Pathogenesis of acute pancreatitis Author Santhi Swaroop Vege, MD Section Editor David C Whitcomb, MD, PhD Deputy Editor

Shilpa Grover, MD, MPH Disclosures All topics are updated as new evidence becomes available and our peer review process is complete Literature review current through: !ct "#$% & This topic last updated: dic ', "#$" INTR D!"TI N ( Acute pancreatitis is an in)lammator* condition o) the pancreas characteri+ed clinicall* b* abdominal pain and elevated levels o) pancreatic en+*mes in the blood A number o) conditions are ,nown to induce this disorder with var*ing degrees o) certaint* However, the pathogenesis o) this disorder is not )ull* understood -his topic review will )ocus on the current understanding o) the pathogenesis o) acute pancreatitis -he etiologic conditions associated with this disorder are discussed separatel* .See /0tiolog* o) acute pancreatitis/ 1 ANI#AL # DELS ( A number o) animal models have been developed to understand the pathogenesis o) acute pancreatitis 2$3 4one is strictl* comparable to the human condition Gallstones and alcohol abuse, )or e5ample, are responsible )or 67 percent o) cases o) acute pancreatitis in humans, but none o) the animal models duplicates these situations 8n addition, the commonl* used agents )or inducing pancreatitis in animal models, such as cerulein and a choline9 de)icient ethionine9supplemented diet, are not recogni+ed causes o) human acute pancreatitis 4evertheless, the structural and biochemical changes seen in earl* phases o) acute pancreatitis are remar,abl* constant in di))erent animal models, and similar changes have been demonstrated in human acute pancreatitis :urthermore, the clinical and pathologic )eatures o) human acute pancreatitis, regardless o) the inciting event, are ver* similar -hus, despite the limitations o) animal models, the data suggest that a similar cascade o) events occurs once pancreatitis begins that is independent o) the inciting event or initial mechanism Animal studies have shown that this cascade cannot be halted success)ull* unless therap* is initiated either proph*lacticall* or within a )ew hours o) the inciting event 8t is not clear )rom these studies wh* some individuals e5perience onl* interstitial or edematous pancreatitis, while others go on to develop the necroti+ing )orm o) the disease IN"ITIN$ E%ENT ( Although a number o) situations can precipitate acute pancreatitis, onl* a small )raction o) patients with these predisposing )actors develop the disease 8t is seen in onl* % to 6 percent o) patients with gallstones 2"3, $# percent o) alcoholics, and )ew patients with h*percalcemia 2%3 -he e5act mechanism o) induction o) pancreatitis b* these agents is not ,nown Alcohol&induced pancreatitis ( 8t is unclear wh* alcohol9induced pancreatitis occurs onl* a)ter man* *ears o) alcohol abuse and not a)ter a single binge in individuals not habituated to alcohol use However, several mechanisms have been proposed 2;3< Sensiti+ation o) acinar cells to CC=9induced premature activation o) +*mogens

Potentiation o) the e))ect o) CC= on the activation o) transcription )actors, nuclear )actor ,>, and activating protein9$ Generation o) to5ic metabolites such as acetaldeh*de and )att* acid eth*l esters Sensiti+ation o) the pancreas to the to5ic e))ects o) co5sac,ie virus >% Activation o) pancreatic stellate cells b* acetaldeh*de and o5idative stress and subse?uent increased production o) collagen and other matri5 proteins

