New Insights Into Acute Pancreatitis: Peter J. Lee and Georgios I. Papachristou

Reviews
New insights into acute pancreatitis

Peter J. Lee1 and Georgios I. Papachristou2*
Abstract | The incidence of acute pancreatitis continues to increase worldwide, and it is one
of the most common gastrointestinal causes for hospital admission in the USA. In the past decade,
substantial advancements have been made in our understanding of the pathophysiological
mechanisms of acute pancreatitis. Studies have elucidated mechanisms of calcium-mediated
acinar cell injury and death and the importance of store-operated calcium entry channels
and mitochondrial permeability transition pores. The cytoprotective role of the unfolded protein
response and autophagy in preventing sustained endoplasmic reticulum stress, apoptosis
and necrosis has also been characterized, as has the central role of unsaturated fatty acids in
causing pancreatic organ failure. Characterization of these pathways has led to the identification
of potential molecular targets for future therapeutic trials. At the patient level, two classification
systems have been developed to classify the severity of acute pancreatitis into prognostically
meaningful groups, and several landmark clinical trials have informed management strategies
in areas of nutritional support and interventions for infected pancreatic necrosis that have
resulted in important changes to acute pancreatitis management paradigms. In this Review,
we provide a summary of recent advances in acute pancreatitis with a special emphasis on
pathophysiological mechanisms and clinical management of the disorder.
Mitochondrial permeability
Acute pancreatitis is an inflammatory disorder of the diabetes after their first episode of acute pancreatitis, and
transition pores pancreas that is associated with substantial morbidity a quarter of all patients with acute pancreatitis develop
Proteins located in the and mortality. Well-known causes of acute pancreati- exocrine pancreatic insufficiency15,16. Necrotizing pan-
inner membrane of the tis such as pancreatic ductal obstruction secondary to creatitis represents the most severe form of parenchymal
mitochondrion, which when
gallstones (the most common cause), alcohol, endo- injury in acute pancreatitis, and it occurs in 5–10% of
open can cause rapid
mitochondrial depolarization scopic retrograde cholangiopancreatography (ERCP) patients3. In the USA, one in two patients with necrotiz-
and dysfunction. and various drugs trigger pathological cellular path- ing pancreatitis files for disability within a year, and qual-
ways and organelle dysfunction that culminate in the ity of life after acute pancreatitis is generally reported to
Calcium release-activated hallmarks of acute pancreatitis — acinar cell death and be markedly reduced12,14. Additionally, ~18% of those
channels
Calcium ion channels that
local and systemic inflammation1–3. The global inci- with acute pancreatitis experience recurrence, and 8%
are activated when calcium dence of acute pancreatitis is 34 affected individuals develop chronic pancreatitis, both of which lead to addi-
stores are depleted from the per 100,000 person-years, and it has been increasing tional financial burden on the health-care system17,18.
endoplasmic reticulum. worldwide4. Acute pancreatitis is currently one of the The annual health-care cost attributable to readmissions
most common gastrointestinal disorders to cause hos- owing to acute pancreatitis exceeded $3.8 billion in 2013
pitalization in the USA and costs the health-care system in the USA6.
$9.3 billion annually5–7. The worldwide obesity epidemic Despite the global burden of disease, currently, no
might also contribute to the increasing global incidence effective therapeutic agents exist to treat or prevent
1
Division of Gastroenterology,
Department of Medicine,
of acute pancreatitis8. Several complications of obesity acute pancreatitis. Nevertheless, important basic sci-
Hospital of the University of that are rising in incidence, including cholelithiasis, ence advances have been made to identify new cellular
Pennsylvania, Philadelphia, hypertriglyceridaemia and diabetes, are independently targets for potential drug development. For example,
PA, USA. associated with acute pancreatitis9,10. elucidation of calcium signalling pathways in acute pan-
2
Division of Gastroenterology, Acute pancreatitis-related mortality has decreased creatitis led to the discovery of mitochondrial permeability
Hepatology and Nutrition, over the past decade from 1.6% to 0.8%11. This trend is transition pores and calcium release-activated channels19–21,
University of Pittsburgh
Medical Center, Pittsburgh,
probably due to improvements in timely and accurate both of which hold promise as therapeutic targets.
PA, USA. diagnoses, as well as in the care of critically ill patients Recognition of mitochondrial dysfunction as a key
*e-mail: papachri@pitt.edu with acute pancreatitis. However, morbidity and long- driver of acute pancreatitis culminated in a multicentre
https://doi.org/10.1038/ term sequelae remain substantial12–14. For example, up trial examining the effect of early high-energy enteral
s41575-019-0158-2 to 40% of patients develop new-onset prediabetes or nutrition on outcomes, which is currently ongoing22. The
NATuRe RevIeWS | GASTroEnTEroLogY & HEPAToLogY volume 16 | AUGUST 2019 | 479

Reviews
Key points can range from gland oedema and peripancreatic fat
stranding (that is, hazy interface between the pancreatic
• The incidence of acute pancreatitis is 34 per 100,000 people in the general parenchyma and surrounding fat on a CT scan; inter-
population, and it is rising worldwide. stitial pancreatitis) to lack of contrast enhancement in
• In addition to premature trypsinogen activation, dysfunctional calcium signalling, the parenchyma (necrotizing pancreatitis) and peripan-
impaired autophagy, endoplasmic reticulum stress, the unfolded protein response creatic fluid collections. A contrast-enhanced CT scan
and mitochondrial dysfunction are key cellular processes in the pathogenesis of acute is required to diagnose necrotizing pancreatitis, and
pancreatitis.
necrosis might not develop until 72 hours after symp-
• Well-designed, adequately powered trials are needed to define and examine the tom onset. For this reason, obtaining a CT scan within
efficacy of aggressive fluid resuscitation.
72 hours of symptom onset is discouraged by published
• Infected walled-off pancreatic necrosis should be managed with an endoscopic guidelines including those of the American College
step-up strategy.
of Gastroenterology and American Gastroenterology
• Diabetes and exocrine pancreatic insufficiency are common complications after Association3,27,28,30.
an episode of acute pancreatitis, occurring in up to one in five patients following
acute pancreatitis.
Nomenclature for local complications
• Acute pancreatitis impairs long-term quality of life, and many patients experience
Local complications mainly refer to collections that can
repeated hospitalizations.
form in and/or around the pancreas. The nomenclature
for these complications, which are broadly labelled pan-
mechanism of obesity-mediated pancreatitis severity has creatic fluid collections, has been updated by the revised
also been elucidated9. Free fatty acids appear to mediate Atlanta classification in 2013 (ref.3). Collections that con-
end-organ failure and have been shown to be released sist purely of fluid with minimal or no solid debris are
from the lipolysis of triglycerides stored in the intrapan- called acute fluid collections. Collections that contain
creatic and peripancreatic adipose tissue23–25. Clinically, necrotic debris from pancreatic and/or peripancreatic
several landmark trials have addressed key management necrosis are defined as acute necrotic collections. The
questions in acute pancreatitis, including the timing terms pseudocyst and walled-off pancreatic necrosis
and mode of nutrition, timing of cholecystectomy in (WOPN) are used when these collections persist for
gallstone-related acute pancreatitis and management of 4 weeks or longer and become organized and encapsu-
infected necrosis. In this Review, we describe important lated, respectively. This nomenclature aims to simplify
advancements made in our understanding of the mecha and unify the definitions of local pancreatic compli-
nisms of acute pancreatitis and highlight important cations, with each term carrying distinct implications
potential therapeutic targets. Additionally, informed by for management3.
the latest evidence, we discuss current management of
acute pancreatitis. Pathophysiology
Cellular events central to the pathogenesis of acute pan-
Diagnosis and nomenclature creatitis include pathological calcium signalling2,20,31,32,
Diagnostic criteria mitochondrial dysfunction19,33,34, premature trypsinogen
Diagnosis of acute pancreatitis is made when two of the activation within the acinar cells and macrophages35–41,
three following criteria are met: typical abdominal pain; endoplasmic reticulum (ER) stress, impaired unfolded
serum amylase and/or lipase elevation more than three protein response (UPR)33,42–44 and impaired autophagy33,45.
times the upper limit of normal; and imaging findings These events are triggered by common acinar cell tox-
consistent with acute pancreatitis. ins, such as alcohol, nicotine and bile acids. Intraductal
No standardized reference range exists for serum events, such as increased pressure caused by ductal
amylase or lipase levels owing to different laboratory obstruction, luminal acidification and ductal cell expo-
techniques in measuring these enzymes. The upper limit sure to bile acid, can also indirectly trigger these events.
of normal ranges between 100 and 300 U/l for amylase The crosstalk between acinar cells and the immune
and 50 and 160 U/l for lipase. The limitations of serum system perpetuates an inflammatory response46–48. At a
amylase and lipase as diagnostic tests for acute pancre- locoregional level, the mediatory role of intrapancreatic
Local complications atitis deserve mention. Amylase levels can be normal in and peripancreatic fat saponification and ischaemia-
A collective term to denote patients with alcoholic or hypertriglyceridaemic pancre- conditioned mesenteric lymph in acute pancreatitis
collections that form within atitis; therefore, diagnosis might be challenging in these severity has been recognized23,24,49–52. Characterization of
and/or around pancreatic
parenchyma as a result of
populations26,27. Furthermore, bowel perforation, infarc- these mechanisms has enabled identification of several
acute pancreatitis. tion, obstruction and abdominal aortic aneurysm can potential therapeutic targets for future drug studies in
also increase amylase levels. Similarly, lipase can be ele- acute pancreatitis (Table 2).
Unfolded protein response vated in acute intestinal pathologies, cholecystitis, peptic
(UPR). A collective term to
ulcer disease and biliary obstruction27. Thus, imaging Animal models
denote a set of compensatory
cellular responses to modalities complement diagnostic work-up for acute Owing to the practical challenges of obtaining human
endoplasmic reticulum stress pancreatitis when diagnosis is in doubt. These diagnostic pancreatic tissue during an acute pancreatitis episode,
criteria are agreed upon by all published guidelines for all the early cellular events during acute pancreatitis
Autophagy acute pancreatitis27–30. Aetiologies of acute pancreatitis have been investigated using animal models53. Animal
An orderly mechanism that
processes, degrades and
are shown in Table 1. models help identify pathophysiological mechanisms
recycles various unwanted CT of the abdomen is the most commonly used imag- to develop and test therapeutic agents. The choice of
cellular components. ing modality to diagnose acute pancreatitis. Findings model type is determined by the pathophysiological
480 | AUGUST 2019 | volume 16 www.nature.com/nrgastro

Reviews
Table 1 | Common and uncommon aetiologies of acute pancreatitis toxicity in humans) and a different distribution of paren-
chymal injury to that seen in humans (diffuse in rodents
Aetiology Examples Suggestive clinical data versus patchy in humans)53,56.
Gallstone NA Choledocholithiasis; ALT over three Alcohol and lipopolysaccharide can be administered
times the upper limit of normal, which in rodents to simulate a model relevant to alcohol-
is variable in different laboratories;
cholelithiasis when other causes have related pancreatitis. This model was used to ascertain
been ruled out mechanisms of alcohol-induced changes in acinar cell
lipid metabolism and subsequent acinar cell injury57,58,
Alcohol NA Drinking history >35 standard drinks
per week for >5 years but it is primarily used to study chronic pancreatitis.
Some investigators utilize models that involve pancre-
Trauma • ERCP Pancreatitis following one of the listed
• EUS with FNA procedures atic duct manipulation to study intraductal events and
• Aortic surgery their association with acute pancreatitis initiation59,60.
• Pancreatic resection American opossums have been used to elucidate the
Pre-malignant • Intraductal papillary • Pre-existing cyst with recurrent pathophysiological mechanism of gallstone-associated
and malignant mucinous neoplasm idiopathic episodes; dilated pancreatitis because of the similarity of their pancreati-
conditions • Ductal adenocarcinoma pancreatic duct in a patient without cobiliary ductal anatomy to that of humans61,62. Studies
prior history of chronic pancreatitis using this model revealed the importance of pancreatic
• Mass with duct dilatation; weight
loss; diabetes diagnosis ductal obstruction as the central initiator of gallstone
acute pancreatitis. However, opossums cannot be bred
Metabolic • Hypertriglyceridaemia272 • Triglyceride level >1,000 mg/dl in the laboratory, and there is also a high intra-animal
• Hypercalcaemia • Elevated calcium level when no other
cause is apparent variability, limiting its popularity as a model63,64.
Ductal cannulation and infusion methods are used
Genetic PRSS1, SPINK1, CFTR, CASR, First-degree family history of
CTRC pancreatitis or pancreatic cancer ; to study the pathophysiology of post-ERCP pancre-
pancreatitis onset <30 years of age atitis and gallstone pancreatitis in rodents and guinea
pigs59. The drawbacks of these models include the need
Autoimmune NA Diagnostic criteria have been
pancreatitis published elsewhere272 for surgery and anaesthesia. Although animal-based
experimental models have improved our understand-
Drugs Mesalamine, furosemide, When all other causes are ruled out,
azothioprine, losartan if the patient is on a class I drug273 ing of the pathogenesis of acute pancreatitis, obvious
and a temporal relationship between differences exist between human and rodent pancreati-
exposure and acute pancreatitis is tis; therefore, the extrapolation of findings from animal
feasible studies to human pancreatitis should be done cautiously
Infections Viral, bacterial and parasitic When pancreatitis occurs in the considering these limitations53. Encouragingly, several
context of other clinical features of ex vivo human studies showed that many of the mech-
the infection anisms identified in the animal studies are applicable
Idiopathic NA When all causes have been ruled out to human pancreatitis models1,65. For example, when
ALT, alanine aminotransferase; ERCP, endoscopic retrograde cholangiopancreatography ; acinar cell responses to a muscarinic agonist and bile
EUS, endoscopic ultrasonography; FNA, fine-needle aspiration; NA, not applicable. acids were examined in human acini extracted from
cadaveric pancreata, trypsinogen activation, ER stress,
mechanism of interest as well as the disease phase of dysfunctional autophagy and mitochondrial dysfunc-
interest. Currently, owing to low-cost and available tion were identified, similar to the responses seen in
strains with genetic deletions, mice are the most widely animal models1.
ER stress
A state in which the demand of
utilized species53.
cellular machinery overwhelms The cerulein-induced pancreatitis model in rodents Updates on cellular mechanisms
the capacity of the is commonly used to investigate early cellular events Calcium signalling. Pathological elevation of Ca2+ con
endoplasmic reticulum (ER), during acute pancreatitis. This model helped charac- centration in acinar cells is a central event in acute
leading to accumulation of
terize the processes of impaired autophagy, pathologi- pancreatitis that mediates pro-c ell death and pro-
misfolded proteins.
cal calcium signalling and ER stress, which are central inflammatory pathways such as premature trypsinogen
Cholecystokinin to the pathogenesis of acute pancreatitis21,33,44,54. In this activation, activation of nuclear factor-κB (NF-κB) and
A hormone that causes model, acute pancreatitis is induced by administering mitochondrial dysfunction48,66,67 (Fig. 1). In a physio-
gallbladder contraction and supraphysiological doses of cerulein (a cholecystokinin logical state, Ca2+ is released from the ER as part of a
pancreatic enzyme secretion.
analogue) at repeated intervals. The effects of cerulein signalling mechanism that initiates zymogen exocytosis
Nuclear factor-κB on the pancreas are dose-dependent. At a high dose, and stimulates production of ATP in the mitochondria21.
(NF-κB). A transcription factor it causes acinar cells to release digestive enzymes. However, the increase in cytosolic Ca2+ concentration
that can cause production of At a supramaximal dose, it inhibits enzyme release is only transient, as two ATP-dependent calcium chan-
pro-inflammatory cytokines
and causes premature digestive enzyme activation55. nels rapidly clear the cytosolic calcium: the smooth ER
and chemokines.
Cerulein-induced pancreatitis models are popular owing Ca2+ channels (SERCAs) move Ca2+ back into the ER,
Inositol 1,4,5-trisphosphate to their low cost and high reproducibility. Severe acute and the plasma membrane Ca2+ channels (PMCAs)
receptor pancreatitis can be studied by modifying the cerulein exude Ca2+ out of the cell21. Alcohol and bile acids
(Ins(1,4,5,)P3R). A glycoprotein administration protocol to increase acute pancreatitis can disrupt this homeostasis and cause a global, sus-
complex located in the
endoplasmic reticulum that
severity. The disadvantages of this model include a clin- tained pathological cytosolic Ca2+ elevation through
can operate as a calcium ically irrelevant initiating mechanism (an excessive cho- the inositol 1,4,5-trisphosphate receptor (Ins(1,4,5)P3R)
channel. linergic stimulus is analogous only to scorpion venom signalling pathway. For example, palmitoleic acid ethyl

