New Insights on Acute Pancreatitis

[Review] 2019 "Nature Review | Gastrointestinal and Liver Diseases" new insights into acute pancreatitis Shijiazhuang Bethune International Peace Hospital : Yan Weimin Source: Critical Care Professionals Translation Group Abstract The incidence of acute pancreatitis continues to increase worldwide.
In the United States, it is also one of the most common reasons for hospitalization for gastrointestinal diseases.

In the past ten years, our understanding of the pathophysiological mechanism of acute pancreatitis has made great progress.

Research has clarified the mechanism of calcium-mediated acinar cell damage and death, and the importance of calcium storage in manipulating calcium ion channels and mitochondrial permeability transition pores.

The cytoprotective effects of unfolded protein response and autophagy on sustained endoplasmic reticulum stress, apoptosis and necrosis, and the central role of unsaturated fatty acids in causing pancreatic organ failure have also been described.

The characterization of these molecular pathways can help us find potential molecular targets for treatment in the future.

At the patient level, two classification systems have been developed to classify groups with predictive significance based on the severity of acute pancreatitis.
At the same time, several landmark clinical trials have enabled us to understand nutritional support and pancreatic necrosis infection.
Intervention, both have an important impact on the outcome of acute pancreatitis.

In this review, we summarized the latest developments in acute pancreatitis, with special emphasis on the pathophysiological mechanism and clinical management of the disease.

Key points•In the general population, the incidence of acute pancreatitis is 34 people per 100,000 people, and it is rising worldwide.

• In addition to premature trypsinogen activation, calcium signal dysfunction, impaired autophagy, endoplasmic reticulum stress, unfolded protein response and mitochondrial dysfunction are key cellular processes in the pathogenesis of acute pancreatitis.

• Well-designed and motivated trials are needed to define and evaluate the effectiveness of active fluid resuscitation.

• Infected closed pancreatic necrosis should be treated with an endoscopic stepped treatment strategy.

• Diabetes and exocrine pancreatic insufficiency are common complications after the onset of acute pancreatitis.
After acute pancreatitis, about one-fifth of patients will appear.

Acute pancreatitis impairs long-term quality of life, and many patients experience repeated hospitalizations.

---------------------------------------------Acute pancreatitis is the pancreas One of the inflammatory diseases is associated with a large number of morbidity and mortality.

Common causes of acute pancreatitis, such as pancreatic duct blockage secondary to gallstones (the most common cause), alcohol, ERCP, and various drugs trigger pathological cell pathways and organelle dysfunctions, which ultimately lead to acute pancreatitis.
-Acinar cell death and local and systemic inflammation.

The global incidence of acute pancreatitis is 34 persons per 100,000 person-years, and it has been increasing worldwide.

In the United States, acute pancreatitis is one of the most common causes of hospitalization for gastrointestinal diseases, costing the medical system US$9.
3 billion annually.

The worldwide obesity epidemic may also lead to an increase in the global incidence of acute pancreatitis.

The incidence of obesity-related complications is increasing, including cholelithiasis, hypertriglyceridemia and diabetes, which are independently related to acute pancreatitis.

In the past decade, the fatality rate associated with acute pancreatitis has dropped from 1.
6% to 0.
8%.
This trend may benefit from timely and accurate diagnosis and the improvement of the quality of acute pancreatitis intensive care.

However, the incidence and long-term sequelae are still not to be underestimated.

For example, after nearly 40% of patients suffered acute pancreatitis for the first time, pre-diabetes or diabetes occurred newly, and a quarter of patients developed exocrine pancreatic insufficiency.

Necrotizing pancreatitis is the most severe type of acute pancreatitis, which accounts for 5-10% of patients.

In the United States, about half of necrotizing pancreatitis is disabled within a year, and it is reported that the quality of life after acute pancreatitis has significantly decreased.

In addition, about 18% of patients with acute pancreatitis relapse, and 8% develop chronic pancreatitis, both of which impose a heavy economic burden on the medical system.

In 2103, the cost of hospitalization for acute pancreatitis in the United States exceeded US$3.
8 billion.

Although the world faces a heavy burden of disease, there is currently no effective drug to treat or prevent acute pancreatitis.

However, important basic scientific advances have been made in identifying and developing drugs that act on new cellular targets.

For example, the elucidation of calcium signaling pathways in acute pancreatitis led to the discovery of mitochondrial permeability transition pores and calcium release activation channels, both of which have promising therapeutic goals.

Mitochondrial dysfunction is a key driver of acute pancreatitis.
A multicenter trial is currently underway to study the impact of early high-energy enteral nutrition on the prognosis.

The mechanism of severe pancreatitis caused by obesity has also been elucidated [9].

Free fatty acids appear to be the mediator of end-organ failure, and it has been shown that it is released from the lipolysis of triglycerides stored in and around the pancreas in fatty tissues.

Clinically, some landmark trials have solved the key issues of acute pancreatitis, including the timing and pattern of nutrition, the timing of cholecystectomy in acute pancreatitis associated with gallstones, and the management of pancreatic infection and necrosis.

In this review, we describe important advances in the pathogenesis of acute pancreatitis and highlight important potential therapeutic targets.

In addition, based on the latest evidence, we will also discuss current clinical management strategies for acute pancreatitis.

Diagnosis and nomenclature 1.
Diagnostic criteria The diagnosis of acute pancreatitis must meet two of the three items: typical abdominal pain, blood amylase and (or) lipase rise exceeding three times the upper limit of the normal value, and imaging conforms to acute pancreatitis .

Due to different laboratory techniques for measuring blood amylase or lipase, there is no standard reference range for blood amylase or lipase.

The upper limit of normal for amylase is 100-300 U/l, and the upper limit of normal for lipase is 50-160 U/l.

The limitations of blood amylase and lipase as diagnostic tests for acute pancreatitis are worth noting.

Patients with alcoholic or high triglyceride pancreatitis can have normal amylase levels.

Therefore, in these populations, diagnosis can be challenging.

In addition, intestinal perforation, infarction, obstruction, and abdominal aortic aneurysms can also increase amylase levels.

Similarly, lipase is also elevated in acute intestinal diseases, cholecystitis, peptic ulcer and bile duct obstruction.