$allstone pancreatitis ( -wo )actors have been suggested as the possible initiating event in gallstone pancreatitis< re)lu5 o) bile into the pancreatic duct due to transient obstruction o) the ampulla during passage o) gallstones 273, or obstruction at the ampulla secondar* to stone.s1 or edema resulting )rom the passage o) a stone 2'3 'yperlipide(ia&induced pancreatitis ( 8n h*perlipidemia, )ree )att* acids are released )rom serum trigl*cerides in to5ic concentrations b* the action o) pancreatic lipase within pancreatic capillaries 263 $enetic (utations in hereditary pancreatitis ( Genetic mutations leading to premature activation o) pancreatic +*mogens within the pancreas has also been proposed as the pathogenetic mechanism )or the acute attac,s o) pancreatitis seen in patients with hereditar* pancreatitis -his ma* be due to a number o) genetic mutations .See /Hereditar* pancreatitis/, section on @Genetics@ 1 ")TR gene (utations ( How C:-A mutations might produce acute pancreatitis is unclear A possible e5planation is that the mutations are associated with production o) a more concentrated and acidic pancreatic Buice leading to ductal obstruction or altered acinar cell )unction .eg, reduced intracellular pH and abnormal intracellular membrane rec*cling or transport1 Mutations in at least one allele o) the c*stic )ibrosis transmembrane conductance regulator .C:-A1 have been demonstrated in appro5imatel* " to %6 percent o) patients with idiopathic chronic and acute recurrent pancreatitis 2C9$"3, and a similar proportion o) patients with recurrent acute pancreatitis associated with pancreas divisum 2$#3 -he prevalence o) C:-A mutations in acute biliar* pancreatitis 2$$3 and chronic pancreatitis associated with alcohol .appro5imatel* # to 7 percent1 2$#3 is no greater than the general population -he diagnostic, prognostic, and therapeutic implications o) these studies remain to be clari)ied 8t is possible that alleged causes o) pancreatitis, such as pancreas divisum and sphincter o) !ddi d*s)unction, are epiphenomena and are instead due to underling C:-A mutations Continued se?uencing o) C:-A in patients with une5plained pancreatitis ma* reveal additional mutations since onl* a limited number o) the more than C7# ,nown C:-A mutations have been loo,ed )or !n the other hand, most subBects in whom a mutation has been identi)ied had a normal sweat chloride and nasal potential di))erence, calling into ?uestion the )unctional signi)icance o) the mutations A better wa* to understand the contribution o) C:-A mutations is to test the nasal potential di))erence .PD1 4asal PD ma* be abnormal even in patients with a normal sweat test -his suggests that the sweat test ma* not be su))icientl* sensitive to detect abnormalities in pancreatic )unction that ma* contribute to pancreatitis in patients with C:-A mutations 4asal PD testing is not readil* available and di))icult to per)orm EARL* A"!TE "'AN$ES ( -he e5ocrine pancreas s*nthesi+es and secretes a variet* o) digestive en+*mes that normall* become activated a)ter reaching the duodenum Small amounts o)

tr*psinogen are spontaneousl* activated, but the pancreas has mechanisms to ?uic,l* remove activated tr*psin< -he )irst line o) de)ense is the pancreatic secretor* tr*psin inhibitor .PS-8 or SP84=$1, which can bind and inactivate about "# percent o) the tr*psin activit* -he second line o) de)ense is autol*sis o) prematurel* activated tr*psin Absence o) this mechanism is postulated to cause hereditar* pancreatitis .See /Hereditar* pancreatitis/ 1 Another de)ense mechanism involves mesotr*psin and en+*me D, which l*ses and inactivates tr*psin 4onspeci)ic antiproteases such as alpha9$ antitr*psin and alpha9"9macroglobulin are present in the pancreatic interstitium

Intraacinar activation of proteolytic en+y(es ( !ne o) the earliest events in di))erent models o) acute pancreatitis is bloc,ade o) secretion o) pancreatic en+*mes while s*nthesis continues 2$%3 8t is becoming increasingl* apparent that the central re?uirement )or induction o) acute pancreatitis is the intraacinar activation o) these proteol*tic en+*mes, which ultimatel* leads to an autodigestive inBur* to the gland A proposed mechanism b* which intraacinar activation occurs and leads to pancreatic destruction in animal models o) pancreatitis is as )ollows 2$%3< A devastating event occurs ver* earl* which allows generation o) large amounts o) active tr*psin within the pancreas Colocali+ation o) l*sosomal en+*mes, such as cathepsin > and digestive en+*mes, including tr*psinogen, occurs in unstable vacuoles within the acinar cell 2$;3 8n the normal acinar cell, these two groups o) en+*mes are care)ull* sorted b* the Golgi networ, 8n earl* pancreatitis, however, cathepsin > cleaves the tr*psinogen activation peptide )rom tr*psinogen within the acinar vacuoles, leading to intrapancreatic activation o) tr*psin -he vacuoles then rupture, releasing the active tr*psin -he normal de)ense mechanisms o) the pancreas are overwhelmed b* the large amounts o) tr*psin released 8n addition, the intrapancreatic release o) tr*psin leads to activation o) more tr*psin, and other pancreatic en+*mes such as phospholipase, ch*motr*psin, and elastase -r*psin also activates other en+*me cascades including complement, ,alli,rein9 ,inin, coagulation, and )ibrinol*sis -he intrapancreatic release o) active pancreatic en+*mes leads to pancreatic autodigestion, setting up a vicious c*cle o) active en+*mes damaging cells, which then release more active en+*mes -he destruction spreads along the gland and into the peripancreatic tissue