Reviews
Table 2 | Potential therapeutic targets and target pathways in acute pancreatitis

Agent Target Target pathway Status
GSK-7975A ORAI1 Store-operated calcium entry Preclinical20,31
channel; calcium signalling pathway
CM4620 Calcium release-activated Store-operated calcium entry Phase II274
calcium channel channel; calcium signalling pathway
TRO40303 Mitochondrial permeability Mitochondrial dysfunction Preclinical19
transition pore
Disaccharide trehalose Unknown Autophagy Preclinical33
HMG-CoA inhibitors HMG-CoA Unfolded protein response Commercially available;
clinical trial in progress97
Lactated Ringer’s Gi protein-coupled NLRP3 inflammasome pathway ; Pilot clinical trial
solution receptor 81 binds free fatty acid completed133,138,195
Pentoxifylline Synthesis of TNF Phosphodiesterase; inflammatory Pilot clinical trial in
response progress144
Orlistat Unsaturated free fatty acids Hydrolysis of triglycerides to free Commercially available;
fatty acids; lipotoxicity no trials conducted
Tocilizumab IL-6 Inhibition of IL-6 receptor ; Preclinical in acute
inflammatory response pancreatitis in progress;
successful clinical trials
in other diseases145,147,275
HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA ; NLRP3, LRR- and pyrin domain-containing 3; ORAI1, calcium release-activated
calcium channel protein 1.
ester is a non-oxidative, metabolic product of alcohol animal models and human acinar cells19,34. TRO40303
by the acinar cells that open Ins(1,4,5)P3Rs, which are has been found to be safe and well-tolerated by patients
Ca2+ channels located in the ER21. This pathway results in when tested in patients with acute myocardial infarction
excessive Ca2+ release from the major intracellular Ca2+ undergoing intervention. Thus, it could be efficiently
store, the ER lumen20,31,66,68. Ca2+ concentration build-up examined in patients with acute pancreatitis72,73. The
causes calcium release-activated calcium channel protein benefits of ATP replenishment through high-calorie
1 (ORAI1) to promote Ca2+ entry into the cell from the nutrition supplementation are also being explored in a
outside, further increasing and sustaining a toxic cellu- multicentre trial of acute pancreatitis22.
lar Ca2+ concentration2,69. Ductal obstruction, which can
occur in post-ERCP pancreatitis and gallstone pancre- Premature trypsinogen activation. Premature trypsino-
atitis, is thought to cause an increase in Ca2+ entry from gen activation is another important pathological cellu-
outside the cell through PIEZO1 — a plasma membrane lar event that can lead to acinar cell necrosis. Various
mechanoreceptor that has cation channel properties and pancreas insults (for example, trauma, pancreatic ductal
is activated by pressure70. obstruction and alcohol) can initiate fusion of the lyso-
The cellular Ca2+ concentration overload causes the some with the zymogens within the acinar cells, a process
mitochondrial permeability transition pores to open in called colocalization37,40 (Fig. 2). Colocalization occurs
a high-c onductance state, and this process results in the context of other toxin-provoked intra-acinar
in the loss of the membrane potential needed to gene cell events, such as decreased exocytosis of protease-
rate ATP34,67,71. ATP depletion perpetuates the toxic containing zymogen granules secondary to cytoskeletal
Ca2+ concentration by disrupting the ATP-dependent dysfunction and increased synthesis of lysosomal and
SERCAs and PMCAs from clearing excessive cytosolic digestive enzymes74. Once the zymogen granule fuses
calcium and impairs cytoprotective mechanisms that with the lysosome, cathepsin B, a key lysosomal enzyme,
need ATP such as autophagy and the UPR21,33. Thus, the activates trypsinogen to trypsin40. The mechanism
mitochondrial dysfunction secondary to cellular calcium of trypsin and cathepsin B release from the vacuoles
toxicity ultimately leads to acinar cell necrosis. remains elusive. Some have suggested that trypsin
Zymogen granules
Vesicles that contain various
On the basis of the central importance of Ca2+ con- causes membrane fragility leading to leaky endocytic
pancreatic enzyme precursors. centration toxicity, ORAI1 channel inhibitors that vacuoles that release trypsin and cathepsin B36. Other
prevent calcium entry into the acinar cells have been studies have suggested that vacuoles might rupture
Cathepsin B developed20,31. ORAI1 inhibitors have been shown to against the cytoskeleton and/or organelles37. Lysosomal
A lysosomal protease.
prevent necrosis in animal models of acute pancre- and zymogen granule membranes can also become
Necroptosis atitis and human acinar cells, reducing both the local fragile from the metabolic products of alcohol and the loss
A regulated form of cell death. and systemic extent of injury20. Preventing ATP deple- of membrane-stabilizing glycoprotein 2, respectively75,76.
tion through inhibition of mitochondrial permeability Once released, trypsin causes autodigestion within and
Receptor-interacting transition pore opening with 3,5-seco-4-nor-cholestan- outside the acinar cells, and cathepsin B release causes
protein kinase
(RIP). A type of protein kinase
5-one oxime-3-ol (TRO40303) also has therapeutic necroptosis, a regulated form of necrosis36,77. Necroptosis
that is implicated in regulation potential. TRO40303 prevented membrane potential is mediated via the receptor-interacting protein kinase
of cell death. loss and necrosis in alcohol-related acute pancreatitis (RIP), including RIP1–RIP3, and mixed lineage kinase

Reviews
domain-like (MLKL) pathway78,79, in which MLKL is released by damaged acinar cells during pancreatitis.
phosphorylated by RIP3, leading to its oligomerization. Interestingly, trypsinogen activation also occurs within
MLKL oligomers then translocate to the plasma mem- macrophages in response to pancreatitis and results
brane and ultimately cause plasma membrane punc- in macrophages becoming pro-inflammatory41. This
ture, resulting in spillage of cellular contents and finding challenges the long-held notion that premature
necroptosis80. Inhibition of the RIP1–RIP3 pathway trypsinogen activation occurs exclusively within the
by genetic modulation or necrostatin (an inhibitor acinar cells.
of RIP1) decreases severity of acinar cell injury and
therefore represents a potential target for acute pan- Autophagy, endoplasmic reticulum stress and the
creatitis therapy77,80. Intracytosolic protease activation unfolded protein response. Pathogenesis of acute pan-
also causes lysosomal membrane disruption, and this creatitis is also driven by impaired cytoprotective
process leads to activation of caspase 3 through mito- mechanisms, such as autophagy and the UPR. Macro-
chondrial release of cytochrome c78. Caspase 3 subse- autophagy is a cytoprotective mechanism that processes
quently mediates apoptosis. Macrophages are among the and recycles various cytoplasmic contents, which are
first immune cells to respond to the chemoattractants aged, defective or damaged45. Selective macro-autophagy
refers to processing and recycling of specific damaged
organelles and misfolded proteins. Acinar cells are
Alcohol highly efficient in producing proteins. Thus, the protein
CCK
Bile acid processing and transporting machinery and the mech-
Acinar cell
anism of unimpaired autophagy are critical to the sur-
1 vival of acinar cells. Autophagy is completed through
a series of steps that start with the enucleation of cyto-
Premature Activation solic contents within an open double membrane formed
trypsinogen Impaired of NF-κB
activation autophagy pathway from the ER, Golgi apparatus and plasma membrane54
(Fig. 3). The double membrane edges meet to form an
5 6 7 autophagosome; this step is mediated by autophagy-
PIEZO1
related proteins (ATGs). Fusion of the autophagosome
with the lysosome and degradation of the enclosed con-
Ductal tents are the final steps33,45. Genetic knockout of ATG5,
hypertension ATG7 and lysosome-associated membrane proteins has
resulted in pancreatitis with extensive inflammation in
Calcium mouse models of acute pancreatitis45,81,82. Additionally,
ORAI1
impaired autophagy results in trypsinogen activation,
MPTP ER stress and mitochondrial dysfunction, and as a
↑ Ca2+ result, acinar cells become more susceptible to other
CypD MPTP
Ins(1,4,5)P3R 2 insults and death33,43,78,83,84. Thus, restoration of effi-
opening PMCA cient macro-autophagy in the acinar cell seems to be
3
ER
an attractive therapeutic target. The disaccharide tre-
Mitochondrion SERCA halose, which increases the efficiency of autophagy,
reduces pancreatic injury and acute pancreatitis sever-
↓ ATP ity in animal models and holds promise as a potential
4 therapeutic agent in acute pancreatitis33. However, the
mechanism by which trehalose induces autophagy has
Necrosis
not been established85.
ER stress refers to the accumulation of misfolded
Fig. 1 | Calcium-mediated mitochondrial dysfunction and cell death in acute
and/or unfolded proteins within the ER lumen. It occurs
pancreatitis. In acinar cells, alcohol, cholecystokinin (CCK) and bile acid cause inositol
1,4,5-trisphosphate receptor (Ins(1,4,5)P3R)-mediated calcium release from the when the capacity of the ER to efficiently process and
endoplasmic reticulum (ER) (1). The resulting low calcium concentration in the ER eliminate proteins is overwhelmed86. When ER stress
triggers opening of calcium release-activated calcium channel protein 1 (ORAI1), devastates the protective cellular responses, apoptosis
through which calcium enters the cell from the extracellular space (2). This results ensues87. Given the heavy protein production of aci-
in pathological global calcium concentration elevation. Calcium elevation results in nar cells, the pancreas is particularly vulnerable to ER
opening of mitochondrial permeability transition pores (MPTPs) to a high-conductance stress, which occurs frequently in acinar cells in acute
state, and loss of membrane potential across the mitochondrial membrane ensues (3). pancreatitis33,43,83,88. Common pancreas toxins (for exam-
This process results in mitochondrial dysfunction and necrosis. Mitochondrial ple, alcohol and its metabolites) cause ER stress by both
dysfunction leads to ATP depletion, which impairs ATP-dependent mechanisms to increasing the demand for the production of proteins
reduce cytosolic calcium (4). This process then accentuates and perpetuates the
such as trypsinogen, chymotrypsinogen, lipase and lyso
pathological calcium toxicity. Pathological calcium elevation also causes other cytotoxic
pathways (5), including premature trypsinogen activation, autophagy impairment (6) somal enzyme cathepsin B and reducing the cellular
and activation of the nuclear factor-κB (NF-κB) pathway (7). The NF-κB pathway leads ability to process and recycle unwanted proteins (that
to production of pro-inflammatory mediators. The PIEZO1 mechanoreceptor, which is, dysfunctional autophagy and mitochondrial dysfunc-
contains cation channel properties and is activated by pressure, also promotes increased tion)33,43. During ER stress, acinar cells activate the UPR
calcium entry from outside the acinar cell (8). CypD, cyclophilin D; PMCA: plasma to restore cellular homeostasis. The UPR alleviates ER
membrane Ca2+ channel; SERCA, smooth ER Ca2+ channel. stress by upregulating the ER degradation machinery for

Reviews
Alcohol and its downstream effectors, such as transcriptional factor

pancreatic toxins CEBP homologous protein (CHOP), promote apopto-
Acinar cell
sis and inflammation87,91. Although CHOP can induce
2 1 autophagy, it eventually promotes cell death during
Zymogen prolonged ER stress. Interestingly, widely available
granule
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) inhibi-
tors promote the UPR92,93. Statin use has been associated
Lysosome with lower incidence and severity of acute pancreatitis
4
Increased in observational studies94–96, and a randomized con-
synthesis of trolled trial is currently ongoing to examine the effects of
TNF lysosome and
3 digestive HMG-CoA inhibitors, such as simvastatin, in preventing
enzymes recurrent attacks of acute pancreatitis97.
TNFR
Cathepsin B Mitochondrion Ductal cell dysfunction and intraductal events. Both
transmembrane water channels (for example, aqua-
6 porin 1 in acinar and ductal cells) and cystic fibrosis
CytC
transmembrane regulator (CFTR) channels are vital to
5
physiological pancreatic fluid secretion98,99. Alcohol
RIP3–RIP1 complex has been shown to markedly reduce CFTR function
Apoptosis and the amount of bicarbonate secretion, which acidi-
P
MLKL MLKL fies the intraductal environment and leads to intraductal
fluid stasis, promoting premature enzyme activation
P P
MLKL MLKL within the duct100–102. Bile acid-mediated and pancreatic
inflammation-mediated reductions in aquaporins also
contribute to this intraductal fluid stasis98. Different intra-
ductal events might also mediate acinar cell injury and
Necrosis
7 death leading to acute pancreatitis59. These events include
increased intraductal pressure, ductal cell exposure to bile
Membrane rupture
acids and intraductal acidification60,70,103,104.
Fig. 2 | Premature trypsinogen activation in acute pancreatitis. In acinar cells, alcohol Increased pressure inside the pancreatic duct can
and other pancreatic toxins increase synthesis of lysosomes and digestive enzymes, activate the mechanoreceptor PIEZO1 in the acinar cells
as well as impair zymogen granule apical exocytosis in the acinar cells by causing to trigger the pathological calcium signalling described
microtubule dysfunction (1). This process results in accumulation of zymogen earlier70. Ductal hypertension can also cause calcineurin-
granules (2). TNF can also cause premature trypsinogen activation by activating the mediated acinar cell injury by promoting inflammation
TNF receptor (TNFR) (3). Preceding events culminate in colocalization in which and activation of the signal transducer and activator of
lysosomes and zymogen granules fuse (4). Cathepsin B activates trypsinogen to trypsin
transcription 3 (STAT3) pathway105. Clinical examples
once colocalization occurs. Cathepsin B and trypsin are released into the cytosol.
Cathepsin B activates the receptor-interacting protein kinase (RIP), including RIP1–RIP3, of ductal hypertension include papillary oedema, acidic
and mixed lineage kinase domain-like (MLKL) pathway, which involves oligomerization contrast injection into the pancreatic duct during ERCP
of MLKL (5). Intracytosolic protease release also leads to activation of the apoptosis and gallstone obstruction of the duct. Acidification of
executioner caspase 3 through release of cytochrome c (CytC) from mitochondria (6). the pancreatic ductal lumen has been shown to activate
Phosphorylation and oligomerization of MLKL translocate it to the cell membrane, transient receptor potential vanilloid 1 (TRPV1) in the
causing membrane rupture and cell necrosis (7). primary sensory neurons and cause acute pancreati-
tis60. As such, luminal acidification can occur when an
acidic contrast agent is used for pancreatography during
unwanted proteins and improves its capacity and effi- ERCP, and PIEZO1-mediated, calcineurin-mediated and
ciency of protein synthesis and folding44,86,87,89 via three TRPV1-mediated mechanisms of acute pancreatitis are
important pathways that respond by acutely decreasing highly relevant to post-ERCP and gallstone pancreati-
protein synthesis. The three functional pathways of tis60,70,106. Additionally, bile acid can cause mitochondrial
the UPR are the inositol-requiring enzyme 1 (IRE1), dysfunction in a dose-dependent manner in the ductal
activating transcription factor 6 (ATF6) and protein cells101. The resulting ATP depletion causes decreased
kinase RNA-like ER kinase (PERK) pathways44,87. The ATP-dependent bicarbonate secretion, and it can also
downstream events of the IRE1 and ATF6 pathways cause ductal cell death. Breakdown of ductal cells
culminate in activation of transcription factors such as exposes acinar cells to the bile acids, with resultant cell
ATF6, and spliced X-box binding protein 1 (sXBP1). injury and death103,107,108. This mechanism is hypothe-
These transcription factors promote the synthesis of sized to be relevant to gallstone pancreatitis, in which
substrates needed for ER expansion, ER chaperones a lodged gallstone in the papilla can expose ductal cells
for protein folding and components of the ER protein to bile acids by creating a common channel. However,
Cystic fibrosis degradation machinery45,54. They also initiate auto- under physiological conditions, pressure within the pan-
transmembrane regulator phagy to eliminate and recycle unfolded and misfolded creatic duct is substantially greater than in the bile duct
(CFTR). A chloride channel
located in pancreatic duct cells
proteins90. When these responses fail to restore homeo — thus, the hypothetical mechanism by which bile acids
that enables passage of anions stasis, the UPR eventually activates the apoptotic pathway. might travel against this pressure gradient has not been
and water. The PERK pathway is the terminal response, whereby delineated109,110.

