Pathogenesis of acute pancreatitis

INTRODUCTION — 

Acute pancreatitis is a common inflammatory condition of the pancreas characterized clinically by abdominal pain and elevated levels of pancreatic enzymes in the blood [1,2]. A number of conditions are known to induce this disorder with varying degrees of certainty. However, the pathogenesis of this disorder is not fully understood.

This topic review will focus on the pathogenesis of acute pancreatitis. The etiologic conditions associated with this disorder are discussed separately. (See "Etiology of acute pancreatitis".)

ANIMAL MODELS — 

A number of animal models have been developed to understand the pathogenesis of acute pancreatitis [3,4]. None is strictly comparable to the human condition. Gallstones and alcohol, for example, are responsible for 75 percent of cases of acute pancreatitis in humans, but none of the animal models duplicates these situations. In addition, the commonly used agents for inducing pancreatitis in animal models, such as cerulein and a choline-deficient ethionine-supplemented diet, are not recognized causes of human acute pancreatitis.

Nevertheless, the structural and biochemical changes seen in early phases of acute pancreatitis are remarkably constant in different animal models, and similar changes have been demonstrated in human acute pancreatitis. Furthermore, the clinical and pathologic features of human acute pancreatitis, regardless of the inciting event, are very similar.

Thus, despite the limitations of animal models, the data suggest that a similar cascade of events occurs once pancreatitis begins that is independent of the inciting event or initial mechanism. Animal studies have shown that this cascade cannot be halted successfully unless therapy is initiated either prophylactically or within a few hours of the inciting event. It is not clear from these studies why some individuals experience only interstitial or edematous pancreatitis, while others go on to develop the necrotizing form of the disease.

INCITING EVENT — 

Although a number of situations can precipitate acute pancreatitis, only a small fraction of patients with these predisposing factors develop the disease. It is seen in only 3 to 7 percent of patients with gallstones [5], less than 10 percent of patients with alcohol use disorder [6], and few patients with hypercalcemia [7].

The exact mechanism of induction of pancreatitis by these agents is not known.

Alcohol-induced pancreatitis — It is unclear why alcohol-induced pancreatitis occurs only after many years of alcohol use and not after a single binge in individuals not habituated to alcohol use. However, several mechanisms have been proposed [8]:

●Sensitization of acinar cells to cholecystokinin (CCK)-induced premature activation of zymogens

●Potentiation of the effect of CCK on the activation of transcription factors, nuclear factor-kB, and activating protein-1

●Generation of toxic metabolites such as acetaldehyde and fatty acid ethyl esters

●Sensitization of the pancreas to the toxic effects of coxsackie virus B3

●Activation of pancreatic stellate cells by acetaldehyde and oxidative stress and subsequent increased production of collagen and other matrix proteins

Smoking and pancreatitis — Several epidemiologic studies clearly demonstrate the association of smoking with acute pancreatitis, which may be additive to alcohol. Pancreatic exocrine and endocrine function, neurohormonal, stellate cell and ductal system integrity can be affected by the different metabolites of cigarette smoke [9].

Gallstone pancreatitis — Two factors have been suggested as the possible initiating event in gallstone pancreatitis: reflux of bile into the pancreatic duct due to transient obstruction of the ampulla during passage of gallstones [10], or obstruction at the ampulla secondary to stone(s) or edema resulting from the passage of a stone [11].

Genetic mutations in hereditary pancreatitis — Genetic mutations leading to premature activation of pancreatic zymogens within the pancreas has also been proposed as the pathogenetic mechanism for the acute attacks of pancreatitis seen in patients with hereditary pancreatitis. This may be due to a number of genetic mutations. (See "Pancreatitis associated with genetic risk factors", section on 'Genetics'.)

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations — How CFTR mutations might produce acute pancreatitis is unclear. A possible explanation is that the mutations are associated with production of a more concentrated and acidic pancreatic juice leading to ductal obstruction or altered acinar cell function (eg, reduced intracellular pH and abnormal intracellular membrane recycling or transport).

Mutations in at least one allele of the CFTR have been demonstrated in approximately 2 to 37 percent of patients with idiopathic chronic and acute recurrent pancreatitis [12-16], and a similar proportion of patients with recurrent acute pancreatitis associated with pancreas divisum [14]. The prevalence of CFTR mutations in acute biliary pancreatitis [15] and chronic pancreatitis associated with alcohol (approximately 0 to 5 percent) [14] is no greater than the general population.