-r*psinogen activation within the pancreas occurs within $# minutes o) in)using rats with a suprama5imall* stimulating dose o) the cholec*sto,inin analogue cerulein, a common agent used to induce pancreatitis in animals 2$73 -he activation o) tr*psinogen occurs be)ore either biochemical or morphological inBur* to acinar cells is evident An in vitro model )ound that complete inhibition o) pancreatic cathepsin > activit* with 09';d .a speci)ic potent and irreversible cathepsin > inhibitor1 prevented cerulein9induced tr*psinogen activation 2$'3 -his observation supports the signi)icance o) cathepsin > activation o) tr*psinogen, and the importance o) colocali+ation o) pancreatic digestive en+*mes and l*sosomal h*drolases 8n addition, it suggests that complete inhibition o) cathepsin > ma* be o) bene)it in either the prevention or treatment o) acute pancreatitis

-his observation has been )urther con)irmed more recentl* 2$;3, although other mechanisms besides cathepsin > have also been suggested to have a role li,e tr*psinogen autoactivation or activation b* other l*sosomal proteinases 8ntracellular calcium concentration also increases earl* on along with a decrease in the intracellular pH -his ma* cause premature activation o) tr*psinogen and then an upregulation o) nuclear )actor ,> and activating protein9$ #icrocirculatory in,ury ( -he release o) pancreatic en+*mes damages the vascular endothelium and the interstitium as well as the acinar cells 2$69$E3 Microcirculator* changes, including vasoconstriction, capillar* stasis, decreased o5*gen saturation, and progressive ischemia, occur earl* in e5perimental models o) acute pancreatitis -hese changes lead to increased vascular permeabilit* and swelling o) the gland .edematous or interstitial pancreatitis1 Vascular inBur* could lead to local microcirculator* )ailure and ampli)ication o) the pancreatic inBur* -here is also speculation about the role o) ischemia9reper)usion inBur* in the pancreas 2$E3 -his mechanism o) inBur* is well9established in other organs such as the heart, intestines, and s,eletal muscle Aeper)usion o) damaged tissues leads to the release o) )ree radicals and in)lammator* c*to,ines into the circulation, which could cause )urther inBur* .See /8schemic reper)usion inBur* o) the heart/ 1 -he importance o) microcirculator* inBur* can be appreciated b* the importance o) aggressive )luid replacement in the management o) acute pancreatitis, which minimi+es this inBur* Leu-ocyte che(oattraction. release of cyto-ines. and o/idative stress ( Microscopic and radionuclide studies using 8ndium9$$$ tagged leu,oc*tes show mar,ed glandular invasion b* macrophages and pol*morphonuclear leu,oc*tes in earl* stages o) animal and human pancreatitis 2"#9""3 Activation o) complement and the subse?uent release o) C7a have a signi)icant role in the recruitment o) these in)lammator* cells However, there is also some evidence that C7a also e5erts anti9in)lammator* e))ect in acute pancreatitis and associated lung inBur*F thus, its net e))ect is unclear 2"%3 Granuloc*te and macrophage activation causes the release o) proin)lammator* c*to,ines .tumor necrosis )actor, interleu,ins $, ', and C1, arachidonic acid metabolites .prostaglandins, platelet9 activating )actor, and leu,otrienes1, proteol*tic and lipol*tic en+*mes, and reactive o5*gen metabolites which overwhelm the scavenging capacit* o) endogenous antio5idant s*stems -hese substances also interact with the pancreatic microcirculation to increase vascular permeabilit* and induce thrombosis and hemorrhage, leading to pancreatic necrosis Activated pancreatic en+*mes, microcirculator* impairment, and the release o) in)lammator* mediators lead to rapid worsening o) pancreatic damage and necrosis -his interaction ma,es it di))icult to estimate the individual roles o) these )actors in inducing pancreatic damage 8n addition, appro5imatel* C# percent o) patients with pancreatitis develop onl* interstitial pancreatitis rather than necroti+ing pancreatitisF the )actors involved in limiting the pancreatic damage are not well understood Heat shoc, protein, angiotensin 88, substance P, and c*cloo5*genase " are the other recentl* described candidate pathogenetic )actors in e5perimental pancreatitis, heat shoc, proteins being the onl* protective )actor 2";3 S*STE#I" RESP NSE ( Some patients with severe pancreatic damage develop s*stemic complications including )ever, acute respirator* distress s*ndrome .AADS1, pleural e))usions, renal )ailure, shoc,, and m*ocardial depression -his s*stemic in)lammator* response s*ndrome .S8AS1 is probabl* mediated b* activated pancreatic en+*mes .phospholipase, elastase, tr*psin, etc1 and c*to,ines .tumor necrosis )actor, platelet activating )actor1 released into the circulation )rom the