Reviews
Alcohol and Once immune cells infiltrate the pancreas, the cel-
1 pancreatic toxins lular contents released from necrotic and injured cells
Acinar cell
activate monocytes and neutrophils and further prop-
Increased 3 agate the inflammation54,124,125. Neutrophilic NADP oxi-
demand
for protein dase causes oxidative stress and increased intra-acinar
synthesis Autophagy Lysosome trypsinogen activation39,126. Neutrophils also produce
neutrophil extracellular traps, which are adhesive webs
composed of granular proteins, DNA and histones that
can cause ductal obstruction, activate pro-inflammatory
Aged organelles
and misfolded proteins Cathepsin B signals and prematurely activate trypsinogen2,47.
2 Activated monocytes are central to systemic inflam-
mation and worsening tissue injury in acute pancreatitis.
Important mediators of monocyte activation are damage-
Mitochondrion associated molecular patterns (DAMPs), which are cellu-
lar contents that are released from the necrotic acinar
4 4 cells. DAMPs mediate their effects by binding to dif-
ER
ferent receptors on the immune cells127–130. For exam-
stress IRE1 sXBP1 ple, the DAMPs high-mobility group box protein 1
5 ER expansion (HMGB1), heat shock protein 70 (HSP70) and double-
Nucleus
4 ATF6 cATF6 ↑ chaperones
ERAD stranded DNA signal through Toll-like receptors (TLRs)
PERK ATF4 to activate the NF-κB pathway. NF-κB mediates the gene
6 expression of pro-inflammatory cytokines, chemo
CHOP kines and adhesion molecules. Other DAMPs, such as
ER ATP and NAD, bind to P2X7 receptors to activate the
Cell death and inflammation inflammasome. Subsequently, pro-IL-1β and pro-IL-18
mature into their biologically active forms through
proteolytic cleavage. These pathways amplify the pro-
Fig. 3 | Endoplasmic reticulum stress, the unfolded protein response and duction of pro-inflammatory cytokines including TNF,
autophagy in acute pancreatitis. In acinar cells, toxins such as alcohol cause an IL-1β, IL-6 and IL-18, among others112,131,132.
increased demand for protein synthesis (1), mitochondrial dysfunction (2) and impaired Macrophages at distant organs are also activated and
autophagy (3). Under physiological conditions, autophagy processes and recycles worsen systemic inflammation and distant organ injury
various aged and defective cytoplasmic contents. Autophagy first enucleates cytosolic in acute pancreatitis, although the mechanisms of dis-
contents within an open double membrane. The double membrane edges meet to form
tal organ injury underlying this effect have not been
an autophagosome, which fuses with a lysosome to form an autolysosome. Hydrolases
in the lysosome then degrade the enclosed contents for recycling. The previous events
fully elucidated. Given the central importance of these
(1–3) result in endoplasmic reticulum (ER) stress, which occurs when demand for protein pathways in driving and accentuating inflammatory
synthesis and build-up of misfolded or unfolded proteins in a cell overwhelm the ER responses in acute pancreatitis, inhibitors of NF-κB and
capacity to process them (4). Transmembrane proteins such as inositol-requiring the inflammasome pathway have been developed and are
enzyme 1 (IRE1), activating transcription factor 6 (ATF6) and protein kinase RNA-like being tested for efficacy in animal models 48,133–137.
ER kinase (PERK) sense misfolded proteins in the ER lumen. The IRE1 and ATF6 pathway Of these, MCC950, a potent inhibitor of the inflamma
effectors spliced X-box binding protein 1 (sXBP1), ATF6 and cleaved ATF6 (cATF6) some pathway, is being tested in other diseases such as
are transcription factors for genes involved in ER expansion, molecular chaperone ischaemic stroke, hepatitis and hepatic fibrosis in which
processes and ER-associated degradation (ERAD), which enable the ER to meet the inflammasome activation also has a crucial pathogenic
metabolic and protein synthesis demands of the cell (5). Under extreme ER stress,
role135,136. Additionally, lactate, administered in the form
the unfolded protein response (UPR) PERK pathway results in apoptosis and
inflammation mediated by CEBP homologous protein (CHOP) (6). Although CHOP of the widely available lactated Ringer’s solution, holds
can induce autophagy, it eventually promotes cell death and inflammation during promise, as it downregulates the inflammasome path-
prolonged ER stress. way and reduces pancreatic injury in acute pancreatitis
animal models133. Lactated Ringer’s solution also showed
promise in clinical trials (discussed later)133,138,139.
Role of immune system. Injured acinar cells release Serum TNF and IL-6 levels have consistently been
chemokines, cytokines and various adhesion molecules associated with increased severity of acute pancreati-
that recruit and mediate infiltration of immune cells tis and acute lung injury140–143. TNF also causes direct
Monocyte chemoattractant into the site of injury21,48,111,112 (Fig. 4). Among these acinar cell necrosis46. Pentoxifylline is a nonselective
protein 1 chemokines, monocyte chemoattractant protein 1 (MCP1) phosphodiesterase inhibitor that reduces synthesis of
(MCP1). A chemokine that facilitates the inflammatory monocyte trafficking, and TNF by downregulating the NF-κB pathway. A pilot
is involved in facilitating
macrophage inflammatory protein 2α (MIP2α) and CXC- double-blind placebo-controlled randomized trial in
migration and recruitment
of monocytes. chemokine ligand 1 (CXCL1) recruit neutrophils1,113. 28 patients found that oral pentoxifylline three times a
Illustrating their importance in the pathogenesis of acute day reduced length of hospital stay144. These promising
Damage-associated pancreatitis, inhibition of chemokines and their recep- findings are currently being validated in a larger scale
molecular patterns tors has been shown to prevent pancreatic and distant clinical trial. Tocilizumab, a commercially available IL-6
(DAMPs). A variety of
substances released by
organ injury in animal models114–122. Increased serum receptor antagonist, is another potential therapeutic
damaged cells that can MCP1 levels also correlate with severe acute pancreatitis agent145,146. Administration of tocilizumab after induc-
activate an immune response. in humans123. tion of severe acute pancreatitis improved outcomes in

Reviews
• MCP1 HMGB1 Blood vessel

• TNF • IL-1 β
• IL-6 • IL-18 • CXCL1 Chemotaxis
• CXCL2 ICAM1
2
2 2
Damage-associated
molecular patterns
1 M1
monocyte
• Oxidative stress
4 3
• Premature
trypsinogen
Acinar cell activation • Inflammasome • Activation
injury and • Trypsinogen of monocytes in
necrosis activation lungs, liver and
• Ductal obstruction 5 • NF-κB peritoneum
• Premature • STAT3 • Multiorgan
trypsinogen • NFAT failure
6
activation
Lipase • Inflammation
7 Multiorgan failure NET Neutrophil

Hydrolysis of
triglycerides
Fig. 4 | Immune response to acinar cell injury and necrosis in acute pancreatitis. Injured acinar cells produce
cytokines, chemokines and adhesion molecules to recruit immune cells to the site of injury (1). Once recruited,
chemokines and cytokines from the acinar cells, and damage-associated molecular patterns, activate immune cells to
amplify an inflammatory response (2). Pathways activated within the M1-polarized monocytes include nuclear factor-κB
(NF-κB) and signal transducer and activator of transcription 3 (STAT3). Monocytes activate monocytes in other organs,
causing remote organ injury (3). Neutrophils cause premature trypsinogen activation and oxidative stress to the acinar
cells by releasing oxidizing substances (4). Neutrophils also release neutrophil extracellular traps (NETs), which cause
ductal obstruction, premature trypsinogen activation and inflammation (5). Owing to a disrupted basolateral barrier,
which results from acinar cell injury from a variety of toxins, intrapancreatic fat is exposed to lipase, which is secreted
to the interstitium (6). Triglyceride-rich intrapancreatic and peripancreatic fats are hydrolysed by lipase (7). This reaction
releases toxic free fatty acids that can cause further acinar cell injury and organ failure. CXCL , CXC-chemokine ligand;
HMGB1, high-mobility group box protein 1; ICAM1, intercellular adhesion molecule 1; MCP1, monocyte chemoattractant
protein 1; NFAT, nuclear factor of activated T cells.
an animal study147. Tocilizumab is probably ready for a mutations is beyond the scope of this Review, but a
clinical trial in human acute pancreatitis given its estab- review has been published that summarizes the genetics
lished safety record and efficacy in patients with other of acute pancreatitis157.
diseases such as giant cell arteritis, rheumatoid arthritis
and graft-versus-host disease146,148,149. Role of unsaturated fatty acids. Obesity and hypertri-
The pro-inflammatory phase in acute pancreatitis glyceridaemia are established risk factors for severe acute
is followed by the compensatory anti-inflammatory pancreatitis9,158. Studies have illuminated the pathophys-
response syndrome, which is characterized by a pre- iological mechanisms by which obesity and hypertri-
dominance of anti-inflammatory cytokines such as glyceridaemia mediate severe acute pancreatitis. During
TGFβ, IL-4 and IL-10 (refs131,150,151). IL-10 is produced an acute pancreatitis episode, several mechanisms dis-
by acinar cells, monocytes, B cells and T cells. It acts rupt the normal apical secretary path of the zymogen
at the transcriptional level to reduce the production granules. Alcohol inhibits apical secretion and instead
of pro-inflammatory cytokines via inhibition of the promotes basolateral secretion57. Acinar cell necrosis
STAT3 pathway and T cell expansion152. Animal studies also causes liberation of enzymes to areas of the pancreas
of acute pancreatitis have shown improved outcomes otherwise shielded from exposure to digestive enzymes.
with the use of insulin-like growth factor 1 and IL-4, For example, lipase is freely released through the baso-
which enhance IL-10 production153,154. During the anti- lateral membranes into the interstitium, peripancreatic
inflammatory response period, patients with acute region and bloodstream25,159–161. Lipase hydrolyses circu-
pancreatitis are susceptible to developing infection of lating triglycerides and those stored in the intrapancreatic
pancreatic necrosis155. and peripancreatic adipocytes into saturated and unsatu-
rated free fatty acids (UFAs). UFAs such as linoleic, oleic
Genetic mutations. Several mutations have been iden- and linolenic acids cause cytotoxicity by inhibiting the
tified that have pathogenic roles in acute pancreatitis, mitochondrial complexes I and V and increasing
including mutations in protease serine 1, serine pro- the levels of TNF and other chemokines augmenting the
tease inhibitor Kazal type 1, chymotrypsin C, CFTR, inflammatory response9,23,162,163. In clinical studies,
claudin 2 and calcium-sensing receptor genes156. An patients with acute pancreatitis with increased visceral
in-depth review of clinical implications of these genetic adiposity and elevated serum triglycerides on admission

Reviews
Systemic inflammatory
were found to be at increased risk of multisystem organ ranging from simple laboratory markers182–184 and bio-
response syndrome failure and pancreatic necrosis, substantiating the markers123,142,185,186 to clinical scoring systems123,140,182,187–189.
(SIRS). A host immune findings of mechanistic studies24,164–166. Prevention of However, despite a plethora of predictive tools being
response to an inflammatory or triglyceride hydrolysis through lipase inhibitors available, none has been shown to be clearly superior
infectious insult that is often
seems to be a promising therapeutic strategy in acute to any other technique in large, head-to-head compari-
characterized by fevers,
leukocytosis, tachycardia, pancreatitis159,167. son studies189–191. Thus, our ability to predict severe dis-
tachypnea and hypotension. ease early in acute pancreatitis is still modest (accuracy
Mesenteric lymph. The course of acute pancreatitis can ~80%). Simple and accurate clinical predictors of sever-
be further worsened by pathological changes in the ity include blood urea nitrogen elevation182,184, persistent
intestines. These changes include ileus and ischaemia– systemic inflammatory response syndrome (SIRS)192 and
reperfusion injuries, which result in translocation of haemoconcentration193. These scores have strong advan-
bacteria through the intestinal barrier and changes tages over other cumbersome scoring systems in that
in the microbiome168. More recently, the importance they are readily available and can be serially followed.
of toxin-containing lymph drainage has been high-
lighted 52,169–171. Ischaemia-c onditioned mesenteric Management of acute pancreatitis
lymph has been associated with cardiac dysfunction and Early management in the first 72 hours
multisystem organ failure in animal acute pancreatitis Once the diagnosis of acute pancreatitis is made in
studies49,52. The responsible constituent in the mesenteric the emergency room, a predictive tool can help triage
lymph has not yet been identified170. However, ligation patients on the basis of predicted severity. Of all the prog-
of the thoracic duct mitigated the deleterious effects of nostic tools, SIRS is a commonly used, validated pre-
the mesenteric lymph in mouse studies49,171,172. Currently dictor of acute pancreatitis severity and mortality192,194.
available percutaneous techniques and endoscopic It can be easily calculated, and its components (body
ultrasonography methods have shown promise in safely temperature, heart rate, white blood cell count and
accessing the thoracic duct173–175. Pending improvements respiratory rate) are readily available clinical variables.
in techniques for accessing the thoracic duct in humans, Other important factors of early management include
redirecting mesenteric lymph flow during an acute pan- fluid resuscitation, nutritional support, identification of
creatitis attack might be an approach to prevent remote aetiology and analgesia (Fig. 5).
organ failure.
Intravenous fluid resuscitation. Society guidelines agree
Assessment of severity that early, adequate fluid administration is the corner-
Revised classifications stone of management in acute pancreatitis27–30. One pilot
The revised Atlanta and determinant-b ased classi- randomized controlled trial compared 20 ml/kg bolus of
fications of acute pancreatitis have been developed lactated Ringer’s solution followed by 3 ml/kg per hour
to classify patients into severity categories that carry versus 10 ml/kg bolus followed by 1.5 ml/kg per hour in
prognostic significance. These classifications have been 60 patients with predicted mild acute pancreatitis195
extensively validated3,176,177. The similarities and differ- (Table 4). The aggressive resuscitation group was asso-
ences between the two classification systems are shown ciated with a 70% clinical improvement rate compared
in Table 3. The two systems reflect important advance- with 42% in the conservative group. It is worth empha-
ments in the understanding of the main determinants of sizing that the trial focused on patients with mild acute
morbidity and mortality in acute pancreatitis. Contrary pancreatitis and was not designed to examine the role
to the traditionally held notion that pancreatic necrosis of fluid volume in preventing necrosis, organ failure
itself is an independent determinant of mortality, there and mortality.
is now convincing evidence that necrosis without super- In patients with predicted severe acute pancreatitis,
imposed infection or organ failure has similar survival some data suggest that aggressive fluid resuscitation
to interstitial pancreatitis, which carries a 1–2% mor- might be harmful. In a randomized controlled clinical
tality3,178,179. Persistent organ failure (lasting >48 hours) trial that included 115 patients, rapid haemodilution to
seems to be the most important determinant of mor- <35% within 48 hours with fluid therapy was associated
tality, which can be as high as 43%3. Duration of organ with increased mortality and occurrence of sepsis of 34%
failure beyond 48 hours does not seem to affect mortality and 79% compared with 15% and 58%, respectively, in
among patients with pancreatic necrosis180. Although the slow-dilution group196. However, observational
patients with sterile pancreatic necrosis and/or peri- data from the past few years suggest that aggressive
pancreatic fluid collections have low mortality, they fluid resuscitation might improve morbidity and sur-
nevertheless experience a complicated hospital course vival197–199. Owing to differences in study design, patient
compared with those with interstitial pancreatitis, and population and definition of interventions, it is difficult
they frequently require prolonged hospitalization to determine the effect of fluid volume on acute pancre-
and frequent readmissions177,179. atitis outcomes. Well-designed, large-scale randomized
trials are sorely needed200.
Prediction of severity Lactated Ringer’s solution is currently preferred over
Severe pancreatitis, defined as persistent organ failure, other crystalloids as the fluid type of choice in acute
carries a mortality of up to 43% during the first attack181. pancreatitis. This preference is based on a small pilot
Many prognostication models have been developed to randomized clinical trial, which showed that adminis-
predict severe pancreatitis early in the disease course, tration of lactated Ringer’s solution is associated with

