Experimental acute pancreatitis models relevant to lipids and obesity

Division of Gastroenterology and Hepatology, Mayo Clinic Scottsdale, AZ

Entry Version: 

Version 1.0, September 1, 2015


Patel, Krutika S. Singh, Vijay P. (2015). Experimental acute pancreatitis models relevant to lipids and obesity.
Pancreapedia: Exocrine Pancreas Knowledge Base, DOI: 10.3998/panc.2015.36

1. Introduction and Background

While severity in conventional animal models of AP is related to etiology, this rarely happens in human disease. Most obese individuals do not experience an episode of acute pancreatitis (AP) during their lifetime, but those who do develop AP are more prone to severe acute pancreatitis (SAP) and associated morbidity and mortality (1).  In this entry, we will discuss the relevance of obesity and lipids as potential modifiers of the course and outcome of AP in the light of limitations posed by conventional models of acute pancreatitis and suggest relevant improvisations with examples in various in vitro and in vivo systems.

From the perspective of pancreatitis and is experimental models, visceral fat depots can be divided into intrapancreatic and those around the pancreas i.e. peripancreatic fat. Both of these can contribute to SAP in humans. The human facts relevant to the nature and amounts of lipid used in the sections on experimental models are: 1. More than 30% body weight may be contributed by adipose tissue during obesity. 2) Obesity is associated with SAP (32, 43, 45, 46) and is defined as a BMI of >30 kg/m2 in western countries or >25 kg/m2 in the East. 3) Clinical studies from the west (12, 36, 44, 47, 81, 89) and Asia (91, 98, 110, 111) report increased SAP above the corresponding BMIs. 4) There is a higher consumption of polyunsaturated fatty acid (PUFA) (42, 84, 88, 103) in Asia compared to the west (41, 42, 88). 5) Dietary PUFAs accumulate in visceral adipocytes (88). 6) 80-90% of adipocyte mass may comprise triglyceride. 7) Intra pancreatic fat increases with BMI (86) and may comprise an average of about 20% pancreatic area in obese individuals.  8) Peripancreatic fat may commonly range from 2-9 Kg in obese individuals. Both these depots may by hydrolyzed in pancreatitis contributing to SAP. While further details on obesity related human data are provided in the chapter “Relationship between obesity and pancreatitis” (63), in this section we shall focus on studying the impact of obesity in animal models of pancreatitis.

Limitations of Current Animal Models in the Context of Human AP

Current animal models of acute pancreatitis are classified for severity on the basis of an inducer/etiology causing pancreatic necrosis (54). This is a significant limitation since severity in human AP is unrelated to pancreatic necrosis or etiology, with the exception of hypertriglyceridemic pancreatitis (25, 26, 55).  Rat caerulein pancreatitis is considered milder due to the lesser pancreatic necrosis (54, 72)  while, mouse caerulein pancreatitis is considered a severe acute pancreatitis model due to the higher amount of acinar necrosis ranging from 5-30% (45, 54, 57). In both these models, the pancreas returns to baseline after a few days of inducing AP. Similarly, lung injury in these is mild and transient with no evidence of impaired gas exchange.

In contrast, development of necrosis during human AP may not result in worse outcomes. While severe pancreatic necrosis is defined as development of pancreatic parenchymal necrosis of more than 30% during human disease (31), a prospective human study from the United Kingdom showed no/minimal relationship between the extent of necrosis and outcome (56). SAP and early mortality in human AP can occur with minimal pancreatic necrosis (16, 32, 61) due to systemic complications or sustained organ failure (31). A number of studies have documented that only about half of patients with necrotizing pancreatitis develop organ failure (46, 78, 97).

Taurocholate induced pancreatitis in rats is considered severe due to the extensive pancreatic hemorrhagic necrosis noted in this model (5, 54, 72). To induced AP 3 to 5% solutions of bile salts  such as sodium taurocholate are injected locally into the bilio- pancreatic duct, aimed at stimulating severe biliary acute pancreatitis (5). This results in a local concentration of 60 to 100 mm, which is 5 to 100 fold above the critical micellar concentration (94) which can cause a detergent like effect on cell membranes in the pancreatic acinar cells. Currently while no published study has verified the appropriateness of these concentrations of bile salts in relevance to human disease, our unpublished data shows bile acid concentrations to average at 25 µM in pancreatic collections from patients with biliary AP. A recent review by Lerch and Gorelick also questioned the injection of bile acids/salts as a model for biliary acute pancreatitis (54).

Clinically, it is often difficult to establish the causal agents responsible for the severity in human acute pancreatitis, since markers and mediators of disease are indistinguishable. Animal models allow initiation and inhibition of steps relevant to the patho-physiology of the disease and are thus important in establishing causality. Several potential targets like trypsin (6, 7, 9, 14, 18, 75, 90, 100, 101) and reactive oxygen species (2) have been considered of therapeutic relevance since their levels may be increased in acute pancreatitis.  However clinical trials of acute pancreatitis targeting reactive oxygen species (2) trypsin (6, 7, 9, 14, 18, 75, 90, 100, 101) and inflammatory mediators (43) have shown limited benefits, although these targets seem scientifically sound in animal models. The discord between modification of outcomes and interpretation of animal models can be seen in the lack of evidence of clinical improvement despite more than 70 trials of serine protease and trypsin inhibition over the last six decades (6, 7, 9, 14, 18, 75, 90, 100, 101). Thus, based on i) lack of relevance of etiology to outcomes, ii) lack of accurate parameters used to define systemic injury, iii) limited clinical benefits of attractive therapeutic targets in animal models and iv) overemphasis of pancreatic necrosis in defining AP severity we need to interpret the relevance of conventional AP models with caution.

2. Role of Obesity and Lipids in Acute Pancreatitis

Obesity is known to be associated with worse acute pancreatitis outcomes (3, 19, 29, 67, 73, 80, 88, 90) and several clinical and epidemiological studies have shown that patients with increased intra-abdominal fat or higher body mass index (BMI) are at an increased risk for developing SAP (33, 67, 84, 111). The two other clinical clues to lipids worsening AP outcomes are i) hypertriglyceridemic pancreatitis generally being severe (13, 25, 26, 55, 106) and ii) AP patients receiving intravenous total parenteral nutrition including IV lipids having worse outcomes (76, 78, 109). Recent reports from North America show the usage of parenteral nutrition to be as high as 40 to 60% in patients with acute pancreatitis (94, 105). The prevalence of organ failure is reported to be more than 50% in patients receiving parenteral nutrition containing intravenous lipid emulsions (76, 78, 109). IV lipids may result in high systemic fatty acid concentrations, 6 to 8 fold above normal (38), consistent with levels found in the serum of patients with SAP (27, 72). These associations of obesity/ lipids in causing worse outcomes suggest the role of fat as a common modifier of AP outcomes.  In the following sub sections, we will discuss the mechanistic, translational and potential therapeutic relevance of obesity in the context of in vitro and in vivo models of acute pancreatitis.

