REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY

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GASTROENTEROLOGY 2007;132:1557–1573

EVIEWS IN BASIC AND CLINICALASTROENTEROLOGY

Wafik El-Diery and David Metz, Section EditorsRoland M. Schmid, Guest Section Editor (p 1557–1573)K. Rajender Reddy, Guest Section Editor (p 1574–1594)

hronic Pancreatitis: Challenges and Advances in Pathogenesis,enetics, Diagnosis, and Therapy

EIKO WITT,* MINOTI V. APTE,‡ VOLKER KEIM,§ and JEREMY S. WILSON‡

Department of Hepatology and Gastroenterology, Charité, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Berlin, Germany; ‡Pancreatic Research Group,§
outh Western Sydney Clinical School, The University of New South Wales, Sydney, Australia; and the Medizinische Klinik und Poliklinik II, Universitätsklinikum
eipzig, Germany

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hronic pancreatitis (CP) is characterized by progres-ive pancreatic damage that eventually results in signif-cant impairment of exocrine as well as endocrine func-ions of the gland. In Western societies, the commonestssociation of chronic pancreatitis is alcohol abuse. Ournderstanding of the pathogenesis of CP has improved

n recent years, though important advances that haveeen made with respect to delineating the mechanismsesponsible for the development of pancreatic fibrosisa constant feature of CP) following repeated acute at-acks of pancreatic necroinflammation (the necrosis-brosis concept). The pancreatic stellate cells (PSCs) areow established as key cells in fibrogenesis, particularlyhen activated either directly by toxic factors associatedith pancreatitis (such as ethanol, its metabolites orxidant stress) or by cytokines released during pancre-tic necroinflammation. In recent years, research effortas also focused on the genetic abnormalities that mayredispose to CP. Genes regulating trypsinogen activa-

ion/inactivation and cystic fibrosis transmembraneonductance regulator (CFTR) function have receivedarticular attention. Mutations in these genes are now

ncreasingly recognized for their potential ‘disease mod-fier’ role in distinct forms of CP including alcoholic,ropical, and idiopathic pancreatitis. Treatment of un-omplicated CP is usally conservative with the majorim being to effectively alleviate pain, maldigestion andiabetes, and consequently, to improve the patient’suality of life. Surgical and endoscopic interventionsre reserved for complications such as pseudocysts, ab-cess, and malignancy.

hronic pancreatitis (CP) is a condition characterizedby progressive and irreversible damage to both exo-

rine and endocrine components of the pancreas, even-
ually resulting in significant exocrine insufficiency (mal-
igestion) and diabetes.1 As such, this review is a naturalxtension of the report by Pandol et al (See March issue007;132:1127–1151). The reported incidence of CP in

ndustrialized countries ranges from 3.5 to 10 per00,000 population. Alcohol abuse is the major associa-ion of CP in Western countries, but other factors such asenetic mutations, pancreatic duct obstruction caused bytrictures, hypertriglyceridemia, hypercalcemia, and auto-mmunity also have been implicated.1–3 Another distinct,on–alcohol-related form of CP that has received increas-

ng attention in recent times is tropical pancreatitis. Theathogenesis of this condition is unknown, although anssociation with a mutation in a serine protease inhibitorene (SPINK1) has been proposed.4 In a minority of casesf CP, no identifiable cause can be found and a diagnosisf idiopathic pancreatitis is made.5 However, it is antic-

pated that with increasing identification of putative ge-etic/environmental factors, the numbers of true idio-athic cases of CP will diminish further.The key histopathologic features of CP (regardless of

tiology) are pancreatic fibrosis, acinar atrophy, chronicnflammation, and distorted and blocked ducts.1,6 Addi-ional distinctive histologic features have been describedn some forms of CP, such as extensive pancreatic calci-cation in tropical pancreatitis4 and a prominent lym-hocytic and plasma cell infiltrate in autoimmune pan-reatitis.7,8

Abbreviations used in this paper: ADH, alcohol dehydrogenase; AIP,utoimmune pancreatitis; CFTR, cystic fibrosis transmembrane con-uctance regulator; CP, chronic pancreatitis; ERCP, endoscopic retro-rade cholangiopancreatography; EUS, endoscopic ultrasonography;AEE, fatty acid ethyl ester; LPS, lipopolysaccharide; MCT, medium-hain triglyceride; MRCP, magnetic resonance cholangiopancreatog-aphy; PSC, pancreatic stellate cell; SO, sphincter of Oddi.

© 2007 by the AGA Institute0016-5085/07/$32.00

doi:10.1053/j.gastro.2007.03.001

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1558 WITT ET AL GASTROENTEROLOGY Vol. 132, No. 4

Clinical FeaturesThe 3 major clinical features of CP are pain, mal-

igestion, and diabetes.

PainAbdominal pain is the most vexing clinical prob-

em and the most common indication for surgical inter-ention in patients with CP. Severe pain decreases appe-ite, thereby contributing to malnutrition and weightoss. The pain is usually epigastric in location (although

ore diffuse pain in the upper abdomen can occur) anday radiate to the back. Although recurrent (type A) or

ontinuous (type B) pain is considered to be the hallmarkf CP, a subgroup of patients may have no pain at all,resenting instead with symptoms of pancreatic insuffi-iency. While the course of pain in CP can be unpredict-ble, in general it is reported to improve or resolve withime in the majority of patients. Whether the alleviationf pain coincides with the onset of exocrine insufficiencyburn-out hypothesis, see below) is still a matter of de-ate.9,10 In patients with known CP, pain also may resultrom an acute attack of pancreatitis, from a pancreaticseudocyst, portal or splenic vein thrombosis, or bileuct obstruction (associated with jaundice). Associatedastric or duodenal ulcers also may contribute to pain inhese patients.