Therefore, when the diagnosis is in doubt, imaging can be used as a supplement to the diagnosis of acute pancreatitis.

These diagnostic criteria are consistent in all published diagnoses of acute pancreatitis.

The etiology of acute pancreatitis is shown in (Table 1).

Abdominal CT is the most commonly used imaging method to diagnose acute pancreatitis.

CT can show glandular edema and peripancreatic fat stranding (that is, the fuzzy interface between the pancreatic parenchyma and surrounding fat on CT scan; interstitial pancreatitis), and the contrast enhancement in parenchyma (necrotizing pancreatitis) and peripancreatic effusion is weakened.

The diagnosis of necrotizing pancreatitis requires an enhanced CT scan, and necrosis may not appear until 72 hours after the onset.

For this reason, the guidelines of the American College of Gastroenterology and the American Gastroenterology Association do not recommend CT scans within 72 hours of the onset of symptoms.

2.
Naming of local complications Local complications mainly refer to the accumulation inside and/or around the pancreas.

The 2013 revision of the Atlanta Classification updated the nomenclature of these complications, which are widely referred to as pancreatic fluid accumulation.

Solid fragments composed of pure liquid with no or very few solid fragments are called acute liquid accumulation.

The accumulation of necrotic tissue containing the pancreas and/or surrounding the pancreas is defined as acute necrotic accumulation.

When these accumulations last for 4 weeks or more and are organized and localized, respectively, the terms "pseudocyst" and "encapsulated necrosis" (WOPN) are used.

This nomenclature is to simplify and unify the definition of local pancreatic complications.

Each term represents this different meaning, and treatment methods are also different.

The main cellular changes in the pathogenesis of pathophysiological acute pancreatitis, including pathological calcium signal transduction, mitochondrial dysfunction, premature activation of trypsinogen in acinar cells and macrophages, endoplasmic reticulum stress, unfolded protein response Impairment and impaired autophagy.

These are caused by common acinar cytotoxins, such as alcohol, nicotine and bile acids.

Intrapancreatic duct events, such as increased pressure caused by obstruction of the pancreatic duct, acidification of the lumen, and exposure of pancreatic duct cells to bile acids, can also trigger these events indirectly.

The interaction between the acinar cells and the immune system allows the inflammatory response to continue.

At the local level, the role of mesenteric lymph in the severity of acute pancreatitis under the conditions of intra- and peripancreatic fat saponification and ischemia has been recognized.

The understanding of these mechanisms allows us to determine potential therapeutic targets for future acute pancreatitis drug research (Table 2).

Animal models Due to the challenge of obtaining human pancreatic tissue during the onset of acute pancreatitis, all early cellular changes in acute pancreatitis have been studied using animal models.

Animal models help to identify pathophysiological mechanisms to develop and test therapeutic drugs.

The choice of model type depends on the pathophysiological mechanism of interest and the disease stage of interest.

Currently, mice are the most widely used species due to the low cost and availability of species with gene deletions.

In rodents, the caerulein-induced pancreatitis model is usually used to study the early cellular events of acute pancreatitis.

This model helps to describe the process of impaired autophagy, pathological calcium signaling and endoplasmic reticulum stress, which are the core of the pathogenesis of acute pancreatitis.

In this model, acute pancreatitis is induced by repeated overdose of bombesin (a cholecystokinin analog).

The effect of bombesin is related to the dose.
At high doses, it causes the pancreatic cells to release digestive enzymes.

At the maximum dose, the release of enzymes is inhibited, leading to premature activation of digestive enzymes [55].

Because of its low cost and good reproducibility, bombesin-induced pancreatitis models are widely used.

By adjusting the bombesin dosage regimen to increase the severity of acute pancreatitis, severe acute pancreatitis can be studied.

The shortcomings of this model include a clinically unrelated initiation mechanism (excessive cholinergic stimulation is only equivalent to human scorpion venom toxicity), and a different distribution of physical damage from humans (causing diffuse damage in rodents, while in humans Only cause local damage).

Alcohol and lipopolysaccharides can be used in rodents to simulate models associated with alcohol-related pancreatitis.

This model was used to determine the mechanism of alcohol-induced lipid metabolism changes in acinar cells and subsequent damage to acinar cells.

But it is mainly used to study chronic pancreatitis.

Some researchers use models involving pancreatic duct manipulation to study the relationship between intraductal events and the onset of acute pancreatitis.

Because the anatomy of the pancreaticobiliary duct of American opossum is similar to that of humans, they have been used to clarify the pathophysiological mechanism of gallstone-related pancreatitis.

Research using this model reveals that pancreatic duct obstruction is an important initiation center for acute pancreatitis of gallstones.

However, possums cannot be reproduced in the laboratory, and there is a high degree of variability among animals, which limits its popularity as a model.

Using catheter intubation and perfusion, the pathophysiology of pancreatitis and gallstone pancreatitis after ERCP in rats and guinea pigs was studied.

The disadvantage of this type of model is that it requires surgery and anesthesia.

Although experiments based on animal models have improved our understanding of the pathogenesis of acute pancreatitis, pancreatitis in humans and mice is significantly different.
Therefore, due to these limitations, conclusions from animals to humans should be carefully considered.

Encouragingly, many in vitro studies in humans have shown that the mechanisms derived from animal experiments can be applied to human pancreatitis models.

For example, when muscarinic agonists and bile acids were detected in human acinars extracted from cadaveric pancreas, trypsinogen activation, endoplasmic reticulum stress, dysfunctional autophagy and mitochondrial dysfunction and animal models were found The response in is similar.

Cellular mechanism update [Calcium signal] The pathological increase of calcium ion concentration in acinar cells is the core event of acute pancreatitis.

Increased calcium ion concentration regulates the pre-apoptotic pathway and the pre-inflammatory pathway, such as premature activation of trypsinogen, activation of nuclear transcription factor (NF-κB), and mitochondrial dysfunction (Figure 1).

Under normal physiological conditions, Ca2+ is released from the endoplasmic reticulum as a part of the signaling mechanism, which initiates the secretion of zymogen and stimulates the production of ATP in mitochondria.