In vitro Models of Fat Mediated Severe Acute Pancreatitis

The purpose of an in vitro model is to replicate the pathophysiology occurring in vivo in a reductionist manner. Therefore, the design of fat induced pancreatic damage model should simulate the in vivo environment. Several studies show evidence of pancreatic parenchymal necrosis around fat necrosis. (4, 48, 62, 67). Physiologically, adipocytes and the neighboring pancreatic acinar cells do not allow their contents to communicate with each other. Acinar cells physiologically secrete digestive enzymes present in zymogen granules from their apical region into the duct lumen; however, an insult which causes pancreatitis can result in basolateral leakage of lipases into the surrounding adipocytes (20, 21, 30, 34, 48, 50) and consequent lipolysis of adipocyte triglyceride, producing free fatty acids(FFA). This is seen histologically as positive Von Kossa staining (4, 62) and high FFA levels in pancreatic necrosis collections (28, 62, 71).

This pathologic in vivo lipolytic flux between adipocytes and acinar cells can be simulated in vitro using a trans-well system which allows macro molecular diffusion between the acinar and adipocyte compartments, while preventing cellular contamination of the individual compartments (Figure 1)  (4, 62). 

Figure 1: Schematic showing the setup to study In Vitro Lipolytic Fluxes. After harvesting, primary acinar cells are added to the upper compartment of the Transwell (with a 3 micron sieve at bottom of insert; Yellow) and primary adipocytes to the lower compartment of the well (Red). Medium from the individual compartments is analyzed for lipolytic and exocrine products, and the acinar cells are harvested for measuring parameters of necrotic cell death.

Figure 2: In Vitro Co-Culture of Acini and Adipocytes results in acinar necrosis. A to C show propidium iodide(PI) uptake in control acini (A), acini cocultured with adipocytes (B) or with adipocytes along with 50 µM orlistat (C). (D) Percentage of acinar cells which are positive for PI uptake in co-culture with adipocytes (Ac+Ad) are higher compared to acini cultured alone (Ac), with 50 µM orlistat (Ac+Orli), or 50 µM orlistat (Ac+Ad+Orli) in co-culture. (E) ATP levels in acinar cells treated as in (D) show a reduction in ATP level in the co-culture. (F) Cytochrome C (upper panel) in mitochondrial (M) and cytoplasmic(C) fractions of Ac, Ac+Ad, and Ac+Ad+Orli, show a migration from the mitochondrial compartment to the cytosolic compartment only in the Ac+Ad group. Mitochondrial marker COX IV (lower Panel) is similar in all groups. (G) Total NEFA concentrations in the medium of acini cells treated as in (D), show increased NEFA in Ac+Ad only. Republished with permission from (62).

The pancreatic lipases released from the acinar compartment diffuse through the transwell into the adipocyte compartment causing an increase in free fatty acids, which in turn diffuse into the acinar cell compartment resulting in acinar cell necrosis (4), seen as increased propidium iodide uptake, a drop in ATP levels, cytochrome C leakage and an increase in NEFA levels (Figure 2) (62). The lipase inhibitor orlistat prevents all these changes in the co-culture system.

Mossner et. al in 1992 showed the direct deleterious effect of long chain unsaturated fatty acids on pancreatic acini (60).  Recently, Navina et. al showed that linoleic acid, oleic acid and linolenic acid were particularly toxic to acinar cells, while the saturated fatty acids palmitic acid and stearic acid were not (62). Incubation of acinar cells with VLDL also results in an increase in free fatty acids, resulting in necrotic injury. (92)  When acinar cells are stimulated with individual fatty acids, cytosolic calcium concentrations, released from an intracellular pool, are increased only with unsaturated fatty acids (Figure 3) (62). Unsaturated fatty acids also cause leakage of lactate dehydrogenase, leakage of cytochrome C into the cytoplasmic fraction and inhibition of mitochondrial complexes I and V, causing a drop in ATP levels to induce necrotic cell death (Figure 3) (62, 71). Unsaturated fatty acids at sublethal concentrations also up-regulate mRNA levels of inflammatory mediators and thus are pro-inflammatory (62). 

Figure 3: Unsaturated fatty acids induce acinar necrosis and inflammatory mediator generation. (A) Intra-acinar calcium concentrations (expressed as 340/380 emission ratio) in response to addition (arrow) of 600 µM fatty acids (LLA, linolenic acid; LA, linoleic acid; OA, oleic acid; SA, stearic acid; PA, palmitic acid), showing release of intra-cellular calcium only with unsaturated fatty acids – LLA, LA and OA (B) Effect of depletion of endoplasmic reticulum calcium with thapsigargin (1 µM) (blue line) and depletion of extracellular calcium by chelation with EGTA (1 mM added 10 min before adding linoleic acid, pink) on 600 µM linoleic acid– induced intracellular calcium increase. (C) Leakage of Lactate Dehydrogenase (LDH) from acinar cells 5 hours after treatment with fatty acids as in (A). Unsaturated fatty acids cause releases of LDH, while saturated do not. (D and E) Effect of linoleic and palmitic acids on mitochondrial complex (Cx.) I and V activity in acini. Linoleic acid paralyses Cx. I and V, while palmitic does not. (F) Effect of linoleic and palmitic acids on TNF-α mRNA in acini. (G) Effect of linoleic and palmitic acids on CXCL1 mRNA in acini. (H) Effect of linoleic and palmitic acid CXCL2 mRNA. Linoleic acid but not palmitic acid causes an increase in all three. Republished with permission from (62).

Exposure of peripheral blood mononuclear cells to unsaturated fatty acids at concentrations lower than those in the serum during SAP, results in their necro-apoptotic cell death (71).  