Maldigestion and DiabetesSteatorrhea and weight loss are further important

eatures of CP. Steatorrhea is a symptom of advancedisease and does not occur until pancreatic lipase secre-ion is reduced to less than 10% of normal. Maldigestionf lipids occurs earlier than that of other nutrients (pro-eins and carbohydrates) since lipase secretion decreases

ore rapidly than protease or amylase secretion. In ad-ition to exocrine insufficiency, diabetes mellitus mayevelop in the long-term course of the disease. The dia-etes is classified as type IIIc according to the Americaniabetes Association11 and is characterized by destruc-

ion of both insulin- and glucagon-producing cells. Theiabetic state often is fragile because the co-existing de-ciency of glucagon synthesis aggravates hypoglycemicituations.

ClassificationChronic pancreatitis may be separated into 4 dif-

erent stages:

I. A pre-clinical stage with absent or uncharacteristicsymptoms

II. Recurrent acute episodes of pancreatitis without def-inite signs of CP

II. Further recurrent episodes with intermittent or con-stant pain in between and signs of CP such as duct
dilatation and pancreatic calcification on imaging h
IV. A final stage, mostly without acute flares and ab-sence or decreased frequency of pain, possibly asso-ciated with evidence of endocrine and exocrine in-sufficiency (burnout, see below)

Single stages may be skipped, eg, some patientsnitially may present with a painless stage IV chronicancreatitis, showing maldigestion, steatorrhea, oriabetes.

Natural HistoryThe natural history of CP has been difficult to

haracterize because of the variability in presentationf the disease and the relative inaccessibility of theancreas to histologic assessment. However, severaltudies involving large series of medical and surgicalases have provided some important insights in thisrea.5,9,10,12–14

Alcohol-induced CP usually develops after a prolongederiod (5–15 y) of heavy alcohol consumption and doesot develop after an isolated bout of heavy drinking. In aecent report (published in 2005), Mullhaupt et al10 an-lyzed a series of 343 patients with CP (265 patients withlcoholic CP, 57 with idiopathic CP, and 11 with hered-tary pancreatitis). They reported that the median age atnset of alcoholic pancreatitis is 36 years, whereas that ofereditary pancreatitis was as early as 10 years. IdiopathicP has 2 forms of clinical presentation: an early onset

juvenile) form with a median age at onset of 23 years,nd a late-onset (senile) form with a median age at onsetf 62 years. Tropical pancreatitis is characterized by anarly onset (mean age, 22 y), rapid progression, and severeancreatic damage in the absence of a history of alcoholbuse or biliary disease.4 On the other hand, autoim-une pancreatitis is reported to occur at a later age, withmean age at onset of 59.4 years.8

The median time to the development of pancreaticnsufficiency after disease onset depends on the type ofancreatitis under consideration. In alcoholic and late-nset idiopathic pancreatitis, exocrine insufficiency de-elops earlier than in early onset idiopathic pancreati-is9,10,15; in alcoholic CP, pancreatic insufficiency canevelop as early as 6 years after the onset of disease.10

imilarly, endocrine insufficiency occurs earlier in alco-olic pancreatitis with a median time of 8 years, com-ared with 27 years in early onset idiopathic pancreatitis.n tropical pancreatitis, both exocrine and endocrine in-ufficiency is reported to be evident at very early stages,ften at the time of presentation in the majority (70%) ofatients.4

With respect to the progression of pancreatic insuffi-iency over time, there are conflicting data. Studies byankisch et al12 and other groups16 –18 described nohange or even slight improvements in pancreatic func-ion over time in patients with CP. In contrast, Mull-
aupt et al10 reported a progressive deterioration of pan-

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April 2007 CHRONIC PANCREATITIS 1559

reatic function during a median follow-up period of 16ears in patients with alcoholic pancreatitis. The reasonsor these discrepant findings are unclear, but may reflectifferences in study design, duration of follow-up evalu-tion, and/or differences in the sensitivities of the testssed to assess pancreatic function.The course of the pain of CP is unpredictable in indi-

idual patients. However, in general, pain is reported tomprove or resolve with time in the majority of patientsith CP. In this regard, Mullhaupt et al10 reported that40 of 251 patients (95.6%) with alcoholic pancreatitischieved pain relief after a median time of 10 yearsrange, 0 –30 y) and that, in the majority of patients, thisain relief coincided with the onset of exocrine andndocrine pancreatic insufficiency (pancreatic “burn-ut”). However, other earlier series reported no correla-ion of pain relief with pancreatic insufficiency.9,12 Absti-ence from alcohol is another important factor

nfluencing pancreatic dysfunction and pain in patientsith alcoholic CP. Abstainers have a slower rate of dete-

ioration of pancreatic function and a better response toain therapy than nonabstainers.10,15,19,20

The risk of developing pancreatic cancer is significantlyigher in patients with CP than in the general popula-ion.21 Alcoholic CP and tropical pancreatitis are associ-ted with a 15-fold and a 5-fold increased risk of pancre-tic cancer, respectively,21,22 whereas the cumulativeifetime risk of cancer in patients with hereditary pancre-titis is reported to be as high as 40%.21

Mortality in CP, particularly alcoholic pancreatitis, ispproximately one-third higher than that in an age- andex-matched general population.23 However, only onefth of this excess mortality can be attributed directly toancreatitis itself. Most of the deaths in CP are caused by

igure 1. Necrosis-fibrosis concept of progressive pancreatic injury.epeated attacks of acute pancreatic necroinflammation result in in-reasing residual damage to the pancreas, eventually resulting in irre-ersible damage to the gland, characterized by acinar atrophy andbrosis.

he effects of alcohol and/or smoking on the liver, lungs, a

nd digestive system. In their recently reported series oflcoholic and idiopathic CP patients, Mullhaupt et al10

eported that the 3 major causes of death were cardio-ascular disease, severe infection, and malignancy.