However, the increase in the concentration of calcium ions in the cytosol is only temporary, because it relies on ATP calcium channels to quickly clear calcium ions in the cytoplasm.

Smooth endoplasmic reticulum channels (SERCAs) transport calcium ions to the endoplasmic reticulum, and serosa Ca2+ channels (PMCAs) allow calcium ions to leak out of the cell.

Alcohol and bile acids can disrupt this homeostasis and lead to a holistic and continuous pathology through the inositol 1,4,5-triphosphate receptor (Ins(1,4,5)P3 R) signaling pathway Sexual cell Ca2+ increased.

For example, ethyl palmitenoate is a non-oxidative metabolite of alcohol.
Acinar cells open the inositol 1,4,5-triphosphate receptor (Ins(1,4,5)P3 R) Ca2+ located in the endoplasmic reticulum.
aisle.

This pathway causes excessive calcium ions to be released from the main calcium ion pool in the cell, which is the lumen of the endoplasmic reticulum.

The increase in calcium ion concentration causes the release of calcium ion activated channel protein (ORAI1) to promote calcium ions from the outside into the cell, thereby increasing and maintaining the toxic intracellular calcium ion concentration.

Pancreatic duct blockage can occur after ERCP pancreatitis and gallstone pancreatitis.
It is currently believed to be caused by the increase of calcium ions from the outside of the cell through the PIEZO1 pathway.
This is a membrane mechanoreceptor with cation channel characteristics.
, Will be activated under pressure.

The intracellular Ca2+ concentration overload causes the mitochondrial permeability transition pore to open in a high-conductivity state, and this process leads to the loss of membrane potential required to produce ATP.

By interfering with ATP-dependent SERCAs and PMCAs, it clears excessive intracytoplasmic calcium and damages the cytoprotective mechanisms that require ATP, such as autophagy and UPR, and consumes ATP to maintain the toxic Ca2+ concentration.

As a result, mitochondrial dysfunction caused by cellular calcium toxicity eventually leads to necrosis of acinar cells.

Based on the theory of toxic calcium ion concentration, the ORAI1 channel inhibitor was developed to prevent calcium ions from entering acinar cells.

ORAI1 inhibitors have been shown to prevent acinar cell necrosis in animals and humans in acute pancreatitis models, and reduce local and systemic damage.

Using 3,5-seco-4-noro-cholestan- 5-one oxime-3-ol (TRO40303) to inhibit the opening of mitochondrial permeability transition pores and prevent ATP consumption also has potential therapeutic effects.

In animal models of alcohol-related acute pancreatitis and human acinar cells, TRO40303 can prevent membrane potential loss and necrosis.

In the intervention treatment of patients with acute myocardial infarction, TRO40303 has been found to be safe and well tolerated.

Therefore, it can be effectively used experimentally for patients with acute pancreatitis.

The benefits of ATP supplementation through high-calorie nutrition are also being explored in multi-center trials of acute pancreatitis.

[Premature trypsinogen activation] Premature activation of trypsinogen is another important pathological cell change that can lead to necrosis of acinar cells.

Various pancreatic injuries (for example, trauma, pancreatic duct obstruction, and alcohol) can trigger the fusion of lysosomes with the zymogen in the acinar cells, a process called colocalization (Figure 2).

Colocalization occurs in the context of other cellular events in the acinus caused by toxins.
The decrease in exocrine of protease zymogen particles is secondary to cytoskeletal dysfunction and increased synthesis of lysosomes and digestive enzymes.

Once the zymogen particles are fused with lysosomes (cathepsin b, a key lysosomal enzyme), trypsinogen is activated as trypsin immediately.

The release mechanism of trypsin and cathepsin B from the vacuole is not clear.

Some people believe that trypsin causes the cell membrane to become fragile, leading to the leakage of intracellular vacuoles and the release of trypsin and cathepsin B.

Other studies have shown that vacuoles may damage the cytoskeleton and/or organelles.

Alcohol metabolites and loss of membrane stability glycoproteins can also make the membranes of lysosomes and zymogen granules fragile, respectively.

Once trypsin is released, it will cause self-digestion inside and outside the acinar cells, and the release of cathepsin B will cause necroptosis, which is also a form of regulation of necrosis.

Necroptosis is mediated by receptor-interacting protein kinases (RIP), including RIP1-RIP3 and mixed family kinase domain-like protein (MLKL) pathways, where MLKL is phosphorylated by RIP3, leading to its oligomerization.

The transfer of MLKL oligomers to the cell membrane will eventually lead to perforation of the cell membrane, resulting in overflow of cell contents and necroptosis.

Inhibition of the RIP1-rip3 pathway through gene regulation or necrostatin (inhibitor of RIP1) can reduce the severity of acinar cell injury, so it has become a potential target for the treatment of acute pancreatitis.

The activation of intracytoplasmic proteases can also lead to the destruction of lysosomal membranes.
This process leads to the activation of caspase 3 through the release of cytochrome C from the mitochondria.

Caspase 3 then mediates apoptosis.

Macrophages are one of the first immune cells that respond to chemotactic agents released by damaged acinar cells during pancreatitis.

Interestingly, trypsinogen activation also occurs in the response of macrophages to pancreatitis and causes macrophages to become pro-inflammatory cells.

This discovery challenges the long-held belief that premature activation of trypsinogen only occurs in acinar cells.

[Autophagy, endoplasmic reticulum stress and unfolded protein response] The pathogenesis of acute pancreatitis is also driven by impaired cytoprotective mechanisms, such as autophagy and UPR (unfolded protein response).

Giant autophagy is a cell protection mechanism that processes and recovers various cytoplasmic contents that are aged, defective or damaged.

Selective macroautophagy refers to the processing and recovery of specific damaged organelles and misfolded proteins.

Acinar cells can efficiently produce protein.

Therefore, the protein processing and transport mechanism and the intact autophagy mechanism are critical to the survival of acinar cells.

Autophagy is accomplished through a series of steps.
First, the cytoplasmic content in the open double membrane formed from the endoplasmic reticulum, Golgi apparatus and plasma membrane is enucleated (Figure 3).

The edges of the double membrane meet to form autophagosomes; this step is mediated by autophagy-related proteins (ATGs).