The diagnostic, prognostic, and therapeutic implications of these studies remain to be clarified. It is possible that alleged causes of pancreatitis, such as pancreas divisum and sphincter of Oddi dysfunction, are epiphenomena and are instead due to underling CFTR mutations. Continued sequencing of CFTR in patients with unexplained pancreatitis may reveal additional mutations since only a limited number of the more than 850 known CFTR mutations have been looked for. On the other hand, most subjects in whom a mutation has been identified had a normal sweat chloride and nasal potential difference, calling into question the functional significance of the mutations.

A better way to understand the contribution of CFTR mutations is to test the nasal potential difference (PD). Nasal PD may be abnormal even in patients with a normal sweat test. This suggests that the sweat test may not be sufficiently sensitive to detect abnormalities in pancreatic function that may contribute to pancreatitis in patients with CFTR mutations. Nasal PD testing is not readily available and difficult to perform.

EARLY ACUTE CHANGES — 

The exocrine pancreas synthesizes and secretes a variety of digestive enzymes that normally become activated after reaching the duodenum. Small amounts of trypsinogen are spontaneously activated, but the pancreas has mechanisms to quickly remove activated trypsin:

●The first line of defense is the pancreatic secretory trypsin inhibitor (PSTI or SPINK1), which can bind and inactivate about 20 percent of the trypsin activity.

●The second line of defense is autolysis of prematurely activated trypsin. Absence of this mechanism is postulated to cause hereditary pancreatitis. (See "Pancreatitis associated with genetic risk factors".)

●Another defense mechanism involves mesotrypsin and enzyme Y, which lyses and inactivates trypsin.

●Nonspecific antiproteases such as alpha-1 antitrypsin and alpha-2-macroglobulin are present in the pancreatic interstitium.

Intraacinar activation of proteolytic enzymes — One of the earliest events in different models of acute pancreatitis is blockade of secretion of pancreatic enzymes while synthesis continues [17]. It is becoming increasingly apparent that the central requirement for induction of acute pancreatitis is the intraacinar activation of these proteolytic enzymes, which ultimately leads to an autodigestive injury to the gland. A proposed mechanism by which intraacinar activation occurs and leads to pancreatic destruction in animal models of pancreatitis is as follows [17]:

●A devastating event occurs very early which allows generation of large amounts of active trypsin within the pancreas. Colocalization of lysosomal enzymes, such as cathepsin B and digestive enzymes, including trypsinogen, occurs in unstable vacuoles within the acinar cell [18]. In the normal acinar cell, these two groups of enzymes are carefully sorted by the Golgi network. In early pancreatitis, however, cathepsin B cleaves the trypsinogen activation peptide from trypsinogen within the acinar vacuoles, leading to intrapancreatic activation of trypsin.

●The vacuoles then rupture, releasing the active trypsin.

●The normal defense mechanisms of the pancreas are overwhelmed by the large amounts of trypsin released. In addition, the intrapancreatic release of trypsin leads to activation of more trypsin, and other pancreatic enzymes such as phospholipase, chymotrypsin, and elastase. Trypsin also activates other enzyme cascades including complement, kallikrein-kinin, coagulation, and fibrinolysis.

●The intrapancreatic release of active pancreatic enzymes leads to pancreatic autodigestion, setting up a vicious cycle of active enzymes damaging cells, which then release more active enzymes. The destruction spreads along the gland and into the peripancreatic tissue.

Trypsinogen activation within the pancreas occurs within 10 minutes of infusing rats with a supramaximally stimulating dose of the cholecystokinin analogue cerulein, a common agent used to induce pancreatitis in animals [19]. The activation of trypsinogen occurs before either biochemical or morphologic injury to acinar cells is evident. An in vitro model found that complete inhibition of pancreatic cathepsin B activity with E-64d (a specific potent and irreversible cathepsin B inhibitor) prevented cerulein-induced trypsinogen activation [20]. This observation supports the significance of cathepsin B activation of trypsinogen, and the importance of colocalization of pancreatic digestive enzymes and lysosomal hydrolases. In addition, it suggests that complete inhibition of cathepsin B may be of benefit in either the prevention or treatment of acute pancreatitis.