Pathogenesis of Chronic PancreatitisResearch into the pathogenesis of CP was initially

ocused on large and small pancreatic ducts and then onhe pancreatic parenchymal and nonparenchymal cells.n more recent times, the genetics of CP has attractedonsiderable attention and has revolutionized our knowl-dge of the possible mechanisms mediating pancreaticnjury (this topic is discussed in more detail later in theection titled “Genetics of Chronic Pancreatitis”). The

ajority of studies related to the pathogenesis of CP haveocused on alcohol-induced CP. (The focus on alcohol inhis article reflects the large amount of available scientificiterature on the topic. Relatively little is known abouthe pathogenesis of acute episodes in tropical or autoim-

une pancreatitis, although there is a growing body ofiterature dealing with autodigestive injury in hereditarycute pancreatitis.) This is not surprising, given thatlcohol abuse is the most common association of CP.raditionally, alcoholic pancreatitis has been thought ofs a form of CP from the start, punctuated during itsourse by acute exacerbations. This notion was based ontudies showing that histologic and radiologic evidencef CP was evident in the pancreas of many patients at theime of their first attack of pancreatitis.24,25 Furthermore,utopsy studies had reported evidence of pancreatic fi-rosis in alcoholics with no clinical history of pancreati-is.26 However, this concept has been challenged in recentears, with current opinion favoring the necrosis-fibrosisypothesis that alcoholic pancreatitis begins as an acuterocess that progresses to chronic irreversible damage asresult of repeated acute attacks (Figure 1).The necrosis-fibrosis concept is supported by both

linical and experimental data. A large prospective studyas reported that clinical manifestations of CP (exocrinend endocrine dysfunction) were more likely to occur inlcoholics with frequent clinical recurrent acute at-acks.10,15 In addition, a postmortem study of patientsith fatal acute alcoholic pancreatitis has shown that in3% of patients there was no evidence of chronic changes

n the pancreas.27

Experimental evidence in support of the necrosis-fibro-is hypothesis has accumulated rapidly in recent yearsnd suggests that this concept is applicable not only tolcoholic CP but also to non–alcohol-related pancreatitissuch as hereditary and tropical pancreatitis), in whichhe clinical course is punctuated with recurrent attacks ofancreatic necroinflammation. Animal models of pancre-tic fibrosis have now been developed by inducing re-eated episodes of acute necroinflammation in the pan-reas using an inhibitor of superoxide dismutase28 or by
dministration of supraphysiologic doses of cerulein

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ith or without other measures such as ethanol admin-stration or pancreatic duct obstruction.29,30 Most re-ently, Vonlaufen et al31 have demonstrated that repeatedancreatic necroinflammation induced by endotoxin ad-inistration in alcohol-fed animals leads to the changes

f CP within the gland. The molecular mechanisms re-ponsible for pancreatic fibrosis after necroinflammatorypisodes now are understood better, largely due to theharacterization of the cells that play a critical role in thebrogenic process, namely, the pancreatic stellate cells

PSCs; see below).

Alcohol-Induced Pancreatic InjuryStudies in the field of alcoholic pancreatitis often

ave been hampered by the lack of suitable animal mod-ls of the disease and the difficulty in obtaining humanancreatic tissue for analysis. Nonetheless, significantdvances have been made in recent years, particularlyith respect to the direct toxic effects of alcohol on theancreatic acinar cell, which may predispose the gland toecroinflammation and the role of PSCs in the produc-ion of pancreatic fibrosis.

Investigations into the pathogenesis of alcoholic pan-reatitis usually have followed 1 of 2 approaches, basedn 2 fundamental clinical observations. One observation

s that the incidence of alcoholic pancreatitis is propor-ional to the level of alcohol consumption, suggestinghe presence of dose-related effects of alcohol on theancreas.32–34 The other observation is that only a mi-ority of alcoholics develop pancreatitis, suggesting thatn additional cofactor or susceptibility factor is requiredo trigger overt disease.35,36

Constant Effects of Alcohol on the PancreasEffect of alcohol on large ducts. Early research

fforts in this area (inspired by Opie’s37 observationsegarding the mechanism responsible for gallstone pan-reatitis) were focused on the effects of alcohol on largeucts and, in particular, the sphincter of Oddi (SO). The

arge-duct theories (biliary-pancreatic reflux, duodeno-ancreatic reflux, and the stimulation-obstruction the-ry) postulated that altered motility of the SO in re-ponse to alcohol administration played a central role inhe development of the disease. However, unresolvedontroversy about the effects of alcohol on SO functionnd pancreatic secretion means that these theories re-ain of doubtful relevance to the pathogenesis of alco-

olic pancreatitis (see review by Apte et al38).Effect of alcohol on small ducts. In the 1970s,

esearchers shifted their focus from large to small pan-reatic ducts, mainly as a result of the work of Sarles,39,40

ho proposed that alcoholic pancreatitis was caused byhe precipitation of secreted pancreatic proteins withinmall pancreatic ducts, leading to acinar atrophy andbrosis. The protein plug theory often has been ques-
ioned because of the lack of clear evidence that protein p
recipitation within pancreatic ducts precedes acinaramage. However, recent reports of an association be-ween mutations of the cystic fibrosis transmembraneonductance regulator (CFTR) gene (which affect ductell function) and the risk of developing idiopathic CPave revived interest in the possible role of ductularysfunction in pancreatic injury.41,42 The association be-ween CFTR mutations and alcoholic pancreatitis is atresent uncertain. Nonetheless, the possibility that theuct cell (in addition to the acinar cell) is an importantite of alcohol-induced injury cannot be discounted. Inhis regard, it is of interest to note that as early as in965, Sarles et al43 had reported that patients with alco-olic pancreatitis manifested increased levels of sweatlectrolytes (chloride and sodium), suggesting CFTR dys-unction in this disease.