The fusion of autophagosomes and lysosomes and the degradation of the contents are the final steps.

Gene knockout of ATG5, ATG7 and lysosomal-associated membrane proteins resulted in a large number of inflammatory responses in a mouse model of acute pancreatitis.

In addition, impaired autophagy can lead to trypsinogen activation, endoplasmic reticulum stress and mitochondrial dysfunction.
Therefore, acinar cells are more susceptible to other damage and death.

Therefore, the restoration of effective macroautophagy in acinar cells seems to be an attractive therapeutic target.

In animal models, the disaccharide trehalose can improve the efficiency of autophagy, reduce the severity of pancreatic injury and acute pancreatitis, and is expected to become a potential therapeutic agent for acute pancreatitis.

However, the mechanism by which trehalose induces autophagy has not been confirmed.

Endoplasmic reticulum stress refers to the accumulation of misfolded and/or unfolded proteins in the lumen of the endoplasmic reticulum.

It occurs when the ability of the endoplasmic reticulum to effectively process and eliminate proteins is overwhelmed.

When the endoplasmic reticulum stress disrupts the protective cell response, cell apoptosis follows.

Considering the large amount of protein produced by pancreatic acinar cells, and endoplasmic reticulum stress often occurs in acinar cells of acute pancreatitis, the pancreas is particularly susceptible to endoplasmic reticulum stress.

Common toxins in the pancreas (for example, alcohol and its metabolites) cause endoplasmic reticulum stress, increase protein production requirements, such as trypsinogen, chymotrypsinogen, lipase enzyme and lysosomal cathepsin B, and reduce cells The ability to process and recover excess protein (ie, disorders of autophagy and mitochondrial dysfunction).

During endoplasmic reticulum stress, acinar cells activate unfolded proteins and restore cell homeostasis.

There are three important ways to reduce protein synthesis, up-regulate the mechanism of the endoplasmic reticulum to degrade harmful proteins, and unfolded proteins can alleviate the stress of the endoplasmic reticulum and improve its ability and efficiency to synthesize and fold proteins.

The three functional pathways are: inositol-requiring enzyme 1 (IRE1), activated transcription factor 6 (ATF6) and protein kinase RNA-like ER kinase (PERK) pathways.

Downstream events in the IRE1 and ATF6 pathways ultimately activate transcription factors, such as ATF6 and spliced ​​X-box binding protein 1 (sXBP1).

These transcription factors promote the synthesis of substrates required for endoplasmic reticulum amplification, endoplasmic reticulum molecular chaperones required for protein folding, and components of the endoplasmic reticulum protein degradation mechanism.

They also initiate autophagy to eliminate and recover unfolded and misfolded proteins.

When these responses fail to restore homeostasis, the unfolded protein response eventually activates the apoptotic pathway.

The PERK pathway is a terminal response, and its downstream effectors, such as the transcription factor CEBP homologous protein (CHOP), promote cell apoptosis and inflammation.

Although CHOP can induce autophagy, it eventually promotes cell death under continuous endoplasmic reticulum stress.

Interestingly, the widespread HMG-CoA inhibitors (statins) promote the unfolded protein response.

Observational studies have found that the use of statins is related to reducing the incidence and severity of acute pancreatitis.

A randomized controlled trial on the detection of statins (such as simvastatin) for the prevention of acute pancreatitis is currently underway.

[Pancreatic duct dysfunction and pancreatic duct events] Transmembrane water channels (such as aquaporin 1 in acinar and ductal cells) and cystic fibrosis transmembrane regulatory channel (CFTR) are both essential for physiological pancreatic secretion.

Alcohol has been proven to significantly reduce the function of CFTR and the secretion of bicarbonate, acidify the environment in the catheter, cause fluid accumulation in the catheter, and promote the premature activation of enzymes in the catheter.

Bile acid-mediated and pancreatic inflammation-mediated reduction of aquaporin may also cause fluid stagnation in this catheter.

Different intraductal events may also mediate the damage and death of acinar cells, leading to acute pancreatitis.

These events include increased pressure in the duct, exposure of duct cells to bile acids, and acidification in the duct.

The increase in pressure in the pancreatic duct can activate the mechanoreceptors (PIEZO1) in acinar cells, thereby triggering the pathological calcium signaling pathway described above.

Increased pressure in the duct can also cause calcineurin-mediated acinar cell damage by promoting inflammation and activation of signal transduction and transcription 3 (STAT3) pathway activators.

Clinical examples include papillary edema, injection of acidic contrast agent into the pancreatic duct during endoscopic retrograde cholangiopancreatography, and biliary obstruction.

Acidification of the pancreatic duct lumen has been shown to activate the transient receptor potential-1 (TRPV1) of primary sensory neurons and cause acute pancreatitis.

Therefore, in endoscopic retrograde cholangiopancreatography (ERCP), when acidic contrast agents are used for pancreatic imaging, luminal acidification occurs, while acute pancreatitis is mediated by PIEZO1, calcineurin, and TRPV1.
The guiding mechanism is highly related to endoscopic retrograde cholangiopancreatography (ERCP) and gallstone pancreatitis.

In addition, bile acids can cause mitochondrial dysfunction in ductal cells in a dose-dependent manner.

The resulting consumption of ATP leads to a decrease in ATP-dependent bicarbonate secretion and can also lead to ductal cell death.

The destruction of ductal cells exposes acinar cells to bile acids, causing cell damage and death.

This mechanism may be related to gallstone pancreatitis, in which gallstones embedded in the nipple can expose ductal cells to bile acids by creating a common channel.

However, under physiological conditions, the pressure in the pancreatic duct is much greater than the pressure in the bile duct-therefore, the mechanism by which bile acids may resist this pressure gradient has not been elucidated.

[The role of the immune system] The damaged acinar cells release chemokines, cytokines, and various adhesion molecules to aggregate and mediate the infiltration of immune cells to the injured site (Figure 4).

Among these chemokines, monocyte chemoattractant protein 1 (MCP1) promotes inflammatory monocyte transport, and macrophage inflammatory protein 2α (MIP2α) and CXC-chemokine ligand 1 (CXCL1) aggregate Sex granulocytes.