Reviews
a significant reduction in SIRS by 84% (P = 0.035) pancreatitis, patients were assigned either to early enteral
compared with normal saline138. Mechanistic evidence tube feeding or to start oral diet at or after 72 hours
might also support this finding133. In a mouse study, (on-demand approach). Both groups developed major
administration of lactated Ringer’s solution reduced the infections at similar rates of approximately 25% (Table 4).
severity of acute pancreatitis by inhibiting the inflam- Additionally, there was no mortality benefit to early
masome and NF-κB pathways133. Additionally, lactated enteral tube feeding compared with the on-demand,
Ringer’s solution contains calcium, which binds to UFAs oral diet approach209. Thus, in patients who are pre-
and potentially mitigates their toxic effects9. In another dicted to have severe acute pancreatitis, it is reasonable
in vitro study, lactated Ringer’s solution inhibited macro to wait at least 72 hours and attempt an oral diet. Enteral
phage polarization towards an inflammatory pheno- feeding might not be feasible in patients who develop
type and inhibited NF-κB activation201. Larger studies ileus as a complication of acute pancreatitis and opioid
are needed to see whether these findings translate to analgesia. This outcome can pose a substantial challenge
meaningful clinical outcomes in humans. to the management of acute pancreatitis. Thus, efforts
When administering intravenous fluid therapy, it is should be made to optimize patient bowel function by
important to closely follow the intravascular volume sta- monitoring and correcting electrolyte disturbances, judi-
tus of the patient to prevent volume overload. In patients ciously using opioid analgesia and encouraging mobil-
who are at risk of fluid sequestration, close monitoring ity when feasible. Parenteral nutrition is considered the
of volume status is critical because they can develop life- last resort because of its association with an increased
threatening abdominal compartment syndrome, which rate of infection and mortality when compared with
is characterized by end-organ dysfunction caused by enteral feeding210,211.
increased abdominal pressure202. A paucity of data exist
on which parameter should guide fluid resuscitation Analgesia. A paucity of studies have assessed the effect
and on the role of maintenance fluid therapy in acute of analgesia on outcomes in acute pancreatitis. Narcotic
pancreatitis200. These areas warrant further studies. analgesia is frequently used in the USA and seems to
be effective212. Interestingly, one animal study showed
Nutritional support. Evidence supports the safe early that morphine use was associated with increased acute
introduction of a solid, low-fat diet in patients with pancreatitis severity and the prevention of pancreatic
mild or moderately severe pancreatitis without taking regeneration213. In a large propensity score-matched
a stepwise approach (that is nil by mouth followed by observational study with 1,003 patients from intensive
liquid and then solid diet)203–205. For those patients who care units, epidural analgesia, predominantly containing
can tolerate an oral diet, an initial low-fat solid diet is non-narcotic anaesthetics (for example, bupivacaine),
preferred203,205. These early and aggressive approaches to was associated with substantially lower mortality than
feeding reduce the length of hospital stay in patients with standard care among patients with severe acute pan-
mild or moderately severe pancreatitis. In patients with creatitis214. Purported benefits of this approach include
mild–moderate acute pancreatitis who do not tolerate improved splanchnic and pancreatic blood flow and anti-
oral feeding within 3–5 days, enteral tube feeding should inflammatory effects215,216. A multicentre, randomized
be considered. Nasojejunal feeding has traditionally controlled trial is underway to elucidate the benefits
been preferred over nasogastric feeding because it of epidural analgesia among critically ill patients with
should theoretically be better tolerated by patients206. acute pancreatitis217. Given the risk of patients becoming
Positioning the feeding tube in the jejunum past the dependent on opioid medications, other modes of effec-
duodenum limits the stimulation of the already inflamed tive analgesia such as non-steroidal anti-inflammatory
pancreas, causing less pain. However, studies comparing agents need to be explored as first-line analgesic agents
nasogastric with nasojejunal feeding did show similar in acute pancreatitis.
tolerance rates207,208.
In patients predicted to have severe pancreatitis, how- Management after the first 72 hours
ever, early enteral feeding (enteral tube feeding within Identification of aetiology and its management. In
24 hours of presentation) has not been shown to improve patients with mild biliary pancreatitis, cholecystectomy
outcomes when compared with oral feeding starting at during their index hospitalization prevents recurrence
72 hours209. In a rigorously designed, randomized con- (risk ratio as low as 0.28) and is cost-effective218. Thus,
trolled trial in 208 patients with predicted severe acute it should be the standard of care218–221 (Table 4). Timing
Table 3 | Comparison between revised Atlanta classification and determinant-based classification

Classification Mild Moderately severe Severe Critical
Revised Atlanta No organ failure, Transient organ failure Persistent organ NA
classification3 local complications (<48 hours), local complications failure
or exacerbation of and/or exacerbation of
comorbid condition comorbid condition
Determinant- No organ failure Sterile (peri)pancreatic Persistent organ Persistent organ
based and no (peri) necrosis and/or transient organ failure (>48 hours) failure (>48 hours)
classification276 pancreatic necrosis failure (<48 hours) or infected (peri) and infected (peri)
pancreatic necrosis pancreatic necrosis
NA, not available.

Reviews
Week 1 Week 2 and beyond
• Severity assessment: Urgent On-demand low-fat solid diet;

BUN; haematocrit; ERCP if intolerant, enteral feeding
and SIRS through a feeding tube
• Prediction of severity: Cholangitis Causing refractory
BISAP; and HAPS or persistent Day 3 symptoms, biliary
• Goal-directed biliary or gastric outlet
aggressive fluid obstruction Increase level of obstruction or
resuscitation with Clinical deterioration care; evidence Yes Sterile deterioration
lactated Ringer's of necrosis or fluid despite maximum
solution; and consider Clinical collection on CECT? Suspected ICU level of care?
following BUN and improvement or proven
urine output for Predicted infection
resuscitation goals severe acute • Cholecystectomy during index
• Analgesia pancreatitis hospitalization for mild biliary • Antibiotics coverage
• Aetiology assessment: or in pancreatitis • Less than 4 weeks: consider
medical history, multisystem • Arrange EUS for idiopathic acute percutaneous drainage if no
abdominal US, pancreatitis improvement despite Yes
organ failure
Ca2+ levels, • Consider genetic testing for maximum supportive care
triglyceride levels and patients <35 years old with • Longer than 4 weeks: consider No
evidence of mass on Consider recurrent idiopathic pancreatitis step-up strategy for WOPN or
cross-sectional ICU level • Identify underlying cause and transmural or transpapillary Supportive
imaging of care address reversible causes drainage for pseudocyst care
Clinical deterioration
Necrotic or fluid collection
Fig. 5 | Acute pancreatitis management algorithm. The goals of acute pancreatitis management in the first week are
to assess severity and assign an appropriate level of care, to ascertain aetiology and address reversible cause, to optimize
nutrition and to arrange appropriate follow-up for the majority of patients being discharged. Up to 80% of patients with
acute pancreatitis will recover and be discharged within a week. Beyond week 1, however, 20% will deteriorate and
will need more long-term care depending on the driver of severity. Hence, goals for patients who deteriorate include
identifying the determinant of severity, and if the deterioration is attributable to a necrotic collection, infection status
and maturity of collection will determine management strategy. If the determinant of morbidity is organ failure, organ
support is the most critical goal of care. BISAP, Bedside Index of Severity in Acute Pancreatitis; BUN, blood urea nitrogen;
CECT, contrast-enhanced CT; ERCP, endoscopic retrograde cholangiopancreatography ; EUS, endoscopic ultrasonography ;
HAPS, Harmless Acute Pancreatitis Score; ICU, intensive care unit; SIRS, systemic inflammatory response syndrome;
US, ultrasonography ; WOPN, walled-off pancreatic necrosis.
of cholecystectomy in patients with moderately severe Role of endoscopic retrograde cholangiopancreatography.

and severe pancreatitis warrants further investigation. The benefit of performing urgent ERCP (within 48 hours)
Although data are lacking, owing to concerns that early in the setting of severe biliary acute pancreatitis and con-
surgery in this setting increases surgical morbidity, wait- comitant cholangitis and/or persistent biliary obstruc-
ing at least 6 weeks to enable maturation or resolution tion is well established27,30,223. However, in most patients
of fluid collections is recommended222–224. with biliary pancreatitis, the common bile duct stone has
Well-designed studies have shown that interventions already passed at the time of presentation; therefore, the
to promote alcohol and smoking cessation reduce acute majority of patients with biliary acute pancreatitis do
pancreatitis recurrence and readmission rates225–227. not require ERCP. An ongoing randomized controlled
Serum triglyceride levels need to be checked and treated trial aims to further evaluate the role of urgent ERCP in
accordingly when above 1,000 mg/dl, as emerging evi- patients with predicted severe biliary acute pancreatitis230.
dence suggests that even mild to moderate non-fasting
hypertriglyceridaemia might contribute to acute pancre- Antibiotic prophylaxis. Many trials have examined the
atitis severity228. However, the benefit of treating non- potential benefit of prophylactic antibiotics in patients
fasting hypertriglyceridaemia to prevent recurrence with either severe pancreatitis or necrotizing pancrea-
needs to be investigated further. titis. However, no clear benefit has been demonstrated
In patients with a dilated pancreatic duct in the in the body of evidence, and therefore, guidelines rec-
absence of prior history of pancreatitis or chronic pan- ommend against routine antibiotic prophylaxis in acute
creatitis, main-duct intraductal papillary mucinous pancreatitis27,29,30.
neoplasm (IPMN) should be considered as an aetiol
ogy. Main-duct IPMNs have high malignant potential, Local complications
so it is essential to recognize and treat them accord- Acute necrotic collections and WOPN
ingly. Pancreatic cancer is another important cause that The management of pancreatic necrotic collections
accounts for approximately 1% of all acute pancreatitis has evolved over the years. The surgical literature has
causes229. For patients over the age of 40 years, a follow- debated about the indication, timing and mode of
up imaging study or endoscopic ultrasonography is intervention for several decades231. Available interven-
important to rule out a mass. tions include minimally invasive surgery (video-assisted

Reviews
Table 4 | Landmark randomized clinical trials in acute pancreatitis management

Trial n Year Main findings
Goal-directed fluid resuscitation versus 40 2011 SIRS reduction: normal saline 0% versus lactated Ringer’s
standard fluid resuscitation138 solution 84%; P = 0.035
Aggressive fluid resuscitation versus 60 2017 • Clinical improvementa at 36 hours: aggressive fluid
standard fluid resuscitation in mild acute resuscitation 70% versus standard fluid resuscitation
pancreatitis195 42%; P = 0.03
• Persistent SIRS: aggressive fluid resuscitation 7.4% versus
standard fluid resuscitation 21.1%; adjusted OR 0.12
(95% CI 0.02–0.94)
Early enteral feeding versus on-demand 208 2014 Major infectionb or death at 6 months: early feeding
oral feeding in predicted severe acute 30% versus on-demand feeding 28%; P = 0.76
pancreatitis209
Cholecystectomy during index 266 2015 • Readmission from recurrent gallstone-related
hospitalization for mild gallstone complicationc: same admission cholecystectomy
pancreatitis218 5% versus delayed cholecystectomy 17%; P = 0.002
• No differences in surgical complications
Efficacy of pentoxifylline in treatment 28 2015 • ICU admission: pentoxifylline 0% versus placebo 28%;
of predicted severe acute pancreatitis144 P = 0.098
• Length of stay >4 days: pentoxifylline 14% versus placebo
57%; P = 0.046
Step-up strategy versus direct 88 2010 Major complicationd or death: step-up strategy 40% versus
necrosectomy238 open necrosectomy group 69%; P = 0.006
Endoscopic step-up versus surgical 98 2018 • Major complicationse or death at 6 months: endoscopic
step-up in WOPN240 step-up 43% versus surgical step-up 45%; P = 0.88
• Pancreatic fistula: endoscopic step-up 5% versus surgical
step-up 32%; P = 0.0011
ICU, intensive care unit; SIRS, systemic inflammatory response syndrome; WOPN, walled-off pancreatic necrosis. aClinical
improvement defined by decreased epigastric pain and decrease in blood urea nitrogen, haematocrit and creatinine. bMajor
infection defined by infected pancreatic necrosis, bacteraemia or pneumonia. cRecurrent gallstone-related complication defined
by pancreatitis, cholangitis, cholecystitis, choledocholithiasis needing endoscopic intervention, biliary colic or mortality. dMajor
complications defined by new-onset multiple organ failure or multiple systemic complications, perforations of a visceral organ or
enterocutaneous fistula or bleeding. eMajor complications defined by new-onset organ failure, bleeding requiring intervention,
perforation of visceral organ requiring intervention, enterocutaneous fistula and incisional hernia.
retroperitoneal debridement or laparoscopy), endo- Mode of intervention. A step-up approach using min-
scopic cystenterostomy with or without direct endoscopic imally invasive endoscopic intervention is the most
necrosectomy and percutaneous catheter drainage. beneficial mode of intervention, as illustrated in well-
Several landmark trials conducted in the past decade designed randomized clinical trials238–240. The step-up
have helped to clarify the role of each of these modalities approach takes a graded approach to WOPN, starting
in the context of managing pancreatic necrosis (Table 4). with the least invasive measure first (drainage of col-
lection using percutaneous catheter or by formation of
Indication. Given the substantial morbidity and mortal- cystenterostomy). An intervention would be stepped
ity associated with the procedure, invasive intervention up to the most invasive option (necrosectomy) when a
is indicated only when a necrotic collection becomes patient’s clinical response is not optimal to the less inva-
infected or causes symptoms, such as gastric outlet sive approach. This step-up approach reduced rates of
obstruction, failure to thrive, biliary obstruction or new organ failure by 28% (absolute risk reduction) and
intractable pain30,232. The role of interventions has been the occurrence of a composite end point of major com-
most rigorously studied in patients with suspected or plications, multiple organ failure, perforation, fistula or
proven infected pancreatic necrosis223. Thus, an interven- death by 29%238. In a randomized controlled trial, drain-
tion should be avoided in patients with sterile necrosis age alone led to a resolution of WOPN in 40% of patients
without symptoms, regardless of the size of the collection. without the need for subsequent necrosectomy241. Data
from a randomized clinical trial in 2018 support use
Timing. Observational studies and a randomized clin- of the endoscopic step-up over the surgical step-up
ical trial have suggested that delaying the pancreatic approach. Specifically, the endoscopic step-up strategy
intervention is associated with lower morbidity and led to a lower rate of pancreaticocutaneous fistula for-
mortality223,233–236. In patients with infected pancreatic mation and shorter length of hospitalization than the
necrosis early in the disease course (that is, <4 weeks from surgical step-up approach240. Notably, in all the above
onset of disease) who become clinically unstable despite randomized clinical trials, the majority of the enrolled
the administration of intravascular antibiotics, a percu- patients had proven infected WOPN239–241. By contrast,
Cystenterostomy taneous drain placement for decompression is advised237. data on the management of symptomatic sterile WOPN
The creation of a connection
between a cyst wall and the
Beyond 4 weeks from the acute pancreatitis onset, endo- have mainly been derived from observational studies242.
wall of the gastrointestinal scopic cystenterostomy with or without necrosectomy or Endoscopic ultrasound-guided transmural drain-
tract. minimally invasive surgery can be considered. age through cystenterostomy can be used safely once