In Vivo Models of Obesity Associated Severe Acute Pancreatitis

Role of Intra Pancreatic Fat (IPF) in Pancreatic Necrosis

Histologically, several studies show pancreatic acinar necrosis to border fat necrosis (48, 62, 65, 75, 86). Those studies analyzing intrapancreatic fat in human autopsy samples (4, 48, 62, 68, 85, 86), surgically resected samples (82) and radiological appearance of pancreas (58, 85) show intrapancreatic fat to be increased with BMI. Intrapancreatic fat amounts in obese individuals are on an average, two fold higher than non-obese individuals (85). Analysis of pancreatic adipocyte triglyceride composition in humans showed increasing amounts of unsaturated triglycerides with higher amounts of fat. (79) Pancreatic necrosis fluid collected from obese patients with necrotizing pancreatitis had higher nonesterfied fatty acid concentrations compared to patients with pseudocysts and cystic neoplasms, who had a lower BMI (28, 62, 70, 72).

Several in vivo models have contributed to our understanding of the role of intrapancreatic fat in severe acute pancreatitis outcomes (28, 62). Obese mice have increased intrapancreatic fat (about 30% of total pancreatic area) resulting in lethal severe acute pancreatitis in response to IL-12, IL-18 that is associated with increased acinar necrosis (62). In these mice, a significant amount of pancreatic acinar necrosis (60-70% area) occurs in areas surrounding the fat necrosis, which is termed peri-fat acinar necrosis (PFAN). This PFAN contributes to about half the total acinar necrosis in these obese mice (62). In contrast, lean mice have less intrapancreatic fat, PFAN and have non-lethal SAP (62). Grossly obese mice have chalky white deposits of saponification, consistent with fat necrosis histologically (62). Evaluation of the triglyceride composition of adipose tissue in these obese mice show unsaturated fatty acids to be significantly increased in obese mice compared to lean mice, with a corresponding relative decrease in saturated fatty acids (62, 75). Normally, visceral fat pads of obese mice have about 70-80% unsaturated fatty acids which is significantly more than in lean mice which have about 50-60% unsaturated fatty acid content (62, 75).

The role of acute lipolytic generation of fatty acids on local pancreatic severity has been studied recently by Durgampudi et. al by injecting unsaturated triglyceride into the pancreato-biliary duct to increase intra pancreatic fat (28). Intraductal triglyceride injection followed by duct ligation, allows for triglyceride to be mixed with pancreatic lipases as would occur with basolateral leakage during acute pancreatitis, causing subsequent lipolysis of glyceryl trilinoleate mimicking intrapancreatic fat necrosis seen in obese patients with SAP (4, 62). Ligation of common bilio-pancreatic duct results in elevated amylase, lipase, bilirubin and ALT, fulfilling all the criteria of mild biliary AP. Intraductal injection of the triglyceride glyceryl trilinoleate (GTL), in amounts equivalent to about 10% of intrapancreatic fat, along with duct ligation, results in severe hemorrhagic pancreatic necrosis with about 70% necrosis of the pancreatic acinar tissue, multisystem organ failure and mortality (28). This acinar parenchymal damage is prevented by inhibition of GTL lipolysis to linoleic acid by Orlistat (28). This inhibition does not affect the increase in serum amylase, bilirubin or ALT which mark biliary AP. Thus, in an animal model simulating biliary AP (classically regarded as a severe AP model), it was shown that outcomes are unrelated to the etiology of AP and intrapancreatic fat is a modifier of outcomes, converting mild AP to SAP (28). Hence, in obesity associated SAP, extracellular basolateral unregulated release of pancreatic lipase consequent to an initial insult may cause lipolysis of intrapancreatic fat, resulting in an increase in free fatty acids, which directly damage the acinar cells, causing necrosis.

A surge in systemic unsaturated fatty acids also results in significant mortality in these experimental models (28, 62, 76), similar to the trend of a rise in free fatty acids, particularly unsaturated fatty acids in the sera of patients with SAP (96). Prevention of lipolysis results in reduction in free fatty acids and systemic inflammatory markers (28, 62, 76). As noted in the spectrum of human SAP, obese animals or animals with higher unsaturated fatty acids generated by the lipolytic surge are more prone to multisystem organ failure in the form of renal failure and lung injury. Renal injury manifests as fat containing tubular vacuoles, tubular apoptosis and necrosis, along with mitochondrial swelling, expression of kidney injury molecule-1 (KIM-1) with associated functional renal injury in the form of high blood urea nitrogen (BUN) levels (28, 62, 76). Lung injury is manifested as increased apoptotic cells and lung myeloperoxidase levels (62, 76). Several isolated studies have previously shown intravenous oleic acid to cause acute respiratory distress syndrome with lung myeloperoxidase increase and apoptosis (39, 40, 49, 108). Unsaturated fatty acids are also known to cause elevation in the serum creatinine and cause renal tubular toxicity (108).This is also associated with release of pro inflammatory cytokines, which have been reported to be increased in human SAP (8, 11, 23, 24, 37, 59, 102, 107). Recent studies from Closa et. al in rats showed unsaturated free fatty acids generated in peritoneal adipose tissue during pancreatitis to accumulate in ascitic fluid, and cause the release of inflammatory mediators that contribute to the progression of the systemic inflammatory response seen in severe acute pancreatitis (35).

In contrast to the intrapancreatic fat of obesity, the pancreatic fat present in chronic pancreatitis patients is rarely associated with severity during pancreatitis (17, 51, 53, 64, 70, 93, 104). A common feature of patients with chronic pancreatitis is fatty replacement of the pancreas after recurrent attacks of acute pancreatitis (82). Secondary fat replacement in chronic pancreatitis is independent of BMI and is associated with fibrosis which causes a protective walling off effect from the adipocyte-acinar lipolytic flux generated during acute pancreatitis (4, 62). This is supported by observations that chronic pancreatitis patients rarely die from acute pancreatitis or its related complications (51, 65, 70). Acharya et. al have showed that unlike obesity associated intrapancreatic fat which worsens acute pancreatitis outcomes, intrapancreatic fat accumulation in chronic pancreatitis is less prone to fat necrosis or surrounding parenchymal damage (4). In reference to fatty acid ethyl esters (FAEEs), it is noteworthy that the landmark study documenting high FAEE amounts in the pancreas of humans at autopsy clearly states that they had no pancreatitis. The study was done on alcoholics who had died from unrelated causes such as motor vehicle accidents (52). Criddle et. al have also shown that it is the conversion of FAEEs to FFAs which results in cell injury (22). This is supported by our studies in which we note the parent fatty acids to be much more toxic than FAEEs (unpublished data). Thus while the role and relevance of FAEEs to AP outcomes is unproven, and the human and experimental data mentioned above strongly support the lipolytic generation of UFAs to convert AP to SAP in obesity.