There is some evidence to suggest that chronic alcoholonsumption facilitates protein plug formation withinancreatic ducts. This includes: (i) increased total proteinoncentration of pancreatic juice in alcoholics44; (ii) anncreased capacity of acinar cells to synthesize lithos-athine on alcohol exposure45 (lithostathine is a knownonstituent of protein plugs with a propensity for pre-ipitation); and (iii) an alcohol-induced decrease in acinarontent of glycoprotein GP246 (possibly because of in-reased secretion into pancreatic juice); this glycoproteinas unique self-aggregating properties and is an impor-ant constituent of protein plugs. Thus, it is possible thatlockage of small intralobular ducts by protein precipi-ates hinders acinar cell secretion, thereby blocking thexit of digestive enzymes and predisposing the cell tocute autodigestive injury (see below).

Effect of alcohol on pancreatic acinar cells. Overhe past 3 decades, the focus of research in alcoholicancreatitis has shifted from pancreatic ducts to theancreatic acinar cell itself. This focus is understandableiven that the cells produce large amounts of digestivenzymes (6 –20 g/day), with the potential to cause con-iderable tissue damage. The acinar cell is normally pro-ected from digesting itself by synthesizing most zymo-ens as inactive precursors, by segregating zymogens intoembrane-bound organelles, and by intracellular anti-

roteases. Disruption of these normal protective mecha-isms results in premature intracellular activation ofigestive enzymes, leading to autodigestive injury.rypsinogen can be autoactivated or activated by the

ysosomal enzyme cathepsin B.47 Active trypsin, in turn,an activate other pro-enzymes and trigger a digestivenzyme activation cascade within the cell.

Evidence to support a role for digestive enzymes inancreatitis comes from several in vitro and in vivo stud-

es (see Apte et al48 for a review), but perhaps the mostompelling evidence to date in support of this theory haseen provided by the identification of mutations in theationic trypsinogen gene in patients with hereditary
ancreatitis. As detailed later in the section on Genetics

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f Chronic Pancreatitis, 2 mutations in particularR122H and N29I) are known to be gain-of-function

utations, resulting in the synthesis of an altered formf trypsin that is resistant to inactivation.2,3,49 A role forigestive enzymes also has been invoked for pancreatitiselated to hypercalcemia (via trypsinogen activation andrypsin stabilization) and tobacco smoking (via reducedrypsin inhibitory capacity).3

Effect of Alcohol on Pancreatic EnzymesSeveral studies have indicated that chronic alco-

ol administration produces changes in the acinar cell,hich may favor premature activation of digestive en-

ymes. Apte et al50 have shown that messenger RNAmRNA) levels and protein content of the digestive en-ymes trypsinogen, chymotrypsinogen, and lipase, as wells the lysosomal enzyme cathepsin B, is increased in theancreas of alcohol-fed rats. This increase in enzymeontent is accompanied by an increase in the fragility ofhe organelles that contain these enzymes (zymogenranules and lysosomes, respectively).51,52 The effect oflcohol on lysosomal fragility is thought to be mediatedy cholesteryl esters and fatty-acid ethyl esters53,54 (sub-tances known to accumulate in the pancreas afterhronic alcohol consumption55,56). The mechanism re-ponsible for the alcohol-induced increase in zymogenranule fragility is unclear, but a study by Apte et al46

uggests that it may be a consequence of reduced GP2evels in zymogen granule membranes since this glyco-rotein is known to determine the shape and stability ofymogen granules. Alcohol-induced oxidant stress maye another factor that plays a role in lysosomal andymogen granule membrane destabilization (see below).he net effect of the alcohol-induced increase in digestivend lysosomal enzyme content in the presence of de-reased stability of the corresponding organelles woulde an increased likelihood of contact between lysosomalnd digestive enzymes, thereby leading to premature in-racellular activation of digestive enzymes and autodiges-ive injury to the gland.

Alcohol Metabolism by Pancreatic AcinarCellsTaking their cues from studies of ethanol-induced

iver toxicity, researchers postulated that ethanol may beetabolized by the pancreatic acinar cell to generate

oxic metabolites that may mediate the changes in theubcellular organelles described above. Indeed, in vitrotudies with cultured acinar cells and isolated acini haveow shown convincingly that the pancreas metabolizesthanol via both the oxidative and nonoxidative path-ays, generating the metabolites acetaldehyde and fattycid ethyl esters (FAEEs), respectively (see review by Wil-on and Apte57). Enzymes catalyzing ethanol oxidationalcohol dehydrogenase, cytochrome P4502E1, and cata-
ase) and nonoxidative ethanol metabolism (FAEE syn- t
hase) have been identified in the pancreas. Furthermore,xidant stress has been shown to occur in both humannd rat pancreas after ethanol exposure, most likely be-ause of increased production of reactive oxygen speciesknown by-products of ethanol oxidation) and decreasedntioxidant defenses.