Reviews
the maturation of the collection wall occurs. Metal or occurs in approximately 15% of patients with acute pan-
plastic stents can be used, but a high-quality comparison creatitis216. The splanchnic vein recanalizes in a third of
of effectiveness data is lacking243. The lumen-apposing patients257,258. On the basis of available data, most SVCs
metal stents for drainage of WOPN have gained popu- in acute pancreatitis do not require anticoagulation
larity owing to their ease of deployment and effective- therapy given their benign natural history259–261. On
ness244–247. However, long-term safety data are lacking, rare occasions, splenic vein thrombosis might lead to
and there are emerging reports of increased incidence of local portal hypertension with isolated gastric varices
delayed bleeding with the placement of lumen-apposing or superior mesenteric vein thrombosis with ascites.
metal stents248–250. Pseudoaneurysms are thought to be a rare complica-
tion of pancreatitis; however, in the era of transmural
Disconnected duct syndrome metal stents, iatrogenic pseudoaneurysms have also been
Disconnected duct syndrome is a complication in which reported to occur ten times more frequently248. Despite
the integrity of the pancreatic duct is lost following an being rare, pseudoaneurysms can be life threatening
attack of necrotizing pancreatitis251. Up to 50% of patients when not recognized and addressed in a timely fashion
with pancreatic fluid collections might have an under with coil embolization via interventional radiology.
lying disconnected duct that can lead to abdominal pain,
recurrent acute pancreatitis or recurrent pancreatic fluid Long-term complications and follow-up
collections252,253. Disconnected duct syndrome is best rec- Disease progression
ognized using secretin-stimulated magnetic resonance Recurrent acute pancreatitis (RAP) occurs in 18%
cholangiopancreatography. In such patients, studies of patients after an episode of acute pancreatitis and
have proposed transmural double pigtail stents to be left results in impairment of patient quality of life13,18,262,263.
indefinitely in the collection with the aim of maintaining Accumulating evidence suggests that patients with RAP
the patency of the pancreaticoenterostomy237,254,255. This are at substantially increased risk of chronic pancrea-
approach was found to be safe, with a decreased risk of titis18,264. Idiopathic aetiology, active alcohol intake and
recurrence when compared with patients without indefi- smoking are the strongest risks for progression to RAP
nite stents (recurrence rate 17.4% versus 1.7%; P < 0.001) and chronic pancreatitis18,264,265. Population-based cohort
in one large observational study of 361 patients with pan- studies have suggested that acute pancreatitis might be
creatic fluid collections253. Thus, this approach might a risk factor for pancreatic cancer229,266–268, but the risk
become a first-line technique when compared with pan- seems to be confined to patients with acute pancreatitis
creatic surgical drainage, which carries a substantial risk who progress to chronic pancreatitis269.
of morbidity and new-onset diabetes.
Endocrine and exocrine complications
Vascular complications of acute pancreatitis Until recently, endocrine and exocrine complications of
Splanchnic vascular complications (SVCs) in acute pan- acute pancreatitis were not well established. Now, studies
creatitis include venous thrombosis and arterial and/or support the idea that approximately one-third of patients
venous pseudoaneurysms256. Severe acute pancreati- will develop prediabetes or diabetes within 5 years
tis and pancreatic necrosis constitute risk factors for of an index episode of acute pancreatitis15,270, but the
the development of SVCs. Splanchnic vein thrombosis mechanisms and risk factors remain to be defined.
Similarly, exocrine pancreatic insufficiency is common
after acute pancreatitis, occurring in 24–40%12,16,270,271.
Box 1 | Future areas of research in acute pancreatitis
Reported risk factors for exocrine pancreatic insufficiency
Knowledge gaps or future directions following acute pancreatitis include pancreatic necrosis,
• Collaborative networks severe acute pancreatitis and alcohol-related aetiology16,270.
-- Build multicentre, collaborative networks with infrastructure to conduct large-scale
clinical trials Quality of life
• Recruitment of patients One prospective observational study has reported that
-- Increase public awareness about acute pancreatitis; develop collaborations with long-term health-related quality of life is reduced among
emergency departments for efficient, early recruitment of patients patients who survived acute pancreatitis when compared
• Analgesia with age-matched and sex-matched individuals without
-- Compare narcotic versus non-opioid; epidural versus intravenous or oral opioid pancreatitis14. Patients who experience multisystem
analgesics organ failure, persistent abdominal pain requiring anal-
• Fluid therapy gesia and/or disability are at increased risk of dimin-
-- Study the optimal type and rate and define goals of fluid therapy ished quality of life. Importantly, among patients who
• Endoscopic retrograde cholangiopancreatography experience extensive pancreatic necrosis, 53% become
-- Assess the benefit of urgent biliary decompression in predicted severe biliary registered as disabled at 1 year following their discharge
pancreatitis from the hospital12.
• Endoscopic drainage and necrosectomy
-- Compare endoscopic therapy in symptomatic sterile necrosis versus conservative Conclusions
management Acute pancreatitis is a common and potentially life-
• Late complications of acute pancreatitis threatening inflammatory disorder of the pancreas.
-- Study the mechanisms of diabetes mellitus and exocrine pancreatic insufficiency Patients who survive the condition frequently develop
following acute pancreatitis
long-term devastating consequences such as diabetes

Reviews
mellitus, exocrine pancreatic insufficiency, chronic pan- after acute pancreatitis. But most importantly, well-
creatitis and poor quality of life. This substantial bur- designed, large studies are needed to examine the safety
den is noticeable at the health-care system level, and the and effectiveness of early, goal-directed fluid therapy; to
increasing incidence of acute pancreatitis highlights clarify the goals of fluid resuscitation; and to determine
the urgent need for therapeutic agents designed to alter the optimal analgesic regimen, the role of early biliary
its natural history. For decades, the exact pathophysio decompression in predicted severe biliary acute pan-
logical mechanisms of acute pancreatitis remained creatitis and the optimal endoscopic management of
an enigma other than recognizing that it might be an symptomatic sterile pancreatic necrosis. Unfortunately,
autodigestive disease. A rich body of work derived from conducting large-scale trials has been extremely chal-
animal models uncovered several important pathophysio lenging owing to a lack of existing collaborative plat-
logical mechanisms that could represent therapeutic forms to execute large clinical trials and difficulty with
targets, and several agents are already in development. recruiting patients early in the course of acute pancre-
Landmark clinical trials have provided insight into atitis. Efforts focusing on constructing a collaborative
aspects of clinical management, such as nutritional network of hospitals to conduct clinical trials with a
support, fluid therapy for mild acute pancreatitis, pre- strong emphasis on recruiting patients very early in their
vention of recurrence in mild gallstone pancreatitis and disease course are urgently needed. More mechanistic
management of infected necrosis. studies are also needed to characterize mechanisms of
Despite the progress, several important research gaps tissue reconstitution and resolution of pancreatic inflam-
remain. Many of the potential therapeutic targets iden- mation following acute pancreatitis, with an emphasis on
tified in translational work need to be tested in phase I endocrine and exocrine dysfunction (see Box 1).
clinical trials. Translational work is required to inves-
tigate mechanisms of endocrine and exocrine failures Published online 28 May 2019
1. Lugea, A. et al. Human pancreatic acinar cells: 16. Hollemans, R. A. et al. Pancreatic exocrine insufficiency concepts and updated points. J. Hepatobiliary
proteomic characterization, physiologic responses, following acute pancreatitis: systematic review and Pancreat. Sci. 22, 433–445 (2015).
and organellar disorders in ex vivo pancreatitis. study level meta-analysis. Pancreatology 18, 30. Working Group IAP/APA Acute Pancreatitis Guidelines.
Am. J. Pathol. 187, 2726–2743 (2017). 253–262 (2018). IAP/APA evidence-based guidelines for the management
2. Gukovskaya, A. S., Pandol, S. J. & Gukovsky, I. 17. Vipperla, K. et al. Risk of and factors associated with of acute pancreatitis. Pancreatology 13, e1–e15
New insights into the pathways initiating and driving readmission after a sentinel attack of acute (2013).
pancreatitis. Curr. Opin. Gastroenterol. 32, 429–435 pancreatitis. Clin. Gastroenterol. Hepatol. 12, 31. Gerasimenko, J. V. et al. Ca2+ release-activated Ca2+
(2016). 1911–1919 (2014). channel blockade as a potential tool in antipancreatitis
3. Banks, P. A. et al. Classification of acute pancreatitis — 18. Ali, U. A. et al. Risk of recurrent pancreatitis and therapy. Proc. Natl Acad. Sci. USA 110, 13186–13191
2012: revision of the Atlanta classification and progression to chronic pancreatitis after a first episode (2013).
definitions by international consensus. Gut 62, of acute pancreatitis. Clin. Gastroenterol. Hepatol. 14, 32. Murphy, J. A. et al. Direct activation of cytosolic Ca2+
102–111 (2013). 738–746 (2016). signaling and enzyme secretion by cholecystokinin in
4. Petrov, M. S. & Yadav, D. Global epidemiology and 19. Javed, M. A. et al. TRO40303 ameliorates alcohol- human pancreatic acinar cells. Gastroenterology 135,
holistic prevention of pancreatitis. Nat. Rev. induced pancreatitis through reduction of fatty acid 632–641 (2008).
Gastroenterol. Hepatol. 16, 175–184 (2018). ethyl ester-induced mitochondrial injury and necrotic 33. Biczo, G. et al. Mitochondrial dysfunction, through
5. Peery, A. F. et al. Burden of gastrointestinal, liver, cell death. Pancreas 47, 18–24 (2018). impaired autophagy, leads to endoplasmic reticulum
and pancreatic diseases in the United States. 20. Wen, L. et al. Inhibitors of ORAI1 prevent cytosolic stress, deregulated lipid metabolism, and pancreatitis
Gastroenterology 149, 1731–1741 (2015). calcium-associated injury of human pancreatic acinar in animal models. Gastroenterology 154, 689–703
6. Munigala, S. et al. Predictors for early readmission in cells and acute pancreatitis in 3 mouse models. (2018).
acute pancreatitis (AP) in the United States (US) — Gastroenterology 149, 481–492 (2015). 34. Mukherjee, R. et al. Mechanism of mitochondrial
a nationwide population based study. Pancreatology 21. Criddle, D. N., McLaughlin, E., Murphy, J. A., permeability transition pore induction and damage in
17, 534–542 (2017). Petersen, O. H. & Sutton, R. The pancreas misled: the pancreas: inhibition prevents acute pancreatitis by
7. Wadhwa, V. et al. Health care utilization and costs signals to pancreatitis. Pancreatology 7, 436–446 protecting production of ATP. Gut 65, 1333–1346
associated with acute pancreatitis. Pancreas 46, (2007). (2016).
410–415 (2017). 22. Marta, K. et al. High versus low energy administration in 35. Aghdassi, A. A. et al. Cathepsin D regulates
8. NCD Risk Factor Collaboration (NCD-RisC). Worldwide the early phase of acute pancreatitis (GOULASH trial): cathepsin B activation and disease severity
trends in body-mass index, underweight, overweight, protocol of a multicentre randomised double-blind predominantly in inflammatory cells during
and obesity from 1975 to 2016: a pooled analysis of clinical trial. BMJ Open 7, e015874 (2017). experimental pancreatitis. J. Biol. Chem. 293,
2416 population-based measurement studies in 23. Noel, P. et al. Peripancreatic fat necrosis worsens 1018–1029 (2018).
128.9 million children, adolescents, and adults. Lancet acute pancreatitis independent of pancreatic necrosis 36. Talukdar, R. et al. Release of cathepsin B in cytosol
390, 2627–2642 (2017). via unsaturated fatty acids increased in human causes cell death in acute pancreatitis. Gastroenterology
9. Khatua, B., El-Kurdi, B. & Singh, V. P. Obesity and pancreatic necrosis collections. Gut 65, 100–111 151, 747–758 (2016).
pancreatitis. Curr. Opin. Gastroenterol. 33, 374–382 (2016). 37. Dawra, R. et al. Intra-acinar trypsinogen activation
(2017). 24. Bradbury, K. E. et al. Lipolysis of visceral adipocyte mediates early stages of pancreatic injury but not
10. Camilleri, M., Malhi, H. & Acosta, A. Gastrointestinal triglyceride by pancreatic lipases converts mild acute inflammation in mice with acute pancreatitis.
complications of obesity. Gastroenterology 152, pancreatitis to severe pancreatitis independent of Gastroenterology 141, 2210–2217 (2011).
1656–1670 (2017). necrosis and inflammation. Gastroenterology 15, 38. Wartmann, T. et al. Cathepsin L inactivates human
11. Krishna, S. G., Kamboj, A. K., Hart, P. A., Hinton, A. 100–111 (2017). trypsinogen, whereas cathepsin L-deletion reduces the
& Conwell, D. L. The changing epidemiology of acute 25. Acharya, C. et al. Fibrosis reduces severity of acute- severity of pancreatitis in mice. Gastroenterology 138,
pancreatitis hospitalizations: a decade of trends and on-chronic pancreatitis in humans. Gastroenterology 726–737 (2010).
the impact of chronic pancreatitis. Pancreas 46, 145, 466–475 (2013). 39. Gukovskaya, A. S. et al. Neutrophils and NADPH
482–488 (2017). 26. Al-Bahrani, A. Z. & Ammori, B. J. Clinical laboratory oxidase mediate intrapancreatic trypsin activation in
12. Umapathy, C. et al. Natural history after acute assessment of acute pancreatitis. Clin. Chim. Acta murine experimental acute pancreatitis.
necrotizing pancreatitis: a large US tertiary care 362, 26–48 (2005). Gastroenterology 122, 974–984 (2002).
experience. J. Gastrointest. Surg. 20, 1844–1853 27. Tenner, S., Baillie, J., DeWitt, J. & Vege, S. S. & 40. Halangk, W. et al. Role of cathepsin B in
(2016). of Gastroenterology, A. C. American College of intracellular trypsinogen activation and the onset of
13. Yadav, D., O’Connell, M. & Papachristou, G. I. Natural Gastroenterology guideline: management of acute acute pancreatitis. J. Clin. Invest. 106, 773–781
history following the first attack of acute pancreatitis. pancreatitis. Am. J. Gastroenterol. 108, 1400–1415 (2000).
Am. J. Gastroenterol. 107, 1096–1103 (2012). (2013). 41. Sendler, M. et al. Cathepsin B-mediated activation of
14. Machicado, J. D. et al. Acute pancreatitis has a long- 28. Crockett, S. D., Wani, S., Gardner, T. B., Falck-Ytter, Y. trypsinogen in endocytosing macrophages increases
term deleterious effect on physical health related & Barkun, A. N. American Gastroenterological severity of pancreatitis in mice. Gastroenterology 154,
quality of life. Clin. Gastroenterol. Hepatol. 15, Association Institute Guideline on Initial Management 704–718 (2018).
1435–1443 (2017). of Acute Pancreatitis. Gastroenterology 154, 42. Zeng, Y., Wang, X., Zhang, W., Wu, K. & Ma, J.
15. Das, S. L. et al. Newly diagnosed diabetes mellitus 1096–1101 (2018). Hypertriglyceridemia aggravates ER stress and
after acute pancreatitis: a systematic review and 29. Isaji, S. et al. Revised Japanese guidelines for the pathogenesis of acute pancreatitis.
meta-analysis. Gut 63, 818–831 (2014). management of acute pancreatitis 2015: revised Hepatogastroenterology 59, 2318–2326 (2012).