Role of Peri Pancreatic Fat in Severe Acute Pancreatitis

Visceral adipose tissue, such as surrounding the pancreas, contributes to about 10 to 30 % of the intra-abdominal area (15). This adipocyte mass can provide a potentially hydrolyzable pool of triglycerides during acute pancreatitis. Adipocytes normally consist of more than 80% fat, stored in the triglyceride form (98). Unregulated release of pancreatic lipases during an acute attack of pancreatitis can result in the breakdown of these triglycerides causing release of very high amounts of free fatty acids, resulting in adverse outcomes.  

Obesity is considered as a proinflammatory state.  A recently published study by Patel et. al has shown a traditionally mild model of caerulein acute pancreatitis to have severe outcomes in obese but not lean mice (75). Mortality in obese mice is associated with fat necrosis and peritoneal saponification, hypocalcemia, an intense cytokine response, lung injury and renal failure which are all commonly used markers in known severity scoring/ predicting systems of acute pancreatitis (10, 75). Visceral fat pads of obese mice with AP showed the presence of active pancreatic lipases (75). The amount of pancreatic necrosis was not significantly different in the lean vs. obese vs. orlistat treated groups. However both the lean and orlistat treated groups had reduced fat necrosis, lack of sustained organ failure, a transient cytokine response and improved survival. Histologically, the areas of fat necrosis were surrounded by intense accumulation of polymorphonuclear neutrophils and macrophages (35, 75) suggesting that these necrotic areas of adipose tissue generate and release inflammatory mediators that contribute to the progression of the inflammation during SAP (75).

A recent study by Noel et. al (70) helped distinguish between the acute unsaturated fatty acid mediated lipotoxicity during SAP from the chronic inflammatory state of obesity. For this the amount of peri-pancreatic triglyceride was acutely changed by administration of triolein (the triglyceride of oleic acid, which is the most abundant UFA in visceral fat) in lean rats with caerulein pancreatitis. This resulted in acute lung and renal injury with minimal pancreatic necrosis and an intense cytokine response, all of which were prevented by inhibiting lipolysis. Conversely, while the co-administration of the cytokines IL8 and IL-1β, which are also increased in pancreatic necrosis collections, did cause pyrexia, they did not lead to any adverse outcomes. Thus peri-pancreatic fat necrosis may worsen inflammation and AP outcomes  independent of the baseline proinflammatory state of obesity (70).

In summary we have learnt that obesity worsens the outcomes of acute pancreatitis due to the acute lipolytic generation of unsaturated fatty acids. This is unrelated to the baseline pro-inflammatory state of obesity and unrelated to the etiology of AP. While the hydrolysis of intrapancreatic fat by pancreatic lipases contributes to pancreatic necrosis in obesity, in chronic pancreatitis fibrosis reduces this lipolytic flux and resulting severity of recurrent AP attacks. Necrosis of the large amounts of peripancreatic fat can worsen AP outcomes independent of pancreatic necrosis. These observations mimic human disease, support obesity as modifier of outcomes, and also suggest a different way to design and interpret models of AP which are not directly linked to the etiology.


This project was supported by Grant Number RO1DK092460 (VPS) and a startup package by the department of medicine Mayo Clinic Arizona (VPS).