To illustrate the importance of chemokines in the pathogenesis of acute pancreatitis, in animal models, the inhibition of chemokines and their receptors has been shown to prevent damage to the pancreas and distant organs.

Elevated levels of MCP1 in serum are also associated with severe acute pancreatitis in humans.

Once immune cells infiltrate the pancreas, the cellular contents released by necrotic and damaged cells activate monocytes and neutrophils, further spreading inflammation.

The oxidation of NADP in neutrophils causes oxidative stress and increases the activation of trypsin in the acinar.

Neutrophils also produce neutrophil extracellular bactericidal networks (NETs), which are adhesion networks composed of granular protein, DNA and histones, which can cause duct blockage, activate pro-inflammatory signals and activate trypsin prematurely original.

Activated monocytes are the central link in the deterioration of systemic inflammation and tissue damage in acute pancreatitis.

An important mediator of monocyte activation is damage-related molecular patterns (DAMPs), which are cellular contents released from necrotic acinar cells.

DAMPs regulate their effects by binding to different receptors on immune cells.

For example, DAMPs high mobility histone box protein 1 (HMGB1), heat shock protein 70 (HSP70) and double-stranded DNA signals activate the NF-κB pathway through toll-like receptors (TLRs).

NF-κB regulates the gene expression of pro-inflammatory cytokines, chemokines and adhesion molecules.

Other DAMPs, such as ATP and NAD, bind to the P2X7 receptor and activate the inflammasome.

Subsequently, pro-IL-1β and pro-IL-18 were grown into their biologically active forms by enzyme digestion.

Among other things, the pro-inflammatory cytokines produced by these pathways include TNF, IL-1β, IL-6 and IL-18.

Although the mechanism of distal organ damage has not been fully elucidated, in acute pancreatitis, macrophages are also activated in distal organs and aggravate systemic inflammation and distal organ damage.

In view of the importance of these pathways in promoting and exacerbating the inflammatory response in the course of acute pancreatitis, in animal models, the development and effect testing of inhibitors of NF-κB and inflammasome pathways have begun.

Among them, MCC950 is an effective inhibitor of the inflammasome pathway.
It is currently being tested for other diseases, such as ischemic stroke, hepatitis and liver fibrosis.
Inflammasome activation also plays an important pathogenic role in these diseases.

In addition, lactate, given in the form of lactated Ringer's solution, because it down-regulates the inflammasome pathway, it is promising to reduce pancreatic damage in animal models of acute pancreatitis.

Lactated Ringer's solution also has application prospects in clinical trials (discussed later).

Serum TNF and IL-6 levels have always been associated with increased severity of acute pancreatitis and acute lung injury.

TNF can also directly cause pancreatic vesicle cell necrosis.

Pentoxifylline is a non-selective phosphodiesterase inhibitor, which can reduce the synthesis of TNF by down-regulating the NF-κB pathway.

A double-blind placebo-controlled randomized trial of 28 patients found that oral pentoxifene three times a day can shorten the length of hospital stay.

These promising findings are currently being verified in larger clinical trials.

The commercially available IL-6 receptor antagonist tozizumab is another potential therapeutic drug.

In an animal study, it was found that treatment with tocilizumab after acute severe pancreatitis can improve the prognosis.

Taking into account the safety and effectiveness of tocilizumab against other diseases such as giant cell arteritis, rheumatoid arthritis and graft-versus-host disease, it may be ready for clinical trials of human acute pancreatitis.

The pro-inflammatory stage of acute pancreatitis is closely followed by the compensatory anti-inflammatory response syndrome, which is characterized by the advantages of anti-inflammatory cytokines, such as TGFβ, IL-4 and IL-10.

IL-10 is produced from pancreatic vesicle cells, monocytes, B cells and T cells.

It reduces the production of pro-inflammatory cytokines at the transcriptional level by inhibiting the STAT3 pathway and T cell expansion.

Animal studies on acute pancreatitis have shown that the use of insulin-like growth factor 1 and IL-4 can increase the production of IL-10, thereby improving the prognosis.

During the anti-inflammatory reaction period, patients with acute pancreatitis are prone to pancreatic infection and necrosis.

[Gene mutations] Several mutations that have pathogenic effects in acute pancreatitis have been identified, including protease serine 1, serine protease inhibitor Kazal type 1, chymotrypsin C, CFTR, claudin 2, and calcium-sensitive receptor genes Mutation.

An in-depth review of the clinical significance of these genetic mutations is beyond the scope of this review, but published reviews summarize the genetics of acute pancreatitis.

[The role of unsaturated fatty acids] It has been confirmed that obesity and hyperlipidemia are risk factors for severe acute pancreatitis.

Studies have clarified the pathophysiological mechanism of severe acute pancreatitis mediated by obesity and hypertriglyceridemia.

During the onset of acute pancreatitis, the normal apical secretion pathway of zymogen granules is disrupted by several mechanisms.

Alcohol inhibits root apical secretion and promotes basolateral secretion.

Acinar cell necrosis can also cause enzymes to be released into certain areas of the pancreas, otherwise digestive enzymes will be blocked.

For example, lipase is freely released through the basal lateral membrane into the interstitium, peripancreatic area, and bloodstream.

Lipase hydrolyzes circulating triglycerides and triglycerides stored in the pancreas and peripancreatic fat cells into saturated and unsaturated free fatty acids (UFAs).

UFAs such as linoleic acid, oleic acid and linolenic acid cause cytotoxicity by inhibiting mitochondrial complex I and V, increasing the levels of TNF and other chemokines and increasing inflammation.

Clinical studies have found that acute pancreatitis patients with increased visceral fat and increased serum triglycerides at admission have an increased risk of multiple system organ failure and pancreatic necrosis, confirming the research mechanism.

Prevention of triglyceride hydrolysis by lipase inhibitors seems to be a promising strategy for the treatment of acute pancreatitis.

【Mesenteric Lymph】Acute pancreatitis can be further exacerbated by pathological changes in the intestines.

These changes include intestinal obstruction and ischemia-reperfusion injury, leading to the transfer of bacteria through the intestinal barrier and changes in the microbiome.

Recently, the importance of toxin-containing lymphatic drainage has been emphasized.