This observation has been confirmed [18], although other mechanisms besides cathepsin B have also been suggested to have a role like trypsinogen autoactivation or activation by other lysosomal proteinases. Intracellular calcium concentration also increases early on along with a decrease in the intracellular pH. This may cause premature activation of trypsinogen and then an upregulation of nuclear factor-kappa B and activating protein-1.

Chymotrypsin, another acinar protease, has been shown to play a critical role in clearing pathologically-activated trypsin and protecting against pancreatic injury [21].

Nuclear factor-kappa B (NF-kB) activation — Studies suggest that premature activation of trypsinogen contributes only to acinar injury. Historically, activation of trypsin and subsequent cascade of events in the acinar cell was considered the most important pathogenetic mechanism. However, it is known that the pancreatic and extra-pancreatic (systemic) inflammatory response is driven by NF-kB [22]. Calcineurin NFAT signaling is responsible for the abnormal rise in intra-cellular calcium, and IL-6 is the key mediator responsible for pancreatitis-associated lung injury. Pathologic calcium signaling, colocalization of lysosomes and zymogens, cellular and extra-cellular pH changes, and bile duct epithelial cells all have also been implicated in the pathogenesis of acute pancreatitis. Endoplasmic reticulum and oxidative stress, together with the induction of a defective autophagic pathway, are other important factors described in the pathogenesis along with TLR4 (Toll-Like Receptor family) [23]. Bacterial cell wall component in Gram-negative bacteria, lipopolysaccharide (LPS), along with other stressors like alcohol, can contribute to the onset and severity of pancreatitis.

Microcirculatory injury — The release of pancreatic enzymes damages the vascular endothelium and the interstitium as well as the acinar cells [24-26]. Microcirculatory changes, including vasoconstriction, capillary stasis, decreased oxygen saturation, and progressive ischemia, occur early in experimental models of acute pancreatitis. These changes lead to increased vascular permeability and swelling of the gland (edematous or interstitial pancreatitis). Vascular injury could lead to local microcirculatory failure and amplification of the pancreatic injury.

There is also speculation about the role of ischemia-reperfusion injury in the pancreas [26]. This mechanism of injury is well-established in other organs such as the heart, intestines, and skeletal muscle. Reperfusion of damaged tissues leads to the release of free radicals and inflammatory cytokines into the circulation, which could cause further injury. (See "Reperfusion injury of the heart".) The importance of microcirculatory injury can be appreciated by the importance of aggressive fluid replacement in the management of acute pancreatitis, which minimizes this injury.

Leukocyte chemoattraction, release of cytokines, and oxidative stress — Microscopic and radionuclide studies using Indium-111 tagged leukocytes show marked glandular invasion by macrophages and polymorphonuclear leukocytes in early stages of animal and human pancreatitis [27-29]. Activation of complement and the subsequent release of C5a have a significant role in the recruitment of these inflammatory cells. However, there is also some evidence that C5a also exerts anti-inflammatory effect in acute pancreatitis and associated lung injury; thus, its net effect is unclear [30].

Granulocyte and macrophage activation causes the release of proinflammatory cytokines (tumor necrosis factor, interleukins 1, 6, and 8), arachidonic acid metabolites (prostaglandins, platelet-activating factor, and leukotrienes), proteolytic and lipolytic enzymes, and reactive oxygen metabolites which overwhelm the scavenging capacity of endogenous antioxidant systems. These substances also interact with the pancreatic microcirculation to increase vascular permeability and induce thrombosis and hemorrhage, leading to pancreatic necrosis.

Activated pancreatic enzymes, microcirculatory impairment, and the release of inflammatory mediators lead to rapid worsening of pancreatic damage and necrosis. This interaction makes it difficult to estimate the individual roles of these factors in inducing pancreatic damage. In addition, approximately 80 percent of patients with pancreatitis develop only interstitial pancreatitis rather than necrotizing pancreatitis; the factors involved in limiting the pancreatic damage are not well understood.

Heat shock protein, angiotensin II, substance P, and cyclooxygenase 2 have been described as pathogenetic factors in experimental pancreatitis, with heat shock proteins being the only protective factor [31].