3. References

  1. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 13(4 Suppl 2): e1-15, 2013. PMID: 24054878.
  2. Abbasinazari M, Mohammad Alizadeh AH, Moshiri K, Pourhoseingholi MA and Zali MR. Does allopurinol prevent post endoscopic retrograde cholangio- pancreatography pancreatitis? A randomized double blind trial. Acta Med Iranica 49(9): 579-583, 2011. PMID: 22052140.
  3. Abu Hilal M and Armstrong T. The impact of obesity on the course and outcome of acute pancreatitis. Obes Surg 18(3): 326-328, 2008. PMID: 18202895.
  4. Acharya C, Cline RA, Jaligama D, Noel P, Delany JP, Bae K, et al. Fibrosis Reduces Severity of Acute-on-Chronic Pancreatitis in Humans. Gastroenterology 145(2): 466-475, 2013. PMID: 23684709.
  5. Aho HJ, Koskensalo SM and Nevalainen TJ. Experimental pancreatitis in the rat. Sodium taurocholate-induced acute haemorrhagic pancreatitis. Scand J Gastroenterol 15(4): 411-416, 1980. PMID: 7433903.
  6. Andriulli A, Caruso N, Quitadamo M, Forlano R, Leandro G, Spirito F, et al. Antisecretory vs. antiproteasic drugs in the prevention of post-ERCP pancreatitis: the evidence-based medicine derived from a meta-analysis study. JOP 4(1): 41-48, 2003. PMID: 12555015.
  7. Andriulli A, Leandro G, Clemente R, Festa V, Caruso N, Annese V, et al. Meta-analysis of somatostatin, octreotide and gabexate mesilate in the therapy of acute pancreatitis. Aliment Pharmacol Ther 12(3): 237-245, 1998. PMID: 9570258.
  8. Aoun E, Chen J, Reighard D, Gleeson FC, Whitcomb DC and Papachristou GI. Diagnostic accuracy of interleukin-6 and interleukin-8 in predicting severe acute pancreatitis: a meta-analysis. Pancreatology 9(6): 777-785, 2009. PMID: 20110745.
  9. Asang E. [Changes in the therapy of inflammatory diseases of the pancreas. A report on 1 year of therapy and prophylaxis with the kallikrein- and trypsin inactivator trasylol (Bayer)]. Langenbecks Arch Klin Chir Ver Dtsch Z Chir 293: 645-670, 1960. PMID: 13794633.
  10. Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut 62(1): 102-111, 2013. PMID: 23100216.
  11. Brivet FG, Emilie D and Galanaud P. Pro- and anti-inflammatory cytokines during acute severe pancreatitis: an early and sustained response, although unpredictable of death. Parisian Study Group on Acute Pancreatitis. Crit Care Med 27(4): 749-755, 1999. PMID: 10321665.
  12. Brown A, James-Stevenson T, Dyson T and Grunkenmeier D. The panc 3 score: a rapid and accurate test for predicting severity on presentation in acute pancreatitis. J Clin Gastroenterol 41(9): 855-858, 2007. PMID: 17881932.
  13. Buch A, Buch J, Carlsen A and Schmidt A. Hyperlipidemia and pancreatitis. World J Surg 4(3): 307-314, 1980. PMID: 7415184.
  14. Buchler M, Malfertheiner P, Uhl W, Scholmerich J, Stockmann F, Adler G, et al. Gabexate mesilate in human acute pancreatitis. German Pancreatitis Study Group. Gastroenterology 104(4): 1165-1170, 1993. PMID: 8462805.
  15. Camhi SM BG, Bouchard C, Greenway FL, Johnson WD, Newton RL, Ravussin E, Ryan DH, Smith SR, Katzmarzyk PT. The relationship of waist circumference and BMI to visceral, subcutaneous, and total body fat: sex and race differences. Obesity 19(2):402-8., 2011. PMID: 20948514.
  16. Carnovale A, Rabitti PG, Manes G, Esposito P, Pacelli L and Uomo G. Mortality in acute pancreatitis: is it an early or a late event? JOP 6(5): 438-444, 2005. PMID: 16186665.
  17. Chaudry G, Navarro OM, Levine DS and Oudjhane K. Abdominal manifestations of cystic fibrosis in children. Pediatr Radiol 36(3): 233-240, 2006. PMID: 16391928.
  18. Chen HM, Chen JC, Hwang TL, Jan YY and Chen MF. Prospective and randomized study of gabexate mesilate for the treatment of severe acute pancreatitis with organ dysfunction. Hepatogastroenterology 47(34): 1147-1150, 2000. PMID: 11020900.
  19. Chen SM, Xiong GS and Wu SM. Is obesity an indicator of complications and mortality in acute pancreatitis? An updated meta-analysis. J Dig Dis 13(5): 244-251, 2012. PMID: 22500786.
  20. Cosen-Binker LI, Binker MG, Wang CC, Hong W and Gaisano HY. VAMP8 is the v-SNARE that mediates basolateral exocytosis in a mouse model of alcoholic pancreatitis. J Clin Invest 118(7): 2535-2551, 2008. PMID: 18535671.
  21. Cosen-Binker LI, Lam PP, Binker MG, Reeve J, Pandol S and Gaisano HY. Alcohol/cholecystokinin-evoked pancreatic acinar basolateral exocytosis is mediated by protein kinase C alpha phosphorylation of Munc18c. J Biol Chem 282(17): 13047-13058, 2007. PMID: 17324928.
  22. Criddle DN, Murphy J, Fistetto G, Barrow S, Tepikin AV, Neoptolemos JP, et al. Fatty acid ethyl esters cause pancreatic calcium toxicity via inositol trisphosphate receptors and loss of ATP synthesis. Gastroenterology 130(3): 781-793, 2006. PMID: 16530519.
  23. Dambrauskas Z, Giese N, Gulbinas A, Giese T, Berberat PO, Pundzius J, et al. Different profiles of cytokine expression during mild and severe acute pancreatitis. World J Gastroenterol 16(15): 1845-1853. PMID: 20397261.
  24. Daniel P, Lesniowski B, Mokrowiecka A, Jasinska A, Pietruczuk M and Malecka-Panas E. Circulating levels of visfatin, resistin and pro-inflammatory cytokine interleukin-8 in acute pancreatitis. Pancreatology 10(4): 477-482, 2010. PMID: 20720449.
  25. Deng LH, Xue P, Xia Q, Yang XN and Wan MH. Effect of admission hypertriglyceridemia on the episodes of severe acute pancreatitis. World J Gastroenterol 14(28): 4558-4561, 2008. PMID: 18680239.
  26. Dominguez-Munoz JE, Malfertheiner P, Ditschuneit HH, Blanco-Chavez J, Uhl W, Buchler M, et al. Hyperlipidemia in acute pancreatitis. Relationship with etiology, onset, and severity of the disease. Int J Pancreatol 10(3-4): 261-267, 1991. PMID: 1787337.
  27. Domschke S, Malfertheiner P, Uhl W, Buchler M and Domschke W. Free fatty acids in serum of patients with acute necrotizing or edematous pancreatitis. Int J Pancreatol 13(2): 105-110, 1993. PMID: 8501351.