Reviews
43. Wu, J. S., Li, W. M., Chen, Y. N., Zhao, Q. & Chen, Q. F. 69. Lur, G. et al. InsP(3)receptors and Orai channels in 94. Wu, B. U., Pandol, S. J. & Liu, I. L. Simvastatin is
Endoplasmic reticulum stress is activated in acute pancreatic acinar cells: co-localization and its associated with reduced risk of acute pancreatitis:
pancreatitis. J. Dig. Dis. 17, 295–303 (2016). consequences. Biochem. J. 436, 231–239 (2011). findings from a regional integrated healthcare system.
44. Lugea, A. et al. Adaptive unfolded protein response 70. Romac, J. M.-J., Shahid, R. A., Swain, S. M., Vigna, S. R. Gut 64, 133–138 (2015).
attenuates alcohol-induced pancreatic damage. & Liddle, R. A. Piezo1 is a mechanically activated ion 95. Gornik, I., Gasparovic, V., Vrdoljak, N. G., Haxiu, A. &
Gastroenterology 140, 987–997 (2011). channel and mediates pressure induced pancreatitis. Vucelic, B. Prior statin therapy is associated with
45. Antonucci, L. et al. Basal autophagy maintains Nat. Commun. 9, 1715 (2018). milder course and better outcome in acute
pancreatic acinar cell homeostasis and protein 71. Elmunzer, B. J. et al. Rectal indomethacin alone versus pancreatitis—a cohort study. Pancreatology 13,
synthesis and prevents ER stress. Proc. Natl Acad. indomethacin and prophylactic pancreatic stent 196–200 (2013).
Sci. USA 112, 6166 (2015). placement for preventing pancreatitis after ERCP: 96. Lee, P. J. et al. Association of statins with decreased
46. Sendler, M. et al. Tumour necrosis factor alpha study protocol for a randomized controlled trial. Trials acute pancreatitis severity: a propensity score
secretion induces protease activation and acinar cell 17, 2 (2016). analysis. J. Clin. Gastroenterol. 52, 742–746 (2017).
necrosis in acute experimental pancreatitis in mice. 72. Atar, D. et al. Effect of intravenous TRO40303 as an 97. US National Library of Medicine. ClinicalTrials.gov
Gut 62, 430–439 (2013). adjunct to primary percutaneous coronary intervention https://clinicaltrials.gov/ct2/show/NCT02743364
47. Merza, M. et al. Neutrophil extracellular traps induce for acute ST-elevation myocardial infarction: MITOCARE (2019).
trypsin activation, inflammation, and tissue damage in study results. Eur. Heart J. 36, 112–119 (2015). 98. Venglovecz, V. et al. The importance of aquaporin 1 in
mice with severe acute pancreatitis. Gastroenterology 73. Le Lamer, S. et al. Translation of TRO40303 from pancreatitis and its relation to the CFTR Cl(-) channel.
149, 1931 (2015). myocardial infarction models to demonstration of Front. Physiol. 9, 854 (2018).
48. Jakkampudi, A. et al. NF-kappaB in acute pancreatitis: safety and tolerance in a randomized phase I trial. 99. Pallagi, P., Hegyi, P. & Rakonczay, Z. J. The physiology
Mechanisms and therapeutic potential. Pancreatology J. Transl Med. 12, 38 (2014). and pathophysiology of pancreatic ductal secretion:
16, 477–488 (2016). 74. Saluja, A. K. et al. Secretagogue-induced digestive the background for clinicians. Pancreas 44, 1211–1233
49. Shanbhag, S. T. et al. Acute pancreatitis conditioned enzyme activation and cell injury in rat pancreatic (2015).
mesenteric lymph causes cardiac dysfunction in rats acini. Am. J. Physiol. 276, G835–G842 (1999). 100. Hegyi, P. et al. CFTR: a new horizon in the
independent of hypotension. Surgery 163, 1097–1105 75. Wilson, J. S. et al. Both ethanol consumption and pathomechanism and treatment of pancreatitis.
(2018). protein deficiency increase the fragility of pancreatic Rev. Physiol. Biochem. Pharmacol. 170, 37–66 (2016).
50. Mole, D. J. et al. Tryptophan catabolites in mesenteric lysosomes. J. Lab. Clin. Med. 115, 749–755 (1990). 101. Hegyi, P. & Petersen, O. H. The exocrine pancreas: the
lymph may contribute to pancreatitis-associated organ 76. Haber, P. S., Wilson, J. S., Apte, M. V., Korsten, M. A. acinar-ductal tango in physiology and pathophysiology.
failure. Br. J. Surg. 95, 855–867 (2008). & Pirola, R. C. Chronic ethanol consumption increases Rev. Physiol. Biochem. Pharmacol. 165, 1–30 (2013).
51. Mittal, A. et al. The proteome of mesenteric lymph the fragility of rat pancreatic zymogen granules. Gut 102. Maleth, J. et al. Alcohol disrupts levels and function of
during acute pancreatitis and implications for 35, 1474–1478 (1994). the cystic fibrosis transmembrane conductance
treatment. JOP 10, 130–142 (2009). 77. Louhimo, J., Steer, M. L. & Perides, G. Necroptosis is regulator to promote development of pancreatitis.
52. Flint, R. S. et al. Acute pancreatitis severity is an important severity determinant and potential Gastroenterology 148, 427–439 (2015).
exacerbated by intestinal ischemia-reperfusion therapeutic target in experimental severe pancreatitis. 103. Venglovecz, V. et al. Effects of bile acids on pancreatic
conditioned mesenteric lymph. Surgery 143, Cell. Mol. Gastroenterol. Hepatol. 2, 519–535 (2016). ductal bicarbonate secretion in guinea pig. Gut 57,
404–413 (2008). 78. Han, J., Zhong, C.-Q. & Zhang, D.-W. Programmed 1102–1112 (2008).
53. Gorelick, F. S. & Lerch, M. M. Do animal models of necrosis: backup to and competitor with apoptosis in 104. Vigna, S. R., Shahid, R. A., Nathan, J. D., McVey, D. C.
acute pancreatitis reproduce human disease? the immune system. Nat. Immunol. 12, 1143–1149 & Liddle, R. A. Leukotriene B4 mediates inflammation
Cell. Mol. Gastroenterol. Hepatol. 4, 251–262 (2017). (2011). via TRPV1 in duct obstruction-induced pancreatitis in
54. Gukovskaya, A. S., Gukovsky, I., Algul, H. & 79. He, S. et al. Receptor interacting protein kinase-3 rats. Pancreas 40, 708–714 (2011).
Habtezion, A. Autophagy, inflammation, and immune determines cellular necrotic response to TNF-alpha. 105. Wen, L. et al. Transient high pressure in pancreatic
dysfunction in the pathogenesis of pancreatitis. Cell 137, 1100–1111 (2009). ducts promotes inflammation and alters tight
Gastroenterology 153, 1212–1226 (2017). 80. Wang, G., Qu, F.-Z., Li, L., Lv, J.-C. & Sun, B. junctions via calcineurin signaling in mice.
55. Lampel, M. & Kern, H. F. Acute interstitial pancreatitis Necroptosis: a potential, promising target and switch Gastroenterology 155, 1250–1263 (2018).
in the rat induced by excessive doses of a pancreatic in acute pancreatitis. Apoptosis 21, 121–129 (2016). 106. Orabi, A. I. et al. Targeted inhibition of pancreatic
secretagogue. Virchows Arch. A 373, 97–117 (1977). 81. Diakopoulos, K. N. et al. Impaired autophagy induces acinar cell calcineurin is a novel strategy to prevent
56. Pandol, S. J., Gukovsky, I., Satoh, A., Lugea, A. & chronic atrophic pancreatitis in mice via sex- and post-ERCP pancreatitis. Cell. Mol. Gastroenterol.
Gukovskaya, A. S. Animal and in vitro models of nutrition-dependent processes. Gastroenterology Hepatol. 3, 119–128 (2017).
alcoholic pancreatitis: role of cholecystokinin. Pancreas 148, 626–638 (2015). 107. Maleth, J. et al. Non-conjugated chenodeoxycholate
27, 297–300 (2003). 82. Mareninova, O. A. et al. Impaired autophagic flux induces severe mitochondrial damage and inhibits
57. Criddle, D. N. The role of fat and alcohol in acute mediates acinar cell vacuole formation and bicarbonate transport in pancreatic duct cells. Gut 60,
pancreatitis: a dangerous liaison. Pancreatology 15, trypsinogen activation in rodent models of acute 136–138 (2011).
S6–S12 (2015). pancreatitis. J. Clin. Invest. 119, 3340–3355 (2009). 108. Perides, G., Laukkarinen, J. M., Vassileva, G. &
58. Huang, W. et al. Fatty acid ethyl ester synthase 83. Lugea, A. et al. The combination of alcohol and cigarette Steer, M. L. Biliary acute pancreatitis in mice is
inhibition ameliorates ethanol-induced Ca2+-dependent smoke induces endoplasmic reticulum stress and cell mediated by the G-protein-coupled cell surface bile
mitochondrial dysfunction and acute pancreatitis. Gut death in pancreatic acinar cells. Gastroenterology 153, acid receptor Gpbar1. Gastroenterology 138,
63, 1313–1324 (2014). 1674–1686 (2017). 715–725 (2010).
59. Hegyi, P., Pandol, S., Venglovecz, V. & Rakonczay, Z. J. 84. Zelic, M. et al. RIP kinase 1-dependent endothelial 109. Elliot, D. W., Williams, R. D. & Zollinger, R. M.
The acinar-ductal tango in the pathogenesis of acute necroptosis underlies systemic inflammatory response Alterations in the pancreatic resistance to bile in the
pancreatitis. Gut 60, 544–552 (2011). syndrome. J. Clin. Invest. 128, 2064–2075 (2018). pathogenesis of acute pancreatitis. Ann. Surg. 146,
60. Noble, M. D., Romac, J., Vigna, S. R. & Liddle, R. A. A. 85. Lee, H.-J., Yoon, Y.-S. & Lee, S.-J. Mechanism of 662–669 (1957).
pH-sensitive, neurogenic pathway mediates disease neuroprotection by trehalose: controversy surrounding 110. Lerch, M. M. & Aghdassi, A. A. The role of bile acids in
severity in a model of post-ERCP pancreatitis. Gut 57, autophagy induction. Cell Death Dis. 9, 712 (2018). gallstone-induced pancreatitis. Gastroenterology 138,
1566–1571 (2008). 86. Ron, D. & Walter, P. Signal integration in the 429–433 (2010).
61. Lerch, M. M. et al. Acute necrotizing pancreatitis in endoplasmic reticulum unfolded protein response. 111. Rakonczay, Z. J., Hegyi, P., Takacs, T., McCarroll, J. &
the opossum: earliest morphological changes involve Nat. Rev. Mol. Cell. Biol. 8, 519–529 (2007). Saluja, A. K. The role of NF-kappaB activation in the
acinar cells. Gastroenterology 103, 205–213 (1992). 87. Kim, I., Xu, W. & Reed, J. C. Cell death and pathogenesis of acute pancreatitis. Gut 57, 259–267
62. Senninger, N., Moody, F. G., Coelho, J. C. endoplasmic reticulum stress: disease relevance and (2008).
& Van Buren, D. H. The role of biliary obstruction in therapeutic opportunities. Nat. Rev. Drug Discov. 7, 112. Watanabe, T., Kudo, M. & Strober, W.
the pathogenesis of acute pancreatitis in the opossum. 1013–1030 (2008). Immunopathogenesis of pancreatitis. Mucosal
Surgery 99, 688–693 (1986). 88. Seyhun, E. et al. Tauroursodeoxycholic acid reduces Immunol. 10, 283–298 (2017).
63. Runkel, N. S., Rodriguez, L. F., Moody, F. G., endoplasmic reticulum stress, acinar cell damage, 113. Griffith, J. W., Sokol, C. L. & Luster, A. D. Chemokines
LaRocco, M. T. & Blasdel, T. Salmonella infection of and systemic inflammation in acute pancreatitis. and chemokine receptors: positioning cells for host
the biliary and intestinal tract of wild opossums. Am. J. Physiol. Liver Physiol. 301, 773 (2011). defense and immunity. Annu. Rev. Immunol. 32,
Lab. Anim. Sci. 41, 54–56 (1991). 89. Pandol, S. J., Gorelick, F. S. & Lugea, A. Environmental 659–702 (2014).
64. Senninger, N. & Runkel, N. in Essentials of Experimental and genetic stressors and the unfolded protein response 114. Zhou, G.-X. et al. Protective effects of MCP-1
Surgery: Gastroenterology Ch. 23 (eds Gregerson, H. in exocrine pancreatic function — a hypothesis. Front. inhibitor on a rat model of severe acute pancreatitis.
et al.) (Gordon and Breach Publishing Group, 1995). Physiol. 2, 8 (2011). Hepatobiliary Pancreat. Dis. Int. 9, 201–207 (2010).
65. Dolai, S. et al. Pancreatitis-induced depletion of 90. Richardson, C. E., Kooistra, T. & Kim, D. H. An essential 115. Bhatia, M. et al. Treatment with neutralising
syntaxin 2 promotes autophagy and increases role for XBP-1 in host protection against immune antibody against cytokine induced neutrophil
basolateral exocytosis. Gastroenterology 154, activation in C. elegans. Nature 463, 1092–1095 chemoattractant (CINC) protects rats against acute
1805–1821 (2018). (2010). pancreatitis associated lung injury. Gut 47, 838–844
66. Kruger, B., Albrecht, E. & Lerch, M. M. The role of 91. Xu, C., Bailly-Maitre, B. & Reed, J. C. Endoplasmic (2000).
intracellular calcium signaling in premature protease reticulum stress: cell life and death decisions. J. Clin. 116. Malla, S. R. et al. Effect of oral administration of
activation and the onset of pancreatitis. Am. J. Pathol. Invest. 115, 2656–2664 (2005). AZD8309, a CXCR2 antagonist, on the severity
157, 43–50 (2000). 92. Chen, J. C., Wu, M. L., Huang, K. C. & Lin, W. W. of experimental pancreatitis. Pancreatology 16,
67. Maleth, J. & Hegyi, P. Ca2+ toxicity and mitochondrial HMG-CoA reductase inhibitors activate the unfolded 761–769 (2016).
damage in acute pancreatitis: translational overview. protein response and induce cytoprotective GRP78 117. Saeki, K. et al. CCL2-induced migration and SOCS3-
Phil. Trans. R. Soc. B 371, 20150425 (2016). expression. Cardiovasc. Res. 80, 138–150 (2008). mediated activation of macrophages are involved in
68. Zhang, S. L. et al. STIM1 is a Ca2+ sensor that 93. Morck, C. et al. Statins inhibit protein lipidation and cerulein-induced pancreatitis in mice. Gastroenterology
activates CRAC channels and migrates from the Ca2+ induce the unfolded protein response in the non-sterol 142, 1010–1020 (2012).
store to the plasma membrane. Nature 437, producing nematode. Caenorhabditis elegans. Proc. 118. Bhatia, M. & Hegde, A. Treatment with antileukinate,
902–905 (2005). Natl Acad. Sci. USA 106, 18285–18290 (2009). a CXCR2 chemokine receptor antagonist, protects