SYSTEMIC RESPONSE — 

Some patients with severe pancreatic damage develop systemic complications including fever, acute respiratory distress syndrome (ARDS), pleural effusions, kidney failure, shock, and myocardial depression. This systemic inflammatory response syndrome (SIRS) is probably mediated by activated pancreatic enzymes (phospholipase, elastase, trypsin, etc) and cytokines (tumor necrosis factor, platelet activating factor) released into the circulation from the inflamed pancreas [32,33]. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)

●ARDS, in addition to being secondary to microvascular thrombosis, may be induced by active phospholipase A (lecithinase), which digests lecithin, a major component of surfactant.

●Myocardial depression and shock are thought to be secondary to vasoactive peptides and a myocardial depressant factor.

●Acute kidney failure has been explained on the basis of hypovolemia and hypotension.

●Metabolic complications include hypocalcemia, hyperlipidemia, hyperglycemia, hypoglycemia, and diabetic ketoacidosis. The pathogenesis of hypocalcemia is multifactorial and includes calcium-soap formation, hormonal imbalances (eg, parathyroid hormone, calcitonin, glucagon), binding of calcium by free fatty acid-albumin complexes, and intracellular translocation of calcium.

These systemic complications are uncommon and much less severe in patients with interstitial pancreatitis than in those with necrotizing pancreatitis. However, only about 50 percent of patients with necrotizing pancreatitis develop organ failure, and this complication cannot be predicted from the degree of pancreatic necrosis or the presence or absence of infected necrosis [33]. One study suggested that an increased tissue concentration of macrophage migration inhibitory factor was a critical factor in the pathogenesis of severe acute pancreatitis [34].

BACTERIAL TRANSLOCATION — 

The normal human gut prevents the translocation of bacteria into the systemic circulation through a complex barrier that consists of immunologic, bacteriologic, and morphologic components. During the course of acute pancreatitis, the gut barrier is compromised, leading to translocation of bacteria, which can result in local and systemic infection [35]. The breakdown in the gut barrier is thought to be a consequence of ischemia due to hypovolemia and pancreatitis-induced gut arteriovenous shunting [36].

Most infections in acute pancreatitis are caused by common enteric organisms suggesting that they originate from the gastrointestinal tract. In a canine model of acute pancreatitis, plasmid-labeled Escherichia coli colonizing the gut were found in the mesenteric lymph nodes and at distant sites [37].

The consequences of bacterial translocation from the gut in acute pancreatitis can be lethal. Local bacterial infection of pancreatic and peripancreatic tissues occurs in approximately 30 percent of patients with severe acute pancreatitis, potentially resulting in multiorgan failure and its sequelae. As a result, attempts to maintain the gut barrier function continue to be studied. Among the best studied interventions is enteral feeding, which is associated with decreased bacterial translocation in animal models of acute pancreatitis and may be beneficial in humans with acute pancreatitis. (See "Management of acute pancreatitis".)

Lung injury may occur in patients with acute pancreatitis. Failure of the gut mucosal barrier and subsequent translocation of gut bacteria in patients with pancreatic necrosis promotes a sequence of inflammatory events resulting in pulmonary injury, collectively referred to as the "pancreas-intestine-inflammation/endotoxin-lung (P-I-I/E-L) pathway". In addition, pattern recognition receptors (PRRS) have been described, which bind with pathogen-associated molecular patterns [38,39].

OTHER FACTORS — 

Other potential factors in the pathogenesis of acute pancreatitis include:

●Inflammatory cascade – For progression of the inflammatory cascade, the gut microbiota-diaminopimelic acid (DAP)-nucleotide-oligomerization and binding domain 1 (NOD1)/receptor-interacting protein 2 (RIP2) signaling pathway may be important [40]. DAP from the cell wall peptidoglycans of bacteria is a ligand for NOD1 that can induce immune responses. After DAP is recognized by NOD1, which is widely expressed in the intestine, pancreas, and most immune cells, it can activate RIP2 and downstream signaling pathways, including NF-kB. The translocation of commensal gut organisms into the blood stream is due to pathogen-associated molecular pattern-mediated cytokine activation.

Interleukin-17 promotes the inflammatory cascade of events and affects the microcirculation [41]. Interleukin-22 is one of the cytokines that has been reported to play a role in the pathogenesis of acute pancreatitis and in being protective [42].