Effect of Toxic Metabolites of EthanolAcetaldehyde, FAEEs, and reactive oxygen species

ll have been shown to cause deleterious effects on theancreatic acinar cell (see review by Apte et al38). Acetal-ehyde causes morphologic damage to both rat and dogancreas and also has been reported to inhibit stimulatedecretion from isolated pancreatic acini. Oxidant stress

ay contribute to the destabilization of zymogen gran-les and lysosomes observed in ethanol-fed rats (notedarlier). FAEEs also have been shown to damage theancreas and its subcellular organelles. As reviewed com-rehensively by Apte et al,58 infusion of FAEEs in rats

eads to pancreatic edema, acinar vacuolization, andrypsinogen activation, and to increased extracellular ma-rix protein levels (a finding that may have relevance tohe development of alcohol-induced pancreatic fibrosis).ome of the intracellular signaling molecules that maylay a role in ethanol-induced acinar cell toxicity haveow been identified. Gukovskaya et al59 have shown thatthanol, acetaldehyde, and FAEEs modulate the levels ofranscription factors nuclear factor �B and activator pro-ein-1 in parenchymal (acinar) cells, which in turn regu-ate the expression of cytokines that mediate pancreaticecroinflammation. More recently, FAEEs also have beenhown to cause a sustained increase in the second mes-enger Ca�� within acinar cells, an effect that is thoughto result in mitochondrial depolarization and celleath.60

Effect of Alcohol on PancreaticMicrocirculationAn aspect of pancreatic physiology that until re-

ently largely had been ignored with respect to the patho-enesis of alcoholic pancreatitis is the microcirculationf the gland. However, 2 recent studies have shown thatcute on chronic ethanol administration to rats signifi-antly decreased pancreatic perfusion.61,62 This effect wasssociated with an increase in leukocyte adhesion andncreased expression of adhesion molecules and cyto-ines in the pancreas. These studies suggest that ethanol-

nduced disturbances in pancreatic microcirculation mayontribute to the processes of pancreatic injury, but fur-her work is required to confirm and characterize theseffects.

Individual Susceptibility to AlcoholicPancreatitisAs seen from the preceding discussion, it is clear

hat alcohol exerts direct, constant, and toxic effects on

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he pancreas that predispose the gland to autodigestionnd necroinflammation. This is most likely the case in allersons who drink heavily. However, as alluded to earlier,

t also is clear that only a minority of heavy drinkersevelop acute pancreatitis, indicating that an additional

nsult or second hit is required to precipitate a clinicalttack of pancreatitis. The search for this trigger factor/ofactor/susceptibility factor has prompted numeroustudies over the past 2 decades, with a number of possibleandidate factors scrutinized. These have included diet,mount and type of alcohol consumed, the pattern oflcohol consumption, hyperlipidemia, and smoking (seeaber et al63 for review). As discussed in a recent review,

he role of smoking in alcoholic pancreatitis is particu-arly controversial.64 Several inherited factors have alsoeen studied (as discussed later in the section on Genet-

cs of Chronic Pancreatitis). Therefore, it is somewhatisappointing that despite the extensive search, the fac-or(s) that unequivocally confer(s) increased susceptibil-ty to alcoholic pancreatitis remain(s) unknown. Thereemain candidate factors that have not yet been exam-ned fully, including polymorphisms of proteins relevanto cellular antioxidant defenses and polymorphisms oflcohol-metabolizing enzymes, particularly FAEE syn-hases, minor CF mutations, and environmental factorsuch as bacterial endotoxin.

Experimentally, putative triggers that have been exam-ned for alcoholic pancreatitis include the secretagogueholecystokinin (CCK) and bacterial endotoxin. There isome evidence that prior alcohol administration sensi-izes rodent pancreas to injury by supraphysiologic levelsf CCK,30,65 but the clinical relevance of CCK as a triggeractor has to be questioned. In human beings CCK iseleased only in picomolar quantities after meals, there-ore it is difficult to envisage a situation in which abnor-

ally high levels of CCK would be released into theirculation to trigger pancreatitis in alcoholics.

In contrast to CCK, endotoxin represents a more plau-ible, physiologically relevant, trigger factor for alcoholicancreatitis. This is because: (i) increased gut permeabil-

ty with translocation of gram-negative bacteria (such asscherichia coli) across the mucosal barrier is known toccur after chronic alcohol intake in both human beingsnd experimental animals66,67; (ii) plasma lipopolysaccha-ide (LPS, an endotoxin that is a component of bacterialell walls) levels have been shown to be significantlyigher in drinkers (either after chronic alcohol intake orsingle binge) compared with nondrinkers68; and (iii)

ndotoxemia is known to be predictive of the severity ofcute pancreatitis (regardless of cause). It is of interest,herefore, that a recent study by Vonlaufen et al31 showedignificant pancreatic necroinflammation in alcohol-fedats injected with 1 dose of LPS, and more importantly,he development of progressive injury as evidenced byancreatic fibrosis in alcohol-fed rats challenged with
epeated doses of LPS. e
Progression of Acute Pancreatitis to ChronicPancreatitisAs noted earlier, it now is generally accepted that

he development of CP is the result of progressive (ac-rued) pancreatic damage after recurrent episodes of pan-reatic necroinflammation. A few years ago, Schneidernd Whitcomb69 proposed the sentinel acute pancreatitisvent hypothesis to explain the progression to CP. Theyostulated that the “sentinel” event in this disease is aout of acute pancreatic injury, which makes the glandarticularly vulnerable, in the recovery phase, to addi-ional insults such as alcohol, metabolic stress, and oxi-ative stress.Research efforts toward elucidating the molecularechanisms of CP, particularly pancreatic fibrosis, were

iven significant impetus with the identification, isola-ion, and characterization of stellate cells in the pancreasreviewed by Apte et al38,70). PSCs are similar morpholog-cally to hepatic stellate cells, the principal effector cellsn liver fibrosis.71 It is now established that activatedSCs play a key role in the fibrogenic process in CP viaheir ability to regulate both the synthesis and degrada-ion of the extracellular matrix proteins that comprisebrous tissue.38,70