  28. Durgampudi C, Noel P, Patel K, Cline R, Trivedi RN, DeLany JP, et al. Acute Lipotoxicity Regulates Severity of Biliary Acute Pancreatitis without Affecting Its Initiation. Am J Pathol 184(6): 1773-1784, 2014. PMID: 24854864.
  29. Evans AC, Papachristou GI and Whitcomb DC. Obesity and the risk of severe acute pancreatitis. Minerva Gastroenterol Dietol 56(2): 169-179. PMID: 20485254.
  30. Fallon MB, Gorelick FS, Anderson JM, Mennone A, Saluja A and Steer ML. Effect of cerulein hyperstimulation on the paracellular barrier of rat exocrine pancreas. Gastroenterology 108(6): 1863-1872, 1995. PMID: 7539388.
  31. Forsmark CE and Baillie J. AGA Institute technical review on acute pancreatitis. Gastroenterology 132(5): 2022-2044, 2007. PMID: 17484894.
  32. Fu CY, Yeh CN, Hsu JT, Jan YY and Hwang TL. Timing of mortality in severe acute pancreatitis: experience from 643 patients. World J Gastroenterol 13(13): 1966-1969, 2007. PMID: 17461498.
  33. Funnell IC, Bornman PC, Weakley SP, Terblanche J and Marks IN. Obesity: an important prognostic factor in acute pancreatitis. Br J Surg 80(4): 484-486, 1993. PMID: 8495317.
  34. Gaisano HY, Lutz MP, Leser J, Sheu L, Lynch G, Tang L, et al. Supramaximal cholecystokinin displaces Munc18c from the pancreatic acinar basal surface, redirecting apical exocytosis to the basal membrane. J Clin Invest 108(11): 1597-1611, 2001. PMID: 11733555.
  35. Gea-Sorli S, Bonjoch L and Closa D. Differences in the inflammatory response induced by acute pancreatitis in different white adipose tissue sites in the rat. PloS one 7(8): e41933, 2012. PMID: 22870264.
  36. Hegazi R, Raina A, Graham T, Rolniak S, Centa P, Kandil H, et al. Early jejunal feeding initiation and clinical outcomes in patients with severe acute pancreatitis. JPEN 35(1): 91-96, 2011. PMID: 21224435.
  37. Hirota M, Nozawa F, Okabe A, Shibata M, Beppu T, Shimada S, et al. Relationship between plasma cytokine concentration and multiple organ failure in patients with acute pancreatitis. Pancreas 21(2): 141-146, 2000. PMID: 10975707.
  38. Hughan KS BR, Lee S, Michaliszyn SF, Arslanian SA. β-Cell lipotoxicity after an overnight intravenous lipid challenge and free fatty acid elevation in African American versus American white overweight/obese adolescents. J Clin Endocrinol Metab 98(5):2062-9), 2013. PMID: 23526462.
  39. Hussain N, Wu F, Zhu L, Thrall RS and Kresch MJ. Neutrophil apoptosis during the development and resolution of oleic acid-induced acute lung injury in the rat. Am J Respir Cell Mol Biol 19(6): 867-874, 1998. PMID: 9843920.
  40. Inoue H, Nakagawa Y, Ikemura M, Usugi E and Nata M. Molecular-biological analysis of acute lung injury (ALI) induced by heat exposure and/or intravenous administration of oleic acid. Leg Med 14(6): 304-308, 2012. PMID: 22819303.
  41. Insull W, Jr. and Bartsch GE. Fatty acid composition of human adipose tissue related to age, sex, and race. Am J Clin Nutr 20(1): 13-23, 1967. PMID: 6017005.
  42. Insull W, Jr., Lang PD, Hsi BP and Yoshimura S. Studies of arteriosclerosis in Japanese and American men. I. Comparison of fatty acid composition of adipose tissue. J Clin Invest 48(7): 1313-1327, 1969. PMID: 5794253.
  43. Johnson CD, Kingsnorth AN, Imrie CW, McMahon MJ, Neoptolemos JP, McKay C, et al. Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis. Gut 48(1): 62-69, 2001. PMID: 11115824.
  44. Johnson CD, Toh SK and Campbell MJ. Combination of APACHE-II score and an obesity score (APACHE-O) for the prediction of severe acute pancreatitis. Pancreatology 4(1): 1-6, 2004. PMID: 14988652.
  45. Kaiser AM, Saluja AK, Sengupta A, Saluja M and Steer ML. Relationship between severity, necrosis, and apoptosis in five models of experimental acute pancreatitis. Am J Physiol 269(5 Pt 1): C1295-1304, 1995. PMID: 7491921.
  46. Karimgani I, Porter KA, Langevin RE and Banks PA. Prognostic factors in sterile pancreatic necrosis. Gastroenterology 103(5): 1636-1640, 1992. PMID: 1426885.
  47. Katuchova J, Bober J, Harbulak P, Hudak A, Gajdzik T, Kalanin R, et al. Obesity as a risk factor for severe acute pancreatitis patients. Wien Klin Wochenschr 126(7-8): 223-227, 2014. PMID: 24522641.
  48. Kloppel G, Dreyer T, Willemer S, Kern HF and Adler G. Human acute pancreatitis: its pathogenesis in the light of immunocytochemical and ultrastructural findings in acinar cells. Virchows Arch A Pathol Anat Histopathol 409(6): 791-803, 1986. PMID: 3094241.
  49. Lai JP, Bao S, Davis IC and Knoell DL. Inhibition of the phosphatase PTEN protects mice against oleic acid-induced acute lung injury. Br J Pharmacol 156(1): 189-200, 2009. PMID: 19134000.
  50. Lam PP, Cosen Binker LI, Lugea A, Pandol SJ and Gaisano HY. Alcohol redirects CCK-mediated apical exocytosis to the acinar basolateral membrane in alcoholic pancreatitis. Traffic 8(5): 605-617, 2007. PMID: 17451559.
  51. Lankisch PG, Breuer N, Bruns A, Weber-Dany B, Lowenfels AB and Maisonneuve P. Natural history of acute pancreatitis: a long-term population-based study. Am J Gastroenterol 104(11): 2797-2805; quiz 2806, 2009. PMID: 19603011.
  52. Laposata EA and Lange LG. Presence of nonoxidative ethanol metabolism in human organs commonly damaged by ethanol abuse. Science 231(4737): 497-499, 1986. PMID: 3941913.
  53. LaRusch J and Whitcomb DC. Genetics of pancreatitis. Curr Opin Gastroenterol 27(5): 467-474. PMID: 21844754.
  54. Lerch MM and Gorelick FS. Models of acute and chronic pancreatitis. Gastroenterology 144(6): 1180-1193, 2013. PMID: 23622127.
  55. Lloret Linares C, Pelletier AL, Czernichow S, Vergnaud AC, Bonnefont-Rousselot D, Levy P, et al. Acute pancreatitis in a cohort of 129 patients referred for severe hypertriglyceridemia. Pancreas 37(1): 13-12, 2008. PMID: 18580438.
  56. London NJ LT, Lavelle JM, Miles K, West KP, Watkin DF, Fossard DP. Rapid-bolus contrast-enhanced dynamic computed tomography in acute pancreatitis: a prospective study. Br J Surg 78(12): 1452-1456, 1991. PMID: 1773324.