●Impaired autophagy – Impaired autophagy as a result of mitochondrial dysfunction may also play a role in acute pancreatitis. In animal models of L-arginine-induced severe acute pancreatitis, the pathway involves interaction of cyclophilin D with ATP synthase. This precedes the release of inflammatory cytokines and follows calcium overloading of the cells [43]. Restoration of autophagy and mitochondrial dysfunction might prove to be a suitable drug target to treat acute pancreatitis [44].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute pancreatitis".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Acute pancreatitis (Beyond the Basics)")

SUMMARY

●Background – Although some conditions can precipitate acute pancreatitis, only a small fraction of patients with these predisposing conditions develops acute pancreatitis. For example, the incidence of acute pancreatitis is only 3 to 7 percent in patients with gallstones and 10 percent in patients with alcohol use disorder. (See 'Inciting event' above.)

●Alcohol-induced pancreatitis – It is unclear why alcohol-induced pancreatitis occurs only after many years of alcohol use and not after a single binge in individuals not habituated to alcohol use. However, several mechanisms have been proposed (see 'Alcohol-induced pancreatitis' above):

•Sensitization of acinar cells to cholecystokinin (CCK)-induced premature activation of zymogens

•Potentiation of the effect of CCK on the activation of transcription factors, nuclear factor-kB, and activating protein-1

•Generation of toxic metabolites such as acetaldehyde and fatty acid ethyl esters

•Sensitization of the pancreas to the toxic effects of coxsackie virus B3

•Activation of pancreatic stellate cells by acetaldehyde and oxidative stress and subsequent increased production of collagen and other matrix proteins

●Gallstone pancreatitis – Two factors have been suggested as the possible initiating event in gallstone pancreatitis: reflux of bile into the pancreatic duct due to transient obstruction of the ampulla during passage of gallstones, or obstruction at the ampulla secondary to stone(s) or edema resulting from the passage of a stone. (See 'Gallstone pancreatitis' above.)

●Genetic risk factors – Premature activation of pancreatic zymogens within the pancreas has also been proposed as the pathogenetic mechanism for the acute attacks of pancreatitis seen in patients with hereditary pancreatitis. (See "Pancreatitis associated with genetic risk factors".)

●CFTR gene mutations – How CFTR mutations might produce acute pancreatitis is unclear. A possible explanation is that the mutations are associated with production of a more concentrated and acidic pancreatic juice leading to ductal obstruction or altered acinar cell function. (See 'Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations' above.)

●Early acute changes – It is becoming increasingly apparent that the central requirement for induction of acute pancreatitis is the intraacinar activation proteolytic enzymes, which ultimately leads to an autodigestive injury to the gland. (See 'Intraacinar activation of proteolytic enzymes' above.)

Pancreatic and extra-pancreatic (systemic) inflammatory response is driven by NF-kB activation. Endoplasmic reticulum and oxidative stress together with the induction of a defective autophagic pathway are other important factors described in the pathogenesis, along with the role of TLR4 (Toll-Like Receptor family). (See 'Nuclear factor-kappa B (NF-kB) activation' above.)

Activated pancreatic enzymes, microcirculatory impairment, and the release of inflammatory mediators lead to rapid worsening of pancreatic damage and necrosis. However, approximately 80 percent of patients with pancreatitis develop only interstitial pancreatitis rather than necrotizing pancreatitis; the factors involved in limiting the pancreatic damage are not well understood. (See 'Leukocyte chemoattraction, release of cytokines, and oxidative stress' above.)

●Systemic response – Some patients with severe pancreatic damage develop systemic inflammatory response syndrome (SIRS) probably mediated by activated pancreatic enzymes and cytokines released into the circulation from the inflamed pancreas. A compensated antiinflammatory response syndrome (CARS) balances SIRS and leads to recovery. An imbalance between SIRS and CARS results in severe organ failure with high morbidity and mortality. The causes for such imbalance are not clearly understood. (See 'Systemic response' above.)

●Bacterial translocation – For patients with acute pancreatitis, the gut barrier is compromised, leading to translocation of bacteria, which can result in local and systemic infection. The consequences of bacterial translocation from the gut in acute pancreatitis can be lethal. Local bacterial infection of pancreatic and peripancreatic tissues occurs in approximately 30 percent of patients with severe acute pancreatitis, potentially resulting in multiorgan failure and its sequelae. (See 'Bacterial translocation' above.)

Intestinal inflammation and translocation of organisms and endotoxin play a role in acute lung injury by NF-kB activation and subsequent cytokine release.