Evidence from both clinical and experimental studiesndicates a role for PSCs in ethanol-induced pancreaticbrosis (see Apte et al38 for review). In vivo studies ofissue from human beings with alcoholic pancreatitis androm animals with experimental pancreatic fibrosis havehown the presence of activated PSCs in areas of fibrosis.n vitro studies have established that PSCs are activatedirectly by ethanol and acetaldehyde as assessed by in-reased extracellular matrix (ECM) protein production byhe cells. Of particular interest is the observation that ratSCs show alcohol dehydrogenase activity, indicatinghat, apart from parenchymal (acinar) cells, ethanol alsoan be metabolized by nonparenchymal cells in the pan-reas. Activation of PSCs by ethanol can be completelynhibited by the alcohol dehydrogenase (ADH) inhibitor-methylpyrazole, indicating that ethanol-induced PSCctivation likely is mediated by its oxidative metabolite,cetaldehyde. Furthermore, both ethanol and acetalde-yde cause oxidant stress within cultured PSCs and,

mportantly, incubation of PSCs with ethanol or acetal-ehyde in the presence of the antioxidant vitamin Erevents the activation of PSCs by the 2 compounds.hese findings suggest that ethanol-induced PSC activa-

ion is most likely mediated by its metabolism (via ADH)o acetaldehyde, and the subsequent generation of oxi-ant stress within the cells. Interestingly, the observa-ions by Vonlaufen et al31 of pancreatic fibrosis in alco-ol-fed rats challenged with LPS are strongly supportedy the in vitro findings of a synergistic effect of alcoholnd LPS on PSC activation.

During prolonged heavy alcohol intake, PSCs could be
xposed not only to ethanol and its metabolites and LPS,

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ut also to proinflammatory cytokines released duringpisodes of ethanol-induced pancreatic necroinflamma-ion. Cytokines such as tumor necrosis factor �, interleu-ins 1 and 6, monocyte chemotactic protein, transform-

ng growth factor �, platelet-derived growth factorknown to be up-regulated during acute pancreatitis)ach have been reported to activate PSCs in vitro.38 Ofarticular note is that PSCs are themselves capable ofynthesizing cytokines, and endogenous cytokine pro-uction by the cells is stimulated by factors such asthanol, acetaldehyde, and other cytokines.72,73 These ob-ervations suggest that, in addition to paracrine path-ays of activation, PSCs also may be activated in anutocrine manner (via endogenous cytokines), whichould cause perpetuation of cell activation, even whenhe initial trigger factors are no longer present. Suchersistent PSC activation may potentiate ECM produc-ion by the cells, eventually causing pancreatic fibrosis.

From the above, it is apparent that during chroniclcohol consumption, PSCs are likely to be activated by 2athways operative in vivo—the necroinflammatory path-ay (via cytokines) and the nonnecroinflammatory path-ay (direct effects of ethanol and its metabolites andxidant stress). The identification of a nonnecroinflam-atory pathway of stellate cell activation implies that

issue necrosis or inflammation may not be an absolutererequisite for the stimulation of fibrogenesis in theancreas during alcohol abuse.

Pathogenesis of Autoimmune Pancreatitis

Autoimmune pancreatitis (AIP) is a relatively un-ommon, non–alcohol-related form of CP that has re-eived increasing attention in recent years. Only about50 cases worldwide have been reported to date (theajority being from Japan).7 Autoimmune pancreatitis is

haracterized by the presence of (i) increased serum gam-aglobulin levels (particularly IgG4); (ii) the presence of

utoantibodies (antinuclear antibodies, antilactoferrinntibodies, anticarbonic anhydrase antibodies, and rheu-atoid factor); (iii) pancreatic fibrosis with lymphocytic

nfiltration and an absence of pancreatic calcification; (iv)n association with other autoimmune diseases; and (v)esponse to steroid therapy. The majority view of pancre-tologists is that AIP does not present as acute attacks.owever, Takayama et al74 reported that a third of AIPatients on prednisolone therapy in their series sufferedrom recurrent attacks of acute pancreatitis over a me-ian follow-up period of 54.5 months. The pathogenesisf this disease remains largely unknown but from clinicalnd experimental studies it is postulated that aberrantLA-DR expression (in AIP HLA-DR expression has been

ound on pancreatic ductal and acinar cells) leads to theresentation of autoantigens to lymphocytes, resulting in
n autoimmune response. a
Genetics of Chronic PancreatitisMore than 50 years ago, it was recognized for the

rst time that CP may cluster in selected families, sug-esting an inherited disease in these patients.75 The un-erlying genetic defect, however, remained obscure forore than 4 decades. As stated in this first report on

nherited pancreatitis, “hereditary chronic relapsing pan-reatitis does not present earmarks which distinguish itrom nonhereditary chronic relapsing pancreatitis.”75 In0%–30% of patients suffering from CP, no apparentnderlying cause, including heredity, can be identified.ecent research indicates that a significant percentage of

hese patients with so-called idiopathic CP may also have aenetic basis for their condition. The section below de-ineates the different genes involved in the pathogenesisf hereditary or idiopathic pancreatitis, the impact ofhese genetic discoveries on other types of CP such aslcohol-related CP and tropical calcific pancreatitis, andhe implications for disease pathogenesis.