in)lamed pancreas 2"7,"'3 .See /Sepsis and the s*stemic in)lammator* response s*ndrome< De)initions, epidemiolog*, and prognosis/ 1 AADS, in addition to being secondar* to microvascular thrombosis, ma* be induced b* active phospholipase A .lecithinase1, which digests lecithin, a maBor component o) sur)actant M*ocardial depression and shoc, are thought to be secondar* to vasoactive peptides and a m*ocardial depressant )actor Acute renal )ailure has been e5plained on the basis o) h*povolemia and h*potension Metabolic complications include h*pocalcemia, h*perlipidemia, h*pergl*cemia, h*pogl*cemia, and diabetic ,etoacidosis -he pathogenesis o) h*pocalcemia is multi)actorial and includes calcium9soap )ormation, hormonal imbalances .eg, parath*roid hormone, calcitonin, glucagon1, binding o) calcium b* )ree )att* acid9albumin comple5es, and intracellular translocation o) calcium

-hese s*stemic complications are uncommon and much less severe in patients with interstitial pancreatitis than in those with necroti+ing pancreatitis However, onl* about 7# percent o) patients with necroti+ing pancreatitis develop organ )ailure, and this complication cannot be predicted )rom the degree o) pancreatic necrosis or the presence or absence o) in)ected necrosis 2"'3 !ne stud* suggested that an increased tissue concentration o) macrophage migration inhibitor* )actor was a critical )actor in the pathogenesis o) severe acute pancreatitis 2"63 0acterial translocation ( -he normal human gut prevents the translocation o) bacteria into the s*stemic circulation through a comple5 barrier that consists o) immunologic, bacteriologic, and morphologic components During the course o) acute pancreatitis, the gut barrier is compromised, leading to translocation o) bacteria, which can result in local and s*stemic in)ection 2"C3 -he brea,down in the gut barrier is thought to be a conse?uence o) ischemia due to h*povolemia and pancreatitis9induced gut arteriovenous shunting 2"E3 Most in)ections in acute pancreatitis are caused b* common enteric organisms suggesting that the* originate )rom the gastrointestinal tract 8n a canine model o) acute pancreatitis, plasmid9labeled 0scherichia coli coloni+ing the gut were )ound in the mesenteric l*mph nodes and at distant sites 2%#3 -he conse?uences o) bacterial translocation )rom the gut in acute pancreatitis can be lethal Gocal bacterial in)ection o) pancreatic and peripancreatic tissues occurs in appro5imatel* %# percent o) patients with severe acute pancreatitis, potentiall* resulting in multiorgan )ailure and its se?uelae As a result, attempts to maintain the gut barrier )unction o) the gut continue to be studied Among the best studied interventions is enteral )eeding, which is associated with decreased bacterial translocation in animal models o) acute pancreatitis and ma* be bene)icial in humans with acute pancreatitis .See /-reatment o) acute pancreatitis/ 1 IN) R#ATI N ) R PATIENTS ( Hp-oDate o))ers two t*pes o) patient education materials, /-he >asics/ and />e*ond the >asics / -he >asics patient education pieces are written in plain language, at the 7th to 'th grade reading level, and the* answer the )our or )ive ,e* ?uestions a patient might have about a given condition -hese articles are best )or patients who want a general overview and who pre)er short, eas*9to9read materials >e*ond the >asics patient education pieces are longer, more sophisticated, and more detailed -hese articles are written at the $#th to $"th grade reading

level and are best )or patients who want in9depth in)ormation and are com)ortable with some medical Bargon Here are the patient education articles that are relevant to this topic We encourage *ou to print or e9mail these topics to *our patients .Dou can also locate patient education articles on a variet* o) subBects b* searching on /patient in)o/ and the ,e*word.s1 o) interest 1 >e*ond the >asics topics .see /Patient in)ormation< Acute pancreatitis .>e*ond the >asics1/1