  57. Mareninova OA, Sung KF, Hong P, Lugea A, Pandol SJ, Gukovsky I, et al. Cell death in pancreatitis: caspases protect from necrotizing pancreatitis. J Biol Chem 281(6): 3370-3381, 2006. PMID: 16339139.
  58. Matsumoto S, Mori H, Miyake H, Takaki H, Maeda T, Yamada Y, et al. Uneven fatty replacement of the pancreas: evaluation with CT. Radiology 194(2): 453-458, 1995. PMID: 7824726.
  59. Messmann H, Vogt W, Falk W, Vogl D, Zirngibl H, Leser HG, et al. Interleukins and their antagonists but not TNF and its receptors are released in post-ERP pancreatitis. Eur J Gastroenterol Hepatol 10(7): 611-617, 1998. PMID: 9855088.
  60. Mossner J, Bodeker H, Kimura W, Meyer F, Bohm S and Fischbach W. Isolated rat pancreatic acini as a model to study the potential role of lipase in the pathogenesis of acinar cell destruction. Int J Pancreatol 12(3): 285-296, 1992. PMID: 1289421.
  61. Mutinga M, Rosenbluth A, Tenner SM, Odze RR, Sica GT and Banks PA. Does mortality occur early or late in acute pancreatitis? Int J Pancreatol 28(2): 91-95, 2000. PMID: 11128978.
  62. Navina S, Acharya C, DeLany JP, Orlichenko LS, Baty CJ, Shiva SS, et al. Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity. Sci Transl Med 3(107): 107ra110, 2011. PMID: 22049070.
  63. Navina S and Singh VP. Relationship between obesity and pancreatitis. Pancreapedia: Exocrine Pancreas Knowledge Base, 2015, DOI: 10.3998/panc.2015.18
  64. Nojgaard C, Becker U, Matzen P, Andersen JR, Holst C and Bendtsen F. Progression from acute to chronic pancreatitis: prognostic factors, mortality, and natural course. Pancreas 40(8): 1195-1200. PMID: 21926938.
  65. Nojgaard C, Matzen P, Bendtsen F, Andersen JR, Christensen E and Becker U. Factors associated with long-term mortality in acute pancreatitis. Scand J Gastroenterol 46(4): 495-502. PMID: 21091094.
  66. Nordback I aLK. Clinical pathology of acute necrotising pancreatitis. J Clin Pathol (39: 68-74, ), 1986. PMID: 3950033.
  67. Nordback IH, Clemens JA, Chacko VP, Olson JL and Cameron JL. Changes in high-energy phosphate metabolism and cell morphology in four models of acute experimental pancreatitis. Ann Surg 213(4): 341-349, 1991. PMID: 2009016.
  68. O'Leary DP, O'Neill D, McLaughlin P, O'Neill S, Myers E, Maher MM, et al. Effects of abdominal fat distribution parameters on severity of acute pancreatitis. World J Surg 36(7): 1679-1685, 2012. PMID: 22491816.
  69. Olsen TS. Lipomatosis of the pancreas in autopsy material and its relation to age and overweight. Acta Pathol Microbiol Scand A 86A(5): 367-373, 1978. PMID: 716899.
  70. Otsuki M. Chronic pancreatitis in Japan: epidemiology, prognosis, diagnostic criteria, and future problems. J Gastroenterol 38(4): 315-326, 2003. PMID: 12743770.
  71. P Noel KP, C Durgampudi, R Trivedi, C Oliveira, M Crowell, R Pannala, K Lee, R Brand, J Chennat, A et al. Peripancreatic fat necrosis worsens acute pancreatitis independent of pancreatic necrosis via unsaturated fatty acids increased in human pancreatic necrosis collections. Gut, 2014. PMID: 25500204
  72. Pandol SJ, Saluja AK, Imrie CW and Banks PA. Acute pancreatitis: bench to the bedside. Gastroenterology 132(3): 1127-1151, 2007. PMID: 17383433.
  73. Panek J, Sztefko K and Drozdz W. Composition of free fatty acid and triglyceride fractions in human necrotic pancreatic tissue. Med Sci Monit 7(5): 894-898, 2001. PMID: 11535930.
  74. Papachristou GI, Papachristou DJ, Avula H, Slivka A and Whitcomb DC. Obesity increases the severity of acute pancreatitis: performance of APACHE-O score and correlation with the inflammatory response. Pancreatology 6(4): 279-285, 2006. PMID: 16636600.
  75. Park KT, Kang DH, Choi CW, Cho M, Park SB, Kim HW, et al. Is high-dose nafamostat mesilate effective for the prevention of post-ERCP pancreatitis, especially in high-risk patients? Pancreas 40(8): 1215-1219, 2011. PMID: 21775918.
  76. Patel K TR, Durgampudi C, Noel P, Cline RA, DeLany JP, Navina S, Singh VP. Lipolysis of visceral adipocyte triglyceride by pancreatic lipases converts mild acute pancreatitis to severe pancreatitis independent of necrosis and inflammation. Am J Pathol  Mar;185(3):808-19, 2015. PMID: 25579844.
  77. Patel KS, Noel P and Singh VP. Potential influence of intravenous lipids on the outcomes of acute pancreatitis. Nutr Clin Pract  29(3): 291-294, 2014. PMID: 24687866.
  78. Perez A WE, Brooks DC, Moore FD Jr, Hughes MD, Sica GT, Zinner MJ, Ashley SW, Banks PA. Is severity of necrotizing pancreatitis increased in extended necrosis and infected necrosis? Pancreas Oct;25(3):229-33, 2002. PMID: 12370532.
  79. Petrov MS, Kukosh MV and Emelyanov NV. A randomized controlled trial of enteral versus parenteral feeding in patients with predicted severe acute pancreatitis shows a significant reduction in mortality and in infected pancreatic complications with total enteral nutrition. Digestive Surg 23(5-6): 336-344; discussion 344-335, 2006. PMID: 17164546.
  80. Pinnick KE, Collins SC, Londos C, Gauguier D, Clark A and Fielding BA. Pancreatic ectopic fat is characterized by adipocyte infiltration and altered lipid composition. Obesity (Silver Spring) 16(3): 522-530, 2008. PMID: 18239594.
  81. Porter KA and Banks PA. Obesity as a predictor of severity in acute pancreatitis. Int J Pancreatol 10(3-4): 247-252, 1991. PMID: 1787336.
  82. Robertson MB, Choe KA and Joseph PM. Review of the abdominal manifestations of cystic fibrosis in the adult patient. Radiographics 26(3): 679-690, 2006. PMID: 16702447.
  83. Rosso E, Casnedi S, Pessaux P, Oussoultzoglou E, Panaro F, Mahfud M, et al. The role of "fatty pancreas" and of BMI in the occurrence of pancreatic fistula after pancreaticoduodenectomy. J Gastrointest Surg 13(10): 1845-1851, 2009. PMID: 19639369.
  84. Ruixing Y, Qiming F, Dezhai Y, Shuquan L, Weixiong L, Shangling P, et al. Comparison of demography, diet, lifestyle, and serum lipid levels between the Guangxi Bai Ku Yao and Han populations. J Lipid Res 48(12): 2673-2681, 2007. PMID: 17890682.