In the study of acute pancreatitis in animals, the mesenteric lymph in pancreatitis is related to cardiac dysfunction and multiple system organ failure.

The main components of mesenteric lymph have not been determined.

However, it was found in experiments in rats that ligation of the thoracic duct can reduce the toxicity of the mesenteric lymph.

There are already safe percutaneous techniques and endoscopic ultrasound methods to enter the thoracic catheter.

In the case of the need to improve the technology of access to the thoracic catheter, in the onset of acute pancreatitis, redirecting the flow of mesenteric lymph may be a way to prevent distal organ failure.

[Severity assessment] [Improved classification method] The revised Atlanta (RAC) and the classification method based on important clinical influence factors (DBC) can be used to distinguish the severity of patients and predict the prognosis.

Both of these classification methods have been extensively validated.

Table 3 shows the similarities and differences between the two methods.

Both of these classification systems reflect important advances in understanding the determinants of acute pancreatitis incidence and mortality.

Contrary to the traditional belief that pancreatic necrosis itself is an independent determinant of death, there is now clear evidence that pancreatic necrosis without additional infection or organ failure has similar survival rates as interstitial pancreatitis, with a mortality rate of 1-2 %.

Persistent organ failure (more than 48h) seems to be the most important factor affecting the mortality rate, close to 43%.

Organ failure lasting longer than 48 hours does not seem to affect the mortality of patients with pancreatic necrosis.

Although the mortality rate of aseptic pancreatic necrosis and/or peripancreatic fluid accumulation is very low, compared with interstitial pancreatitis, they will go through a complicated hospitalization process, and the hospital stay will be longer and repeated hospitalizations.

[Predicted severity] Severe pancreatitis, defined as persistent organ failure, has a fatality rate of 43% when the first strike occurs.

Many predictive models have been established to predict the early severity of the disease, including intermittent laboratory and biomarker and clinical scoring systems.

However, in large-scale direct comparative studies, although there are many forecasting tools, it has not yet shown which one is more advantageous.

Therefore, we are still cautious about the early prediction of acute pancreatitis (with an accuracy of about 80%).

Intermittent and accurate clinical predictors for predicting severity include: elevated urea nitrogen, persistent SIRS status, and blood viscosity.

These indicators are easy to obtain and can be continuously monitored, so they have more advantages than other complex scoring systems.

[Management of acute pancreatitis] [Early management (first 72h)] Once acute pancreatitis is diagnosed in the emergency room, predictive tools can be used to classify the severity immediately.

Among all the prediction tools, SIRS is a validated and commonly used tool to predict the severity and mortality of pancreatitis.

SIRS parameters can be easily obtained and calculated scores, mainly including: body temperature, heart rate, white blood cell count and respiratory rate.

Other important early treatments include fluid resuscitation, nutritional support, finding the cause, and analgesia (Figure 5).

[Liquid resuscitation] The guidelines of the Society believe that early and adequate fluid resuscitation is the cornerstone of the treatment of acute pancreatitis.

A small randomized controlled trial involving 60 patients with mild acute pancreatitis compared two resuscitation methods.
One group was given 20ml/kg lactated Ringer’s solution as a pellet infusion, followed by 3ml/kg per hour infusion, and the other The group received 10ml/kg lactate Ringer's solution in bolus form, and then 1.
5ml/kg was infused every hour.

The active resuscitation group showed a clinical improvement rate of 70%, and the conservative group had an improvement rate of 42%.

It is worth noting that the trial is mainly aimed at patients with mild acute pancreatitis, and is not designed to study the role of fluid volume in preventing necrosis, organ failure, and death.

    In patients with severe pancreatitis, some data suggest that active fluid resuscitation may be harmful.

In an RCT study involving 115 patients, the rapid dilution of blood to a hematocrit of <35% within 48 hours resulted in a 34% increase in fatality rate, 79% of sepsis incidence, and 15% fatality in the slow dilution group.
The incidence of toxicosis was 58%.

However, observational data many years ago show that active fluid resuscitation may improve mortality and survival rates.

Due to differences in study design, patient groups, and intervention definitions, it is difficult to determine the effect of fluid volume on the outcome of acute pancreatitis.

There is an urgent need for well-designed large-scale randomized trials.

    Recently, it has been shown in the treatment of acute pancreatitis that Ringer lactate solution is superior to other crystalloid solutions.

This result is based on a small RCT study, showing that lactated Ringer's solution and normal saline can significantly reduce the SIRS score by 84% (P=0.
035).

Mechanical evidence also supports this finding.

An experiment in rats found that the application of lactated Ringer's solution can reduce the severity of acute pancreatitis by inhibiting inflammasome and NF-κB bypass.

In addition, lactated Ringer's solution contains calcium, which can be combined with UFAs, which may reduce its toxic effects.

In another in vitro test, lactated Ringer's solution inhibited the polarization of macrophages to the inflammatory phenotype and inhibited the activation of NF-κB.

Large-scale studies are needed to confirm whether these findings are meaningful for improving the clinical outcome of patients.

    When implementing fluid rehydration therapy, it is necessary to pay attention to the patient's volume status to prevent fluid overload.

If the patient is at risk of excessive volume, it is very important to closely monitor the volume status, because there may be a risk of ACS, which may cause intra-abdominal hypertension and cause organ dysfunction.

Which parameter can guide fluid resuscitation? At present, there are few data and no conclusions.
More research is needed.

  [Nutrition Support] Research evidence shows that it is safe to give a solid, low-fat diet in the early stage of mild to moderate pancreatitis, instead of a liquid food followed by a solid diet.

Because these patients can tolerate oral intake, a low-fat diet is preferred.

This early active nutrition strategy reduces the length of stay in patients with mild to moderate pancreatitis.

If patients with mild to moderate pancreatitis cannot tolerate oral intake within 3-5 days, enteral nutrition can be considered.

Naso-intestinal tube feeding is better than nasogastric tube because in theory the patient is more tolerant.

Place the feeding tube across the duodenum and reach the jejunum, reducing the irritation of pancreatitis and making the pain less.

However, studies comparing nasogastric tubes and naso-intestinal tubes found that the tolerance rates of the two are similar.