Reviews
mice against acute pancreatitis and associated lung pancreatitis. J. Gastroenterol. Hepatol. 22, 550–554 necrosis and inflammation. Am. J. Pathol. 185,
injury. Regul. Pept. 138, 40–48 (2007). (2007). 808–819 (2015).
119. Pastor, C. M. et al. Role of macrophage inflammatory 143. Dianliang, Z., Jieshou, L., Zhiwei, J. & Baojun, Y. 168. Ammori, B. J. et al. Early increase in intestinal
peptide-2 in cerulein-induced acute pancreatitis and Association of plasma levels of tumor necrosis factor permeability in patients with severe acute pancreatitis:
pancreatitis-associated lung injury. Lab. Invest. 83, (TNF)-alpha and its soluble receptors, two correlation with endotoxemia, organ failure, and
471–478 (2003). polymorphisms of the TNF gene, with acute severe mortality. J. Gastrointest. Surg. 3, 252–262 (1999).
120. Frossard, J. L. et al. Role of CCL-2, CCR-2 and CCR-4 pancreatitis and early septic shock due to it. Pancreas 169. Blenkiron, C. et al. MicroRNAs in mesenteric lymph
in cerulein-induced acute pancreatitis and pancreatitis- 26, 339–343 (2003). and plasma during acute pancreatitis. Ann. Surg. 260,
associated lung injury. J. Clin. Pathol. 64, 387–393 144. Vege, S. S. et al. Pentoxifylline treatment in severe 341–347 (2014).
(2011). acute pancreatitis: a pilot, double-blind, placebo- 170. Landahl, P., Ansari, D. & Andersson, R. Severe acute
121. Gerard, C. et al. Targeted disruption of the beta- controlled, randomized trial. Gastroenterology 149, pancreatitis: gut barrier failure, systemic inflammatory
chemokine receptor CCR1 protects against pancreatitis- 318–320 (2015). response, acute lung injury, and the role of the
associated lung injury. J. Clin. Invest. 100, 2022–2027 145. Stone, J. H. et al. Trial of tocilizumab in giant-cell mesenteric lymph. Surg. Infect. 16, 651–656 (2015).
(1997). arteritis. N. Engl. J. Med. 377, 317–328 (2017). 171. Peng, H. et al. Blocking abdominal lymphatic flow
122. He, M., Horuk, R. & Bhatia, M. Treatment with 146. Schirmer, M., Muratore, F. & Salvarani, C. Tocilizumab attenuates acute hemorrhagic necrotizing pancreatitis
BX471, a nonpeptide CCR1 antagonist, protects mice for the treatment of giant cell arteritis. Expert Rev. -associated lung injury in rats. J. Inflamm. 10, 9 (2013).
against acute pancreatitis-associated lung injury by Clin. Immunol. 14, 339–349 (2018). 172. Zhang, D., Tsui, N., Li, Y. & Wang, F. Thoracic duct
modulating neutrophil recruitment. Pancreas 34, 147. Chen, K.-L. et al. Effects of tocilizumab on experimental ligation in the rat attenuates lung injuries in acute
233–241 (2007). severe acute pancreatitis and associated acute lung pancreatitis. Lymphology 46, 144–149 (2013).
123. Papachristou, G. I. Prediction of severe acute injury. Crit. Care Med. 44, e664–e677 (2016). 173. Toliyat, M. et al. Interventional radiology in the
pancreatitis: current knowledge and novel insights. 148. Yucebay, F. et al. Tocilizumab as first-line therapy for management of thoracic duct injuries: anatomy,
World J. Gastroenterol. 14, 6273–6275 (2008). steroid-refractory acute graft-versus-host-disease: techniques and results. Clin. Imaging 42, 183–192
124. Jakkampudi, A. et al. Acinar injury and early cytokine analysis of a single-center experience. Leuk. Lymphoma (2017).
response in human acute biliary pancreatitis. Sci. Rep. 15, 1–7 (2019). 174. Girotra, M., Horwhat, J. D., Settle, T. L. & Parasher, V. K.
7, 2 (2017). 149. Pablos, J. L. et al. Efficacy of tocilizumab monotherapy Endoscopic ultrasound-guided transesophageal thoracic
125. Gu, H. et al. Necro-inflammatory response of after response to combined tocilizumab and duct puncture in a Swine model: a survival study.
pancreatic acinar cells in the pathogenesis of acute methotrexate in patients with rheumatoid arthritis: J. Laparoendosc. Adv. Surg. Tech. A 23, 588–591
alcoholic pancreatitis. Cell Death Dis. 4, e816 (2013). the randomised JUST-ACT study. Clin. Exp. Rheumatol. (2013).
126. Ushio-Fukai, M. Compartmentalization of redox (in the press). 175. Parasher, V. K. et al. Lymph sampling and
signaling through NADPH oxidase-derived ROS. 150. Friess, H. et al. Enhanced expression of TGF-betas and lymphangiography via EUS-guided transesophageal
Antioxid. Redox Signal. 11, 1289–1299 (2009). their receptors in human acute pancreatitis. Ann. Surg. thoracic duct puncture in a swine model. Gastrointest.
127. Eppensteiner, J., Davis, R. P., Barbas, A. S., Kwun, J. 227, 95–104 (1998). Endosc. 59, 564–567 (2004).
& Lee, J. Immunothrombotic activity of damage- 151. Deviere, J. et al. Interleukin 10 reduces the incidence 176. Choi, J.-H. et al. Revised Atlanta classification and
associated molecular patterns and extracellular of pancreatitis after therapeutic endoscopic retrograde determinant-based classification: Which one better
vesicles in secondary organ failure induced by trauma cholangiopancreatography. Gastroenterology 120, at stratifying outcomes of patients with acute
and sterile insults. Front. Immunol. 9, 190 (2018). 498–505 (2001). pancreatitis? Pancreatology 17, 194–200 (2017).
128. Yasuda, T. et al. Significant increase of serum high- 152. Hutchins, A. P., Diez, D. & Miranda-Saavedra, D. 177. Zubia-Olaskoaga, F. et al. Comparison between
mobility group box chromosomal protein 1 levels in The IL-10/STAT3-mediated anti-inflammatory revised Atlanta classification and determinant-based
patients with severe acute pancreatitis. Pancreas 33, response: recent developments and future challenges. classification for acute pancreatitis in intensive care
359–363 (2006). Brief. Funct. Genomics 12, 489–498 (2013). medicine. Why do not use a modified determinant-
129. Sharif, R. et al. Impact of toll-like receptor 4 on the 153. Lin, R. et al. Interleukin-10 attenuates impairment of based classification? Crit. Care Med. 44, 910–917
severity of acute pancreatitis and pancreatitis- the blood-brain barrier in a severe acute pancreatitis (2016).
associated lung injury in mice. Gut 58, 813–819 rat model. J. Inflamm. 15, 4 (2018). 178. Talukdar, R., Clemens, M. & Vege, S. S. Moderately
(2009). 154. Warzecha, Z. et al. IGF-1 stimulates production of severe acute pancreatitis: prospective validation of
130. Hoque, R. et al. TLR9 and the NLRP3 inflammasome interleukin-10 and inhibits development of caerulein- this new subgroup of acute pancreatitis. Pancreas 41,
link acinar cell death with inflammation in acute induced pancreatitis. J. Physiol. Pharmacol. 54, 306–309 (2012).
pancreatitis. Gastroenterology 141, 358–369 (2011). 575–590 (2003). 179. Vege, S. S. et al. Low mortality and high morbidity in
131. Lee, B., Zhao, Q. & Habtezion, A. Immunology of 155. Sharma, D. et al. Association of systemic inflammatory severe acute pancreatitis without organ failure: a case
pancreatitis and environmental factors. Curr. Opin. and anti-inflammatory responses with adverse for revising the Atlanta classification to include
Gastroenterol. 33, 383–389 (2017). outcomes in acute pancreatitis: preliminary results of an ‘moderately severe acute pancreatitis’. Am. J.
132. Hoque, R. Update on innate immunity and perspectives ongoing study. Dig. Dis. Sci. 62, 3468–3478 (2017). Gastroenterol. 104, 710–715 (2009).
on metabolite regulation in acute pancreatitis. Curr. 156. Hasan, A., Moscoso, D. I. & Kastrinos, F. The role of 180. Schepers, N. J. et al. Impact of characteristics of organ
Opin. Gastroenterol. 32, 507–512 (2016). genetics in pancreatitis. Gastrointest. Endosc. Clin. failure and infected necrosis on mortality in necrotising
133. Hoque, R., Farooq, A., Ghani, A., Gorelick, F. & N. Am. 28, 587–603 (2018). pancreatitis. Gut. https://doi.org/10.1136/gutjnl-2017-
Mehal, W. Z. Lactate reduces liver and pancreatic 157. Zator, Z. & Whitcomb, D. C. Insights into the genetic 314657 (2018).
injury in Toll-like receptor- and inflammasome- risk factors for the development of pancreatic disease. 181. Petrov, M. S., Shanbhag, S., Chakraborty, M.,
mediated inflammation via GPR81-mediated Therap. Adv. Gastroenterol. 10, 323–336 (2017). Phillips, A. R. J. & Windsor, J. A. Organ failure and
suppression of innate immunity. Gastroenterology 158. Krishna, S. G. et al. Morbid obesity is associated with infection of pancreatic necrosis as determinants of
146, 1763–1774 (2014). adverse clinical outcomes in acute pancreatitis: mortality in patients with acute pancreatitis.
134. Primiano, M. J. et al. Efficacy and pharmacology of the a propensity-matched study. Am. J. Gastroenterol. Gastroenterology 139, 813–820 (2010).
NLRP3 inflammasome inhibitor CP-456,773 (CRID3) 110, 1608–1619 (2015). 182. Wu, B. U. et al. Blood urea nitrogen in the early
in murine models of dermal and pulmonary 159. Navina, S. et al. Lipotoxicity causes multisystem organ assessment of acute pancreatitis: an international
inflammation. J. Immunol. 197, 2421–2433 (2016). failure and exacerbates acute pancreatitis in obesity. validation study. Arch. Intern. Med. 171, 669–676
135. Mridha, A. R. et al. NLRP3 inflammasome blockade Sci. Transl Med. 3, 107ra110 (2011). (2011).
reduces liver inflammation and fibrosis in experimental 160. Fallon, M. B. et al. Effect of cerulein hyperstimulation 183. Brown, A., Orav, J. & Banks, P. A. Hemoconcentration
NASH in mice. J. Hepatol. 66, 1037–1046 (2017). on the paracellular barrier of rat exocrine pancreas. is an early marker for organ failure and necrotizing
136. Gao, L. et al. NLRP3 inflammasome: a promising Gastroenterology 108, 1863–1872 (1995). pancreatitis. Pancreas 20, 367–372 (2000).
target in ischemic stroke. Inflamm. Res. 66, 17–24 161. Gaisano, H. Y. et al. Supramaximal cholecystokinin 184. Koutroumpakis, E. et al. Admission hematocrit and rise
(2017). displaces Munc18c from the pancreatic acinar basal in blood urea nitrogen at 24h outperform other
137. Li, G. et al. TLR4-mediated NF-kappaB signaling surface, redirecting apical exocytosis to the basal laboratory markers in predicting persistent organ
pathway mediates HMGB1-induced pancreatic injury membrane. J. Clin. Invest. 108, 1597–1611 (2001). failure and pancreatic necrosis in acute pancreatitis:
in mice with severe acute pancreatitis. Int. J. Mol. Med. 162. Durgampudi, C. et al. Acute lipotoxicity regulates a post hoc analysis of three large prospective databases.
37, 99–107 (2016). severity of biliary acute pancreatitis without affecting Am. J. Gastroenterol. 110, 1707–1716 (2015).
138. Wu, B. U. et al. Lactated Ringer’s solution reduces its initiation. Am. J. Pathol. 184, 1773–1784 (2014). 185. Karpavicius, A., Dambrauskas, Z., Sileikis, A.,
systemic inflammation compared with saline in 163. Umpaichitra, V., Banerji, M. A. & Castells, S. Vitkus, D. & Strupas, K. Value of adipokines in
patients with acute pancreatitis. Clin. Gastroenterol. Postprandial hyperlipidemia after a fat loading test in predicting the severity of acute pancreatitis:
Hepatol. 9, 717 (2011). minority adolescents with type 2 diabetes mellitus and comprehensive review. World J. Gastroenterol. 18,
139. Choi, J. H., Kim, H. J., Lee, B. U., Kim, T. H. & obesity. J. Pediatr. Endocrinol. Metab. 17, 853–864 6620–6627 (2012).
Song, I. H. Vigorous periprocedural hydration with (2004). 186. Deng, L. H. et al. Plasma cytokines can help to identify
lactated Ringer’s solution reduces the risk of 164. Natu, A. et al. Visceral adiposity predicts severity of the development of severe acute pancreatitis on
pancreatitis after retrograde cholangiopancreatography acute pancreatitis. Pancreas 46, 776–781 (2017). admission. Medicine 96, e7312 (2017).
in hospitalized patients. Clin. Gastroenterol. Hepatol. 165. Halleux, C. M. et al. Secretion of adiponectin and 187. Mentula, P. et al. Early prediction of organ failure by
15, 92 (2017). regulation of apM1 gene expression in human visceral combined markers in patients with acute pancreatitis.
140. Aoun, E. et al. Diagnostic accuracy of interleukin-6 and adipose tissue. Biochem. Biophys. Res. Commun. 288, Br. J. Surg. 92, 68–75 (2005).
interleukin-8 in predicting severe acute pancreatitis: 1102–1107 (2001). 188. Zhang, Y.-P. et al. Early prediction of persistent organ
a meta-analysis. Pancreatology 9, 777–785 (2009). 166. Nawaz, H. et al. Elevated serum triglycerides are failure by serum angiopoietin-2 in patients with acute
141. Zhang, H. et al. IL-6 trans-signaling promotes independently associated with persistent organ failure pancreatitis. Dig. Dis. Sci. 61, 3584–3591 (2016).
pancreatitis-associated lung injury and lethality. in acute pancreatitis. Am. J. Gastroenterol. 110, 189. Di, M.-Y. et al. Prediction models of mortality in acute
J. Clin. Invest. 123, 1019–1031 (2013). 1497–1503 (2015). pancreatitis in adults: a systematic review. Ann. Intern.
142. Sathyanarayan, G., Garg, P. K., Prasad, H. & 167. Patel, K. et al. Lipolysis of visceral adipocyte Med. 165, 482–490 (2016).
Tandon, R. K. Elevated level of interleukin-6 predicts triglyceride by pancreatic lipases converts mild acute 190. Mounzer, R. et al. Comparison of existing clinical
organ failure and severe disease in patients with acute pancreatitis to severe pancreatitis independent of scoring systems to predict persistent organ failure in

