13.3%) patients,
respectively. Obesity calculated by BMI was identified as a significant risk
factor for local and systemic complications (p < 0.02 and p < 0.03,
respectively). Moreover, in this study, obesity was also categorized by waist
circumference and was confirmed as a risk factor (p < 0.01). The overall
mortality rate was 2.4%, i.e., nine patients died. This study indicates that
obesity can have a statistically significant influence on the mortality of SAP
patients [27].
Jana Katuchova
76
CONCLUSION
Obesity has now reached epidemic proportions worldwide. As with all
other coincident diseases, determining the impact of obesity on clinical
outcome is a research priority. The findings indicate obesity is associated with
an elevated systemic inflammatory response, an increased risk of local and
systemic complications and is a prognostic factor for mortality in AP. With the
improvements in the classification of AP severity, there is an opportunity for
further studies to determine the extent to which obesity impacts the outcome
for each of the severity categories. Recent targeted systematic reviews confirm
that obesity has a clinically relevant impact on the course and outcome of AP.
This founding could improve the clinical management of obese patients with
AP will require further study.
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Impact of Obesity to Severity of Acute Pancreatitis
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[8] Beger H. G., Rau B., Mayer J. et al. Natural course of acute pancreatitis.
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[21] Petrov M. S. Abdominal fat: A key player in metabolic acute
pancreatitis. Am J Gastroenterol 2013;108(1):140-142.
[22] Navina S., Acharya C., DeLany J. P. et al. Lipotoxicity causes
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[23] Acharya C., Cline R. A., Jaligama D. et al. Gastroenterology 2013;145:
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[25] Pinnick K. E., Collins S. C., Londos C. et al. Pancreatic ectopic fat is
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[26] Panek J., Sztefko K., Drozdz W. Composition of free fatty acid and
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In: Acute Pancreatitis ISBN: 978-1-63485-229-6
Editor: Shane Copeland © 2016 Nova Science Publishers, Inc.
Chapter 5
SEVERE ACUTE PANCREATITIS:
SINCE THE CLASSICAL
Alejandra Guillermina Miranda-Díaz
1,*
,
José Manuel Hermosillo-Sandoval
2
and Carlos Alberto Gutiérrez-Martínez
3
1
Department of Physiology, University Health Sciences Centre,
University of Guadalajara (Centro Universitario de Ciencias de la Salud,
Universidad de Guadalajara), Guadalajara, Jalisco, México
2
Department of General Surgery, Specialities Hospital, National Occidental
Medical Centre, Mexican Social Security Institute
(Hospital de Especialidades, Centro Médico Nacional de Occidente,
Instituto Mexicano del Seguro Social), Guadalajara, Jalisco, México
3
Intensive Care Unit, Specialties Hospital, National Occidental Medical
Centre, Mexican Social Security Institute, Guadalajara, Jalisco, México
ABSTRACT
Acute pancreatitis (AP) is the inflammatory process secondary to
damage of the pancreatic acinar cells. The Atlanta classification describes
*
Corresponding author: Alejandra Guillermina Miranda-Díaz, MD, FACS, PhD. University
Health Sciences Centre, University of Guadalajara, Guadalajara, Jalisco, México. Av. La
Paz No. 2758, Col. Arcos Sur, Guadalajara, Jalisco, México, CP 44150, Telephone: +52
331-058-5200 ext. 33658; Fax: +52 333-617-3499, E-mail: kindalex1@outlook.com.
Alejandra Guillermina Miranda-Díaz et al.
80
AP as mild, moderate, and severe. Mild AP is the most common, is
present in 85% of patients, is self-limited and resolves without serious
complications in about one week. In moderate AP there are local or
systemic complications, organ failure is transient, and the event generally
lasts about 2-3 weeks. Severe AP (SAP) is an abdominal and systemic
catastrophe characterized by multiple persistent organ failure >48 h. In
SAP local and systemic complications are present (accumulation of
peripancreatic fluid, and sterile or infected pancreatic and peripancreatic
necrosis). Early diagnosis should be managed aggressively in order to
prevent multiple, lethal, organ failure. There are many options to support
the precise diagnosis, from the classical methods, to more advanced
methods among them advances in imaging through tomographic slices,
with or without contrast, and magnetic resonance imaging. In the actual
management of SAP, vigorous administration of fluids continues to
predominate. Early artificial enteral nutrition and the administration of
select antibiotics help of infected AP. Nevertheless, some interesting
alternative treatments are emerging that could offer better results in
selected patients than traditional ones: analgesia and peridural anesthesia.
Drotrecogin alpha (activated), through its anti-thrombotic, anti-
inflammatory and pro-fibrinolytic properties, is capable of reducing
mortality in SAP and severe sepsis. The recombinant human soluble
thrombomodulin emerges as an alternative in the prevention and
development of walled-off pancreatic necrosis in SAP. Among emerging
surgical therapies is the management of sterile or infected pancreatic
necrosis. Peritoneal lavage of different types continues to be a useful tool.
The approach to pancreatic necrosis through the minimally invasive or
video-assisted ‘Step up’ approach emerges as an attractive, viable
alternative. The bio-technological system of vacuum-assisted closure
(VAC) as an aid to programmed open necrosectomy, seems to offer
additional benefits, and the combination of Drotrecogin alpha (activated)
plus VAC could offer even better results in decreasing mortality and
hospital stays in SAP. However, all the methodological and therapeutic
advances in SAP have no significant impact in reducing mortality of
patients affected.
Keywords: acute pancreatitis, severe acute pancreatitis, drotrecogin alpha
activated, vacuum-assisted closure system
INTRODUCTION
Acute pancreatitis (AP) is the inflammatory process secondary to damage
of the pancreatic acinar cells characterized by activation of the pancreatic