S!##AR* Although a number o) conditions can precipitate acute pancreatitis, onl* a small )raction o) patients with these predisposing conditions develops acute pancreatitis :or e5ample, the incidence o) acute pancreatitis is onl* % to 6 percent in patients with gallstones and $# percent in alcoholics .See @8nciting event@ above 1 8t is unclear wh* alcohol9induced pancreatitis occurs onl* a)ter man* *ears o) alcohol abuse and not a)ter a single binge in individuals not habituated to alcohol use However, several mechanisms have been proposed .see@8nciting event@ above1< Sensiti+ation o) acinar cells to CC=9induced premature activation o) +*mogens Potentiation o) the e))ect o) CC= on the activation o) transcription )actors, nuclear )actor ,>, and activating protein9$ Generation o) to5ic metabolites such as acetaldeh*de and )att* acid eth*l esters Sensiti+ation o) the pancreas to the to5ic e))ects o) co5sac,ie virus >% Activation o) pancreatic stellate cells b* acetaldeh*de and o5idative stress and subse?uent increased production o) collagen and other matri5 proteins -wo )actors have been suggested as the possible initiating event in gallstone pancreatitis< re)lu5 o) bile into the pancreatic duct due to transient obstruction o) the ampulla during passage o) gallstones, or obstruction at the ampulla secondar* to stone.s1 or edema resulting )rom the passage o) a stone .See @Gallstone pancreatitis@ above 1 8n h*pertrigl*ceridemia, )ree )att* acids are released )rom serum trigl*cerides in to5ic concentrations b* the action o) pancreatic lipase within pancreatic capillaries .See @H*perlipidemia9induced pancreatitis@ above 1 Premature activation o) pancreatic +*mogens within the pancreas has also been proposed as the pathogenetic mechanism )or the acute attac,s o) pancreatitis seen in patients with hereditar* pancreatitis .See/Hereditar* pancreatitis/ 1 How C:-A mutations might produce acute pancreatitis is unclear A possible e5planation is that the mutations are associated with production o) a more concentrated and acidic pancreatic Buice leading to ductal obstruction or altered acinar cell )unction .See @C:-A gene mutations@ above 1 8t is becoming increasingl* apparent that the central re?uirement )or induction o) acute pancreatitis is the intraacinar activation proteol*tic en+*mes, which ultimatel* leads to an autodigestive inBur* to the gland .See@8ntraacinar activation o) proteol*tic en+*mes@ above 1 Activated pancreatic en+*mes, microcirculator* impairment, and the release o) in)lammator* mediators lead to rapid worsening o) pancreatic damage and necrosis

However, appro5imatel* C# percent o) patients with pancreatitis develop onl* interstitial pancreatitis rather than necroti+ing pancreatitisF the )actors involved in limiting the pancreatic damage are not well understood .See @0arl* acute changes@ above 1 Some patients with severe pancreatic damage develop s*stemic in)lammator* response s*ndrome .S8AS1 probabl* mediated b* activated pancreatic en+*mes and c*to,ines released into the circulation )rom the in)lamed pancreas A compensated antiin)lammator* response s*ndrome .CAAS1 balances S8AS and leads to recover* An imbalance between S8AS and CAAS results in severe organ )ailure with high morbidit* and mortalit* -he causes )or such imbalance are not clearl* understood .See @S*stemic response@ above 1 During the course o) acute pancreatitis, the gut barrier is compromised, leading to translocation o) bacteria, which can result in local and s*stemic in)ection -he conse?uences o) bacterial translocation )rom the gut in acute pancreatitis can be lethal Gocal bacterial in)ection o) pancreatic and peripancreatic tissues occurs in appro5imatel* %# percent o) patients with severe acute pancreatitis, potentiall* resulting in multiorgan )ailure and its se?uelae .See @>acterial translocation@ above