Reviews
patients with acute pancreatitis. Gastroenterology acute pancreatitis: a randomized experimental trial. 239. Bakker, O. J. et al. Endoscopic transgastric versus
142, 1476 (2012). Crit. Care 17, R281 (2013). surgical necrosectomy for infected necrotizing
191. Forsmark, C. E. & Yadav, D. Predicting the prognosis 216. Richards, E. R., Kabir, S. I., McNaught, C.-E. & pancreatitis: a randomized trial. JAMA 307,
of acute pancreatitis. Ann. Intern. Med. 165, MacFie, J. Effect of thoracic epidural anaesthesia on 1053–1061 (2012).
523–524 (2016). splanchnic blood flow. Br. J. Surg. 100, 316–321 240. van Brunschot, S. et al. Endoscopic or surgical step-up
192. Mofidi, R. et al. Association between early systemic (2013). approach for infected necrotising pancreatitis:
inflammatory response, severity of multiorgan 217. Bulyez, S. et al. Epidural analgesia in critically ill a multicentre randomised trial. Lancet 391, 51–58
dysfunction and death in acute pancreatitis. Br. J. Surg. patients with acute pancreatitis: the multicentre (2018).
93, 738–744 (2006). randomised controlled EPIPAN study protocol. 241. Kumar, N., Conwell, D. L. & Thompson, C. C. Direct
193. Lankisch, P. G. et al. Hemoconcentration: an early BMJ Open 7, e015280 (2017). endoscopic necrosectomy versus step-up approach for
marker of severe and/or necrotizing pancreatitis? 218. da Costa, D. W. et al. Same-admission versus interval walled-off pancreatic necrosis: comparison of clinical
A critical appraisal. Am. J. Gastroenterol. 96, cholecystectomy for mild gallstone pancreatitis outcome and health care utilization. Pancreas 43,
2081–2085 (2001). (PONCHO): a multicentre randomised controlled trial. 1334–1339 (2014).
194. Singh, V. K. et al. Early systemic inflammatory Lancet 386, 1261–1268 (2015). 242. Guo, J. et al. A multi-institutional consensus on how to
response syndrome is associated with severe acute 219. da Costa, D. W. et al. Cost-effectiveness of same- perform endoscopic ultrasound-guided peri-pancreatic
pancreatitis. Clin. Gastroenterol. Hepatol. 7, admission versus interval cholecystectomy after mild fluid collection drainage and endoscopic necrosectomy.
1247–1251 (2009). gallstone pancreatitis in the PONCHO trial. Br. J. Surg. Endosc. Ultrasound 6, 285–291 (2017).
195. Buxbaum, J. L. et al. Early aggressive hydration 103, 1695–1703 (2016). 243. Gurusamy, K. S., Pallari, E., Hawkins, N., Pereira, S. P.
hastens clinical improvement in mild acute pancreatitis. 220. Young, S.-H. et al. Cholecystectomy reduces recurrent & Davidson, B. R. Management strategies for
Am. J. Gastroenterol. 112, 797–803 (2017). pancreatitis and improves survival after endoscopic pancreatic pseudocysts. Cochrane Database Syst. Rev.
196. Mao, E. Q. et al. Rapid hemodilution is associated with sphincterotomy. J. Gastrointest. Surg. 21, 294–301 4, CD011392 (2016).
increased sepsis and mortality among patients (2017). 244. Hammad, T. et al. Efficacy and safety of lumen-
with severe acute pancreatitis. Chin. Med. J. 123, 221. Noel, R. et al. Index versus delayed cholecystectomy in apposing metal stents in management of pancreatic
1639–1644 (2010). mild gallstone pancreatitis: results of a randomized fluid collections: are they better than plastic stents?
197. Wall, I. et al. Decreased mortality in acute pancreatitis controlled trial. HPB 20, 932–938 (2018). A systematic review and meta-analysis. Dig. Dis. Sci.
related to early aggressive hydration. Pancreas 40, 222. Nealon, W. H., Bawduniak, J. & Walser, E. M. 63, 289–301 (2018).
547–550 (2011). Appropriate timing of cholecystectomy in patients who 245. Siddiqui, A. A. et al. Fully covered self-expanding
198. Singh, V. K. et al. An international multicenter study of present with moderate to severe gallstone-associated metal stents versus lumen-apposing fully covered self-
early intravenous fluid administration and outcome in acute pancreatitis with peripancreatic fluid collections. expanding metal stent versus plastic stents for
acute pancreatitis. United European Gastroenterol. J. Ann. Surg. 239, 741–751 (2004). endoscopic drainage of pancreatic walled-off necrosis:
5, 491–498 (2017). 223. van Dijk, S. M. et al. Acute pancreatitis: recent advances clinical outcomes and success. Gastrointest. Endosc.
199. Yamashita, T. et al. Large volume fluid resuscitation for through randomised trials. Gut 66, 2024–2032 85, 758–765 (2017).
severe acute pancreatitis is associated with reduced (2017). 246. Sharaiha, R. Z. et al. Endoscopic therapy with lumen-
mortality: a multicenter retrospective study. J. Clin. 224. Tang, E., Stain, S. C., Tang, G., Froes, E. & Berne, T. V. apposing metal stents is safe and effective for patients
Gastroenterol. 53, 385–391 (2018). Timing of laparoscopic surgery in gallstone with pancreatic walled-off necrosis. Clin. Gastroenterol.
200. Haydock, M. D. et al. Fluid therapy in acute pancreatitis: pancreatitis. Arch. Surg. 130, 496–500 (1995). Hepatol. 14, 1797–1803 (2016).
anybody’s guess. Ann. Surg. 257, 182–188 (2013). 225. Nikkola, J., Laukkarinen, J., Huhtala, H. & Sand, J. 247. Siddiqui, A. A. et al. EUS-guided drainage of
201. de-Madaria, E. et al. Fluid resuscitation with lactated The intensity of brief interventions in patients with peripancreatic fluid collections and necrosis by using
Ringer’s solution versus normal saline in acute acute alcoholic pancreatitis should be increased, a novel lumen-apposing stent: a large retrospective,
pancreatitis: a triple-blind, randomized, controlled especially in young patients with heavy alcohol multicenter U.S. experience (with videos).
trial. United European Gastroenterol. J. 6, 63–72 consumption. Alcohol Alcohol. 52, 453–459 (2017). Gastrointest. Endosc. 83, 699–707 (2016).
(2018). 226. Xiang, J.-X. et al. Impact of cigarette smoking on 248. Stecher, S. S. et al. Delayed severe bleeding
202. van Brunschot, S. et al. Abdominal compartment recurrence of hyperlipidemic acute pancreatitis. complications after treatment of pancreatic fluid
syndrome in acute pancreatitis: a systematic review. World J. Gastroenterol. 23, 8387–8394 (2017). collections with lumen-apposing metal stents. Gut 66,
Pancreas 43, 665–674 (2014). 227. Nordback, I. et al. The recurrence of acute alcohol- 1871–1872 (2017).
203. Larino-Noia, J. et al. Early and/or immediately full associated pancreatitis can be reduced: a randomized 249. Bang, J. Y., Hasan, M., Navaneethan, U., Hawes, R.
caloric diet versus standard refeeding in mild acute controlled trial. Gastroenterology 136, 848–855 & Varadarajulu, S. Lumen-apposing metal stents (LAMS)
pancreatitis: a randomized open-label trial. (2009). for pancreatic fluid collection (PFC) drainage: may not
Pancreatology 14, 167–173 (2014). 228. Pedersen, S. B., Langsted, A. & Nordestgaard, B. G. be business as usual. Gut 66, 2054–2056 (2017).
204. Zhao, X. L. et al. Early oral refeeding based on hunger in Nonfasting mild-to-moderate hypertriglyceridemia and 250. Brimhall, B. et al. Increased incidence of
moderate and severe acute pancreatitis: a prospective risk of acute pancreatitis. JAMA Intern. Med. 176, pseudoaneurysm bleeding with lumen-apposing metal
controlled, randomized clinical trial. Nutrition 31, 1834–1842 (2016). stents compared to double-pigtail plastic stents in
171–175 (2015). 229. Munigala, S., Kanwal, F., Xian, H., Scherrer, J. F. & patients with peripancreatic fluid collections.
205. Vaughn, V. M. et al. Early versus delayed feeding in Agarwal, B. Increased risk of pancreatic adenocarcinoma Clin. Gastroenterol. Hepatol. 16, 1521–1528 (2018).
patients with acute pancreatitis: a systematic review. after acute pancreatitis. Clin. Gastroenterol. Hepatol. 251. Larsen, M. & Kozarek, R. A. Management of
Ann. Intern. Med. 166, 883–892 (2017). 12, 1143–1150 (2014). disconnected pancreatic duct syndrome. Curr. Treat.
206. Machicado, J. D. et al. Practice patterns and 230. Schepers, N. J. et al. Early biliary decompression Opt. Gastroenterol. 14, 348–359 (2016).
utilization of tube feedings in acute pancreatitis versus conservative treatment in acute biliary 252. Rana, S. S. et al. Prevention of recurrence of fluid
patients at a large US referral center. Pancreas 47, pancreatitis (APEC trial): study protocol for a collections in walled off pancreatic necrosis and
1150–1155 (2018). randomized controlled trial. Trials 17, 5 (2016). disconnected pancreatic duct syndrome: Comparative
207. Eatock, F. C. et al. A randomized study of early 231. Bradley, E. L. 3rd & Dexter, N. D. Management of study of one versus two long term transmural stents.
nasogastric versus nasojejunal feeding in severe acute severe acute pancreatitis: a surgical odyssey. Ann. Surg. Pancreatology 16, 687–688 (2016).
pancreatitis. Am. J. Gastroenterol. 100, 432–439 251, 6–17 (2010). 253. Bang, J. Y. et al. Impact of disconnected pancreatic
(2005). 232. Gosnell, F. E., O’Neill, B. B. & Harris, H. W. Necrotizing duct syndrome on the endoscopic management of
208. Petrov, M. S., Correia, M. I. T. D. & Windsor, J. A. pancreatitis during pregnancy: a rare cause and review pancreatic fluid collections. Ann. Surg. 267, 561–568
Nasogastric tube feeding in predicted severe acute of the literature. J. Gastrointest. Surg. 5, 371–376 (2018).
pancreatitis. A systematic review of the literature to (2001). 254. Tellez-Avina, F. I. et al. Permanent indwelling
determine safety and tolerance. JOP 9, 440–448 233. Sun, J. et al. Conservative treatment and percutaneous transmural stents for endoscopic treatment of patients
(2008). catheter drainage improve outcome of necrotizing with disconnected pancreatic duct syndrome: long-
209. Bakker, O. J. et al. Early versus on-demand nasoenteric pancreatitis. Hepatogastroenterology 62, 195–199 term results. J. Clin. Gastroenterol. 52, 85–90 (2018).
tube feeding in acute pancreatitis. N. Engl. J. Med. (2015). 255. Rana, S. S., Bhasin, D. K., Rao, C., Sharma, R. &
371, 1983–1993 (2014). 234. Mouli, V. P., Sreenivas, V. & Garg, P. K. Efficacy of Gupta, R. Consequences of long term indwelling
210. Al-Omran, M., Albalawi, Z. H., Tashkandi, M. F. & conservative treatment, without necrosectomy, for transmural stents in patients with walled off pancreatic
Al-Ansary, L. A. Enteral versus parenteral nutrition for infected pancreatic necrosis: a systematic review and necrosis & disconnected pancreatic duct syndrome.
acute pancreatitis. Cochrane Database Syst. Rev. 1, meta-analysis. Gastroenterology 144, 333–340 Pancreatology 13, 486–490 (2013).
CD002837 (2010). (2013). 256. Ahmed, M., Aziz, M. U., Mansoor, M. A. & Anwar, S.
211. Yao, H., He, C., Deng, L. & Liao, G. Enteral versus 235. van Santvoort, H. C. et al. A conservative and Vascular complications in cases of acute pancreatitis
parenteral nutrition in critically ill patients with severe minimally invasive approach to necrotizing — CT scan based study. J. Pak. Med. Assoc. 66,
pancreatitis: a meta-analysis. Eur. J. Clin. Nutr. 72, pancreatitis improves outcome. Gastroenterology 977–989 (2016).
66–68 (2018). 141, 1254–1263 (2011). 257. Harris, S., Nadkarni, N. A., Naina, H. V. & Vege, S. S.
212. Basurto Ona, X., Rigau Comas, D. & Urrutia, G. 236. Mier, J., Leon, E. L., Castillo, A., Robledo, F. & Splanchnic vein thrombosis in acute pancreatitis: a
Opioids for acute pancreatitis pain. Cochrane Blanco, R. Early versus late necrosectomy in severe single-center experience. Pancreas 42, 1251–1254
Database Syst. Rev. 7, CD009179 (2013). necrotizing pancreatitis. Am. J. Surg. 173, 71–75 (2013).
213. Barlass, U. et al. Morphine worsens the severity and (1997). 258. Gonzelez, H. J., Sahay, S. J., Samadi, B., Davidson, B. R.
prevents pancreatic regeneration in mouse models of 237. Arvanitakis, M. et al. Endoscopic management of & Rahman, S. H. Splanchnic vein thrombosis in severe
acute pancreatitis. Gut 67, 600–602 (2018). acute necrotizing pancreatitis: European Society of acute pancreatitis: a 2-year, single-institution
214. Jabaudon, M. et al. Thoracic epidural analgesia and Gastrointestinal Endoscopy (ESGE) evidence-based experience. HPB 13, 860–864 (2011).
mortality in acute pancreatitis: a multicenter multidisciplinary guidelines. Endoscopy 50, 524–546 259. Easler, J. et al. Portosplenomesenteric venous
propensity analysis. Crit. Care Med. 46, e198–e205 (2018). thrombosis in patients with acute pancreatitis is
(2018). 238. van Santvoort, H. C. et al. A step-up approach or open associated with pancreatic necrosis and usually has
215. Bachmann, K. A. et al. Effects of thoracic epidural necrosectomy for necrotizing pancreatitis. N. Engl. a benign course. Clin. Gastroenterol. Hepatol. 12,
anesthesia on survival and microcirculation in severe J. Med. 362, 1491–1502 (2010). 854–862 (2014).

Reviews
260. Xu, W., Qi, X., Chen, J., Su, C. & Guo, X. Prevalence of 267. Shinzeki, M. et al. Serum immunosuppressive acidic 274. US National Library of Medicine. ClinicalTrials.gov
splanchnic vein thrombosis in pancreatitis: a systematic protein levels in patients with severe acute https://clinicaltrials.gov/ct2/show/NCT03401190 (2019).
review and meta-analysis of observational studies. pancreatitis. Pancreas 35, 327–333 (2007). 275. Bae, S.-C. & Lee, Y. H. Comparison of the efficacy and
Gastroenterol. Res. Pract. 2015, 245460 (2015). 268. Chung, S.-D., Chen, K.-Y., Xirasagar, S., Tsai, M.-C. tolerability of tocilizumab, sarilumab, and sirukumab
261. Toque, L. et al. Predictive factors of splanchnic vein & Lin, H.-C. More than 9-times increased risk for in patients with active rheumatoid arthritis: a Bayesian
thrombosis in acute pancreatitis: a 6-year single- pancreatic cancer among patients with acute network meta-analysis of randomized controlled trials.
center experience. J. Dig. Dis. 16, 734–740 (2015). pancreatitis in Chinese population. Pancreas 41, Clin. Rheumatol. 37, 1471–1479 (2018).
262. Machicado, J. D. & Yadav, D. Epidemiology of 142–146 (2012). 276. Dellinger, E. P. et al. Determinant-based classification
recurrent acute and chronic pancreatitis: similarities 269. Rijkers, A. P. et al. Risk of pancreatic cancer after of acute pancreatitis severity: an international
and differences. Dig. Dis. Sci. 62, 1683–1691 (2017). a primary episode of acute pancreatitis. Pancreas 46, multidisciplinary consultation. Ann. Surg. 256,
263. Cote, G. A. et al. Recurrent acute pancreatitis 1018–1022 (2017). 875–880 (2012).
significantly reduces quality of life even in the absence 270. Nikkola, J. et al. The long-term prospective follow-up
of overt chronic pancreatitis. Am. J. Gastroenterol. of pancreatic function after the first episode of acute Author contributions
113, 906–912 (2018). alcoholic pancreatitis: recurrence predisposes one to P.J.L. researched data for the article. Both authors contributed
264. Sankaran, S. J. et al. Frequency of progression from pancreatic dysfunction and pancreatogenic diabetes. equally to all other aspects of the manuscript.
acute to chronic pancreatitis and risk factors: J. Clin. Gastroenterol. 51, 183–190 (2017).
a meta-analysis. Gastroenterology 149, 1490–1500 271. Das, S. L. M. et al. Relationship between the Competing interests
(2015). exocrine and endocrine pancreas after acute The authors declare no competing interests.
265. Sliwinska-Mosson, M. et al. The effect of smoking on pancreatitis. World J. Gastroenterol. 20,
expression of IL-6 and antioxidants in pancreatic fluids 17196–17205 (2014). Publisher’s note
and tissues in patients with chronic pancreatitis. 272. Shimosegawa, T. et al. International consensus Springer Nature remains neutral with regard to jurisdictional
Pancreatology 12, 295–304 (2012). diagnostic criteria for autoimmune pancreatitis: claims in published maps and institutional affiliations.
266. Kirkegard, J., Cronin-Fenton, D., Heide-Jorgensen, U. guidelines of the International Association of
& Mortensen, F. V. Acute pancreatitis and pancreatic Pancreatology. Pancreas 40, 352–358 (2011). Reviewer information
cancer risk: a nationwide matched-cohort study in 273. Badalov, N. et al. Drug-induced acute pancreatitis: Nature Reviews Gastroenterology & Hepatology thanks
Denmark. Gastroenterology 154, 1729–1736 an evidence-based review. Clin. Gastroenterol. Hepatol. F. Gorelick, P. Hegyi and J. Mayerle for their contribution to
(2018). 5, 648–661 (2007). the peer review of this work.

New Insights Into Acute Pancreatitis: Peter J. Lee and Georgios I. Papachristou

Uploaded by

Copyright:

Available Formats

New Insights Into Acute Pancreatitis: Peter J. Lee and Georgios I. Papachristou

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

New Insights Into Acute Pancreatitis: Peter J. Lee and Georgios I. Papachristou

Uploaded by

Copyright:

Available Formats

Reviews

New insights into acute pancreatitis

NATuRe RevIeWS | GASTroEnTEroLogY & HEPAToLogY volume 16 | AUGUST 2019 | 479

480 | AUGUST 2019 | volume 16 www.nature.com/nrgastro

NATuRe RevIeWS | GASTroEnTEroLogY & HEPAToLogY volume 16 | AUGUST 2019 | 481

Table 2 | Potential therapeutic targets and target pathways in acute pancreatitis

482 | AUGUST 2019 | volume 16 www.nature.com/nrgastro

NATuRe RevIeWS | GASTroEnTEroLogY & HEPAToLogY volume 16 | AUGUST 2019 | 483

Alcohol and its downstream effectors, such as transcriptional factor

484 | AUGUST 2019 | volume 16 www.nature.com/nrgastro

NATuRe RevIeWS | GASTroEnTEroLogY & HEPAToLogY volume 16 | AUGUST 2019 | 485

• MCP1 HMGB1 Blood vessel

7 Multiorgan failure NET Neutrophil

486 | AUGUST 2019 | volume 16 www.nature.com/nrgastro

NATuRe RevIeWS | GASTroEnTEroLogY & HEPAToLogY volume 16 | AUGUST 2019 | 487

Table 3 | Comparison between revised Atlanta classification and determinant-​based classification

488 | AUGUST 2019 | volume 16 www.nature.com/nrgastro

Week 1 Week 2 and beyond

• Severity assessment: Urgent On-demand low-fat solid diet;

Necrotic or fluid collection

of cholecystectomy in patients with moderately severe Role of endoscopic retrograde cholangiopancreatography.

NATuRe RevIeWS | GASTroEnTEroLogY & HEPAToLogY volume 16 | AUGUST 2019 | 489

Table 4 | Landmark randomized clinical trials in acute pancreatitis management

490 | AUGUST 2019 | volume 16 www.nature.com/nrgastro

NATuRe RevIeWS | GASTroEnTEroLogY & HEPAToLogY volume 16 | AUGUST 2019 | 491

492 | AUGUST 2019 | volume 16 www.nature.com/nrgastro

NATuRe RevIeWS | GASTroEnTEroLogY & HEPAToLogY volume 16 | AUGUST 2019 | 493

494 | AUGUST 2019 | volume 16 www.nature.com/nrgastro

NATuRe RevIeWS | GASTroEnTEroLogY & HEPAToLogY volume 16 | AUGUST 2019 | 495

496 | AUGUST 2019 | volume 16 www.nature.com/nrgastro

You might also like

Table 3 | Comparison between revised Atlanta classification and determinant-based classification