Cationic Trypsinogen (PRSS1)In 1896, Chiari76 postulated that pancreatitis re-

ults from autodigestion of the gland. An inappropriateonversion of pancreatic zymogens to active enzymesithin the pancreatic parenchyma was proposed to ini-

iate the inflammatory process. A key role has been at-ributed to the activation of trypsinogen to trypsin, con-erting all proteolytic proenzymes to their active form.hree different trypsinogens have been described inuman pancreatic juice and have been designated, ac-ording to their electrophoretic mobility, as cationicrypsinogen (PRSS1), anionic trypsinogen (PRSS2), and

esotrypsinogen (PRSS3). Compared with the anionicsoenzyme, the cationic trypsinogen autoactivates moreasily and is more resistant to autolysis.

By linkage analysis, several groups located a gene forereditary pancreatitis on the long arm of chromosome

(7q35). Subsequently, a mutation in the cationicrypsinogen gene, also referred to as serine protease 1PRSS1) (OMIM 276000), was identified as 1 of severalossible underlying defects. In 5 families, a c.365G�Aransition leading to a substitution of arginine by histi-ine at residue 122 (p.R122H) segregated with the dis-ase.77 R122H appears to be the most common PRSS1utation observed worldwide. Subsequent studies have

eported other PRSS1 alterations including p.A16V,.N29I, p.N29T, p.R116C, and p.R122C, as well as severalthers, in families with suspected hereditary pancreatitisr in patients without a family history (for detailed in-ormation of the different variants see: www.uni-leipzig.e/pancreasmutation). The functional relevance ofRSS1 mutations has been examined by studies usingecombinant cationic trypsinogen subjected to site-di-ected mutagenesis. Mutations such as N29I and R122Hnhance trypsinogen autoactivation; R122H also inhibits
utolysis of the active enzyme.78,79 Thus, gain-of-function
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utations leading to enhanced intrapancreatic trypsino-en activation may be the common initiating step ofancreatitis caused by PRSS1 mutations, whereas stabili-ation of trypsin may be an accessory mechanism.

Two PRSS1 variants, p.E79K and p.A16V, displaynique features: E79K trypsinogen does not alter cata-

ytic activity or autolysis of trypsin, nor does it influencenhibition of its activity by the trypsin inhibitorPINK1. However, it activates anionic trypsinogen,RSS2, at least 2-fold better than wild-type cationicrypsin. Thus, E79K can lead to increased trypsinogenctivation by transactivation of PRSS2 instead of au-oactivation,80 but its pathogenic relevance remains toe elucidated because this variant also has been found

n healthy controls. Recombinant A16V also has noffect on trypsinogen activation. Instead, it increasesby 4-fold) the rate of activation peptide processing

ediated by chymotrypsin C, resulting in acceleratedrypsinogen activation in vitro.81 In contrast to R122Hnd N29I, which display a penetrance of 70%– 80%,16V is found almost exclusively in patients without a

amily history of pancreatitis.82 Recently, a triplicationf an approximately 605-kb segment containing PRSS1nd PRSS2 was reported in 5 families with hereditaryancreatitis.83 Thus, besides point mutations, a gain ofrypsin through a gene-dosage effect also may contrib-te to the disease pathogenesis. The importance ofRSS1 mutations as pathogenic mediators in heredi-ary pancreatitis is supported by a recent study using aransgenic mouse model expressing mutant R122H

ouse trypsinogen. The pancreas of these mice dis-layed early onset acinar injury, inflammatory cell in-ltration, and enhanced response to cerulein-inducedancreatitis. With progressing age, pancreatic fibrosisnd acinar cell dedifferentiation developed.84

Anionic Trypsinogen (PRSS2)Because increased proteolytic activity caused by

utated PRSS1 enhances the risk for CP, it was thoughthat mutations in the anionic isoenzyme PRSS2 (OMIM01564) also may predispose to disease. Notably, how-ver, a recent study indicated that the PRSS2 mutationay be a protective factor against CP. A recent study

eported a c.571G�A transition resulting in substitutionf glycine by arginine at codon 191 (p.G191R), which wasound in 220 of 6459 (3.4%) controls but only in 32 of466 (1.3%) patients (odds ratio, 0.37; P � 1.1 � 10-8).85

urther analyses showed that patients (with hereditary,diopathic, and alcoholic pancreatitis) with G191R weref an older age than those without the protective variant.

In vitro studies showed that recombinant G191R pro-ein, on activation by enterokinase or trypsin, showed aomplete loss of trypsin activity due to the introductionf a novel tryptic cleavage site that renders the enzymeypersensitive to autocatalytic proteolysis. Thus, it ap-
ears that the G191R PRSS2 variant mitigates intrapan- c
reatic trypsin activity, thereby playing a protective rolegainst CP. Although the overall contribution of G191Ro disease pathogenesis is low, the functional character-zation of G191R provides the first example in pancreati-is for a disease-protective genetic variant.