  85. Sadr-Azodi O, Orsini N, Andren-Sandberg A and Wolk A. Abdominal and total adiposity and the risk of acute pancreatitis: a population-based prospective cohort study. Am J Gastroenterol 108(1): 133-139, 2013. PMID: 23147519.
  86. Saisho Y, Butler AE, Meier JJ, Monchamp T, Allen-Auerbach M, Rizza RA, et al. Pancreas volumes in humans from birth to age one hundred taking into account sex, obesity, and presence of type-2 diabetes. Clin Anat 20(8): 933-942, 2007. PMID: 17879305.
  87. Schmitz-Moormann P. Comparative radiological and morphological study of the human pancreas. IV. Acute necrotizing pancreatitis in man. Pathol Res Pract 171(3-4): 325-335, 1981. PMID: 7279784.
  88. Scott RF, Lee KT, Kim DN, Morrison ES and Goodale F. Fatty Acids of Serum and Adipose Tissue in Six Groups Eating Natural Diets Containing 7 to 40 Per Cent Fat. Am J Clin Nutr 14: 280-290, 1964. PMID: 14157830.
  89. Sempere L, Martinez J, de Madaria E, Lozano B, Sanchez-Paya J, Jover R, et al. Obesity and fat distribution imply a greater systemic inflammatory response and a worse prognosis in acute pancreatitis. Pancreatology 8(3): 257-264, 2008. PMID: 18497538.
  90. Seta T, Noguchi Y, Shimada T, Shikata S and Fukui T. Treatment of acute pancreatitis with protease inhibitors: a meta-analysis. Eur J Gastroenterol Hepatol 16(12): 1287-1293, 2004. PMID: 15618834.
  91. Shin KY, Lee WS, Chung DW, Heo J, Jung MK, Tak WY, et al. Influence of obesity on the severity and clinical outcome of acute pancreatitis. Gut Liver 5(3): 335-339, 2011. PMID: 21927663.
  92. Siech M, Zhou Z, Zhou S, Bair B, Alt A, Hamm S, et al. Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL). Am J Physiol Gastrointest Liver Physiol 297(6): G1163-1171, 2009. PMID: 19779015.
  93. Soyer P, Spelle L, Pelage JP, Dufresne AC, Rondeau Y, Gouhiri M, et al. Cystic fibrosis in adolescents and adults: fatty replacement of the pancreas--CT evaluation and functional correlation. Radiology 210(3): 611-615, 1999. PMID: 10207457.
  94. Spivak W, Morrison C, Devinuto D and Yuey W. Spectrophotometric determination of the critical micellar concentration of bile salts using bilirubin monoglucuronide as a micellar probe. Utility of derivative spectroscopy. Biochem J 252(1): 275-281, 1988. PMID: 3421905.
  95. Sun E TM, Kapoor S, Chakravarty R, Salhab A, Buscaglia JM, Nagula S. Poor compliance with ACG guidelines for nutrition and antibiotics in the management of acute pancreatitis: a North American survey of gastrointestinal specialists and primary care physicians. JOP 14(3):221-7, 2013. PMID: 23669469.
  96. Sztefko K and Panek J. Serum free fatty acid concentration in patients with acute pancreatitis. Pancreatology 1(3): 230-236, 2001. PMID: 12120200.
  97. Tenner S SG, Hughes M, Noordhoek E, Feng S, Zinner M, Banks PA. Relationship of necrosis to organ failure in severe acute pancreatitis. Gastroenterology 113(3):899-903, 1997. PMID: 9287982.
  98. Thandassery RB, Appasani S, Yadav TD, Dutta U, Indrajit A, Singh K, et al. Implementation of the Asia-Pacific Guidelines of Obesity Classification on the APACHE-O Scoring System and Its Role in the Prediction of Outcomes of Acute Pancreatitis: A Study from India. Dig Dis Sci, 2013. PMID: 24374646.
  99. Thomas LW. The chemical composition of adipose tissue of man and mice. Q J Exp Physiol Cogn Med Sci 47: 179-188, 1962. PMID: 13920823.
  100. Trapnell JE, Rigby CC, Talbot CH and Duncan EH. A controlled trial of Trasylol in the treatment of acute pancreatitis. Brit J Surg 61(3): 177-182, 1974. PMID: 4595174.
  101. Trapnell JE, Talbot CH and Capper WM. Trasylol in acute pancreatitis. Am J Dig Dis 12(4): 409-412, 1967. PMID: 5336018.
  102. Ueda T, Takeyama Y, Yasuda T, Matsumura N, Sawa H, Nakajima T, et al. Significant elevation of serum interleukin-18 levels in patients with acute pancreatitis. J Gastroenterol 41(2): 158-165, 2006. PMID: 16568375.
  103. Ueshima H, Stamler J, Elliott P, Chan Q, Brown IJ, Carnethon MR, et al. Food omega-3 fatty acid intake of individuals (total, linolenic acid, long-chain) and their blood pressure: INTERMAP study. Hypertension 50(2): 313-319, 2007. PMID: 17548718.
  104. Vaughn DD, Jabra AA and Fishman EK. Pancreatic disease in children and young adults: evaluation with CT. Radiographics 18(5): 1171-1187, 1998. PMID: 9747614.
  105. Vlada AC SB, Perry A, Trevino JG, Behrns KE, Hughes SJ. Failure to follow evidence-based best practice guidelines in the treatment of severe acute pancreatitis. HPB 15(10):822-827, 2013. PMID: 24028271.
  106. Warshaw AL, Lesser PB, Rie M and Cullen DJ. The pathogenesis of pulmonary edema in acute pancreatitis. Ann Surg 182(4): 505-510, 1975. PMID: 1101836.
  107. Wereszczynska-Siemiatkowska U, Mroczko B and Siemiatkowski A. Serum profiles of interleukin-18 in different severity forms of human acute pancreatitis. Scand J Gastroenterol 37(9): 1097-1102, 2002. PMID: 12374236.
  108. Wu RP, Liang XB, Guo H, Zhou XS, Zhao L, Wang C, et al. Protective effect of low potassium dextran solution on acute kidney injury following acute lung injury induced by oleic acid in piglets. Chin Med J (Engl)125(17): 3093-3097, 2012. PMID: 22932187.
  109. Wu XM, Ji KQ, Wang HY, Li GF, Zang B and Chen WM. Total enteral nutrition in prevention of pancreatic necrotic infection in severe acute pancreatitis. Pancreas 39(2): 248-251, 2010. PMID: 19910834.
  110. Yang F, Wu H, Li Y, Li Z, Wang C, Yang J, et al. Prevention of severe acute pancreatitis with octreotide in obese patients: a prospective multi-center randomized controlled trial. Pancreas 41(8): 1206-1212, 2012. PMID: 23086244.
  111. Yashima Y, Isayama H, Tsujino T, Nagano R, Yamamoto K, Mizuno S, et al. A large volume of visceral adipose tissue leads to severe acute pancreatitis. J Gastroenterol 46(10): 1213-1218, 2011. PMID: 21805069.