     If the patient has severe pancreatitis, early enteral nutrition (within 24h of onset) does not show an improved prognosis compared with oral feeding (on-demand) at 72h.

A rigorous RCT study included 208 patients with severe pancreatitis.
The patients were divided into an early enteral nutrition group and a 72-hour oral feeding group.

The incidence of major infections was similar in the two groups, approximately 25%.

In addition, the early enteral nutrition group did not show an advantage in mortality.

Therefore, for severe pancreatitis, it is reasonable to try oral diet after 72 hours of onset.

For intestinal obstruction caused by acute pancreatitis or opioid analgesics, enteral nutrition is not feasible.

This result poses a challenge to the treatment of pancreatitis.

Therefore, monitor and correct electrolyte disturbances, use opioid analgesics with caution, and encourage patient activity if feasible, and through these efforts, the patient's intestinal function can be optimized.

Because compared with enteral nutrition, parenteral nutrition increases the infection rate and mortality, and is often used as a last resort.

   [Analgesia] There are few research data on the effect of analgesia on the outcome of acute pancreatitis.

Frequent use of anesthesia for analgesia in the United States seems to be effective.

Interestingly, an animal experiment showed that the use of morphine can increase the severity of acute pancreatitis and inhibit pancreatic regeneration.

In a large observational study with matching propensity scores, 1003 patients in the ICU were included.
Epidural anesthesia mainly uses costly analgesics (such as bupivacaine).
Compared with the standard anesthesia group, it can greatly reduce mortality rate.

Reasons for possible benefits include improved visceral and pancreatic blood flow and anti-inflammatory effects.

A multicenter RCT study is ongoing to clarify the benefits of epidural anesthesia in patients with critically ill acute pancreatitis.

In view of the risk of addiction to opioids, other effective analgesics such as non-steroidal anti-inflammatory drugs need to be developed as first-line drugs as soon as possible.

   [Treatment after the first 72 hours] [Cause identification and treatment] For mild biliary pancreatitis, cholecystectomy can effectively prevent recurrence (risk rate 0.
28), and it is very cost-effective.

Therefore, it should be used as standard treatment.

The timing of cholecystectomy for moderate to severe pancreatitis needs further observation.

Although there is a lack of research data, because early surgical procedures increase the incidence of surgical complications, it is recommended to wait at least 6 weeks for the effusion to mature or be distinguishable before surgery.

  Well-designed studies have shown that interventions to promote smoking and alcohol cessation reduce the recurrence and rehospitalization rates of acute pancreatitis.

Triglycerides are said to require testing.
If it exceeds 1000 mg/dl, lipid-lowering treatment needs to be initiated, because newly released research evidence shows that even mild to moderate non-fasting hypertriglyceridemia can also lead to aggravation of acute pancreatitis.

However, whether it is beneficial to prevent recurrence by treating non-fasting hyperlipidemia requires further observation and research.

    For patients with pancreatic duct expansion without a history of pancreatitis or chronic pancreatitis, the main pancreatic duct papillary mucinous tumor (IPMN) should be regarded as one of the causes, and the risk of malignancy is relatively high.

Therefore, it is very necessary to identify and make corresponding treatment.

Pancreatic cancer is another important cause of acute pancreatitis, accounting for approximately 1% of all causes.

For patients over 40 years old, follow-up imaging or ultrasound endoscopy is very important to rule out tumors.

    [Endoscopic retrograde cholangiopancreatography] For biliary pancreatitis with cholangitis or persistent biliary obstruction, the benefits of emergency ERCP within 48 hours have been well confirmed.

However, in most patients with biliary pancreatitis, choledocholithiasis has been discharged when symptoms appear.
Therefore, most patients with biliary pancreatitis do not need ERCP.

An ongoing RCT study is evaluating the role of emergency ERCP in the treatment of expected severe biliary pancreatitis.

    [Prophylactic use of antibiotics] Many studies have investigated the possible benefits of preventive use of antibiotics in the treatment of severe and necrotizing pancreatitis.

However, there is no clear evidence of benefit.
Therefore, the guidelines recommend against the routine preventive use of antibiotics.

             [Local Complications] [Acute Necrosis Accumulation and WOPN] The treatment of pancreatic necrosis accumulation has made a lot of progress in recent years.

The indications, timing, and methods of intervention have been debated in surgical literature for decades.

Available treatment methods include minimally invasive surgery (video-assisted retroperitoneal debridement or laparoscopy), endoscopic cystoenterostomy (including or excluding direct endoscopic necrosis), and percutaneous catheter drainage.

Several landmark trials conducted in the past decade have helped clarify the role of each treatment in the management of pancreatic necrosis (Table 4).

   [Indications] Considering the large number of morbidity and mortality associated with this operation, invasive intervention is only recommended when necrotizing mass infections or causing symptoms such as gastric outlet obstruction, poor growth, biliary obstruction or intractable pain.

In patients with suspected or confirmed pancreatic necrosis, the role of intervention has been the most rigorously studied.

Therefore, for asymptomatic aseptic necrosis patients, regardless of the size of the cluster, intervention should be avoided.

  [Timing] Observational studies and randomized controlled trials have shown that delayed pancreatic intervention is associated with low morbidity and mortality.

In the early stage of pancreatic infection and necrosis (ie, the onset of symptoms <4 weeks), although antibiotics have been applied, when the patient's clinical symptoms are still unstable, percutaneous drainage and decompression are recommended.

4 weeks after the onset of acute pancreatitis, an endoscopic gallbladder jejunostomy can be considered, with or without necrotic tissue removal or minimally invasive surgery.

   [Intervention method] Many well-designed randomized controlled experiments show that stepwise minimally invasive endoscopic intervention is the best intervention method.

Gradual approach adopts graded approach to WOPN, and first adopts minimally invasive measures (percutaneous catheter drainage or cystojejunostomy).

When the patient's clinical response is unsatisfactory, the intervention will be promoted to the most invasive option (necrotic resection).

This gradual approach reduced the incidence of new organ failure by 28% (absolute risk) and reduced the incidence of composite endpoints of major complications, multiple organ failure, perforation, fistula, or death by 29%.

In a randomized controlled trial, 40% of patients were able to eliminate WOPN by drainage alone, without the need for subsequent necrosis.

Data from a randomized clinical trial in 2018 supports endoscopic step treatment, which is better than surgical step treatment.

Specifically, step treatment under endoscopy has a lower incidence of pancreatic fistula and shorter hospital stay than step treatment in surgery.

It is worth noting that in all the above randomized clinical trials, most of the selected patients have been confirmed to be infected with WOPN.

In contrast, the treatment data for symptomatic aseptic WOPN mainly comes from observational studies.

    Once the accumulation has matured, the transintestinal drainage of the endoscopic ultrasound-guided transcystintestinal anastomosis can be used safely.

Metal or plastic stents can be used, but there is a lack of high-quality efficacy comparison data.

The lumen and metal stent drainage WOPN is very popular because of its convenient use and good effect.

However, there is a lack of long-term safety data, and there are emerging reports of increased incidence of delayed bleeding after luminal metal stent placement.

[Pancreatic duct disconnection syndrome] Pancreatic duct disconnection syndrome is a complication of the loss of pancreatic duct integrity after the onset of necrotizing pancreatitis.

Up to 50% of patients with accumulation of pancreatic juice may have a potential disconnection, which can lead to abdominal pain, recurrent acute pancreatitis, or recurrent accumulation of pancreatic juice.

Pancreatic duct disconnection syndrome is best identified using secretin-stimulated magnetic resonance cholangography.

In such patients, the study recommends that the transmural double pigtail tube stent be left indefinitely to keep the pancreaticojejunostomy unobstructed.

In a large observational study of 361 patients with accumulation of pancreatic juice, this method was found to be safe, and the risk of recurrence was reduced compared with patients without an indefinite stent (recurrence rate 17.
4% vs.
1.
7%, P < 0.
001).

Therefore, compared with pancreatic drainage, this method may become a first-line technique, and pancreatic drainage has a great risk for the incidence of diabetes and new-onset diabetes.

[Vascular complications of acute pancreatitis] Visceral vascular complications of acute pancreatitis include venous thrombosis and pseudoaneurysms of arteries or veins.

Severe pancreatitis and pancreatic necrosis are risk factors for the formation of SVCs.

The incidence of visceral venous thrombosis in patients with acute pancreatitis is approximately 15%.

Visceral veins can recanalize in one-third of patients.

According to available data, considering their benign natural course, most SVCs of acute pancreatitis do not require anticoagulation therapy.

In rare cases, splenic vein thrombosis may lead to local pulse hypertension with isolated gastric varices, or superior mesenteric vein thrombosis with ascites.

Pseudoaneurysm is considered a rare complication of pancreatitis; however, in the era of transmural metal stents, the incidence of iatrogenic pseudoaneurysms is more frequent, reportedly ten times higher.

Although pseudoaneurysms are rare, they can be life-threatening if they are not detected in time and treated with coil embolization through interventional radiology.

[Long-term complications and follow-up] [Disease progression] Recurrent acute pancreatitis (RAP) accounts for about 18% of patients with acute pancreatitis and affects the quality of life of patients.

The accumulated evidence currently shows that RAP is at a high risk of becoming chronic pancreatitis.

Idiopathic causes, active drinking and smoking are the greatest risks of progression to RAP and chronic pancreatitis.

Population-based cohort studies have shown that acute pancreatitis may be a risk factor for pancreatic cancer, but the risk seems to be limited to patients whose acute pancreatitis progresses to chronic pancreatitis.

  [Endocrine and exocrine complications] So far, the endocrine and exocrine complications of acute pancreatitis have not been well confirmed.

Now, research supports the view that approximately one-third of patients will develop prediabetes or diabetes within 5 years after the onset of acute pancreatitis, but the related pathogenesis and risk factors have not yet been determined.

Similarly, pancreatic exocrine insufficiency is common after acute pancreatitis, and the incidence is about 24%-40%.

According to reports, risk factors for pancreatic exocrine dysfunction after acute pancreatitis include pancreatic necrosis, severe pancreatitis and alcohol-related causes.

  [Quality of Life] A prospective observational study showed that compared with people of the same age and sex who did not suffer from acute pancreatitis, patients who survived acute pancreatitis had a significantly lower long-term health-related quality of life.

Patients who experience excessive organ failure, persistent abdominal pain requiring analgesia, or (and) disability, are at significantly increased risk of reduced quality of life.

Importantly, among patients who experienced extensive pancreatic necrosis, 53% were registered as disabled one year after discharge.

   [Summary] Acute pancreatitis is a common and potentially life-threatening inflammatory disease of the pancreas.

Surviving patients often develop terrible long-term outcomes such as diabetes, pancreatic exocrine insufficiency, chronic pancreatitis, and decreased quality of life.

This serious disease burden is obvious, and the increasing incidence rate every year makes it urgent to develop drugs that change the natural course of the disease.

For decades, apart from recognizing that acute pancreatitis may be a disease of its own digestive system, its exact pathophysiological mechanism has been a mystery.

A large amount of work from animal models has revealed several important pathophysiological mechanisms, which can represent therapeutic targets, and some drugs are already in development.

Landmark clinical trials provide insights in clinical management, such as nutritional support, fluid therapy for mild acute pancreatitis, prevention of recurrence of mild gallstone pancreatitis, and management of infection and necrosis.

 Despite the progress made, several important research gaps still exist.

Many of the identified potential therapeutic targets need to be tested in phase I clinical trials.

Translational medicine needs to study the mechanism of endocrine and exocrine dysfunction after acute pancreatitis.

But more importantly, the safety and effectiveness of early goal-oriented fluid therapy, clarifying the goals of fluid resuscitation, determining the best analgesic principles, and the role of early biliary decompression in predicting severe biliary acute pancreatitis, symptomatic The best endoscopic treatment of sterile pancreatic necrosis requires careful design and large-scale research.

Unfortunately, due to the lack of an existing collaborative platform to perform large-scale clinical trials and the difficulty in recruiting patients in the early stages of acute pancreatitis, it has been extremely challenging to carry out large-scale trials.

There is an urgent need to work on establishing a hospital collaboration network to conduct clinical trials, and focus on recruiting patients early in the course of their illness (see Box 1).

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