Serine Protease Inhibitor, Kazal Type 1(SPINK1)The serine protease inhibitor, Kazal type 1

SPINK1) (OMIM 167790), also known as pancreatic secre-ory trypsin inhibitor, is thought to be a potent inhibitor ofntrapancreatic trypsin activity. SPINK1 was first isolatedn the bovine pancreas by Kazal et al in 1948.86 It pos-esses a reactive site that serves as a specific target forrypsin. However, trypsin inhibition by SPINK1 is onlyemporary because the trypsin-SPINK1 complex itselferves as a substrate for trypsin, resulting in the subse-uent degradation of the inhibitor molecule and resto-ation of the original trypsin activity.87

The focus on SPINK1 mutations as possible pathoge-etic factors in pancreatitis was the result of the knowl-dge that a significant number of hereditary pancreatitisatients do not show a PRSS1 mutation, indicating thatefects in other genes might be involved in disease patho-enesis. It was hypothesized that, in addition to gain-of-unction mutations in PRSS1 as a cause of pancreatitis,P also may be a result of “loss-of-function” mutations

n pancreatic trypsin inhibitors. A mutation in thePINK1 gene (a c.101A�G transition leading to substi-ution of asparagine by serine at codon 34 [p.N34S]) haseen found in 18 of 96 unrelated pediatric pancreatitisatients; 6 patients were homozygous for this muta-ion.88 No phenotypic differences between heterozygousnd homozygous N34S patients were detected. This as-ociation between N34S and CP has now been confirmedy several other studies.

N34S is found mostly in patients without a familyistory of CP: 15%– 40% of patients with so-called idio-athic CP carry N34S on 1 allele or on both alleles. Datarom 8 large studies in Europe and the United Statesndicate that 12.6% of patients with CP are heterozygousnd 3.6% are homozygous for N34S, whereas only 1.9% ofontrols are heterozygous for this variant. Interestingly,he N34S mutation also has been reported in about halfhe patients with tropical calcific pancreatitis from In-ia.89 The pathogenic action of N34S, however, remainslusive. Recombinant N34S mutated human SPINK1oes not show any altered trypsin inhibitor capacity.90 It

s worth noting that N34S is in complete linkage disequi-ibrium (LD) with 4 other intronic sequence variants:.56-37T�C, c.87�268A�G, c.195-604G�A, and c195-6_-65insTTTT.88 Thus, it may be speculated that it isne of these intronic alterations and not N34S itself that

s the pathogenic relevant mutation.The second most common SPINK1 mutation,

.194�2T�C, affects position 2 of the splice donor site

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n the third intron, which is highly conserved in eu-aryotes. Analysis of mutated mRNA shows a truncatedPINK1 because exon 3 is skipped.91 Several otherPINK1 alterations have been described in recent years,ainly in single patients or families only (for detailed

nformation of the different variants see: www.uni-eipzig.de/pancreasmutation). With the exception of aew mutations that strongly suggest a loss of function byestruction of the ATG initiation codon (c.2T�C) or byhift of reading frame with premature terminationc.27delC, c.98dupA), the functional consequences of

ost variants are unknown. Recently, expression studiesf 2 dominant inherited mutations affecting the signaleptide, c.41T�C (p.L14P) and c.41T�G (p.L14R), re-orted a rapid intracellular degradation of the mutant

nhibitor molecules leading to abolished SPINK1 secre-ion.92 Similar to and perhaps even more pronouncedhan for PRSS1, SPINK1 mutations display a markedariability of penetrance and inheritance pattern. Someariants that are likely to lead to complete functional lossf the mutated allele such as c.2T�C, c.27delC, or codon4 mutations, appear to follow a dominant trait, whereashe N34S variant appears to be a recessive or complexrait.

The role of SPINK1 in pancreatitis has been evaluatedecently in 2 genetically engineered animal models.ransgenic expression of rat Spink1 in mice, which leads

o an increased endogenous trypsin inhibitor capacity by90%, significantly reduced the severity of cerulein-in-uced pancreatitis,93 while targeted disruption of Spink3

the murine homologue of human SPINK1) resulted inutophagic degeneration of acinar cells, impaired regen-ration, and death within 2 weeks after birth.94 In theatter model, enhanced tryptic activity was detected inancreatic acini prepared 1 day after birth.95

Cystic Fibrosis Transmembrane ConductanceRegulator (CFTR)Cystic fibrosis transmembrane conductance regu-

ator (CFTR) is an apical membrane chloride channelritical for fluid and electrolyte secretion in the respira-ory and digestive tracts. In the pancreas, CFTR is local-zed to centroacinar and proximal ducts and regulatesuctal bicarbonate secretion. Abnormal CFTR functions a result of CFTR gene mutations is associated with CF,n autosomal-recessive disease characterized by pulmo-ary dysfunction and pancreatic insufficiency. A minorityf CF patients suffer from recurrent pancreatitis. In 1998,studies described an association between idiopathic CP

nd mutations in the CFTR gene (OMIM 602421).96,97

ne study tested 134 patients with CP, including 60atients with idiopathic and 71 patients with alcohol-

nduced disease, for 22 mutations.97 Eighteen patients13.4%), including 12 with idiopathic CP (20%), wereeterozygous for a CFTR mutation. The frequency of
FTR mutations in alcohol-related CP was twice what o
as expected and in idiopathic CP it was 4 times asxpected. In the other study, 17 CFTR mutations in 27atients with idiopathic CP were investigated.41 Sevenatients (25.9%) had at least 1 CFTR mutation and 1atient was compound heterozygous. The frequency ofFTR mutations in idiopathic CP was 6 times higher

han expected. However, both these studies only investi-ated the most common of the approximately 1000 CFTRutations that now have been described. Subsequent

tudies analyzing the complete CFTR coding sequence asell as PRSS1 and SPINK1 in idiopathic CP patients

ound that 25%–30% of patients carried at least 1 CFTRutation, but that only a few patients were compound

eterozygous.98,99 Thus, idiopathic CP actually may rep-esent “atypical” cystic fibrosis caused by the combina-ion of 2 mild or of 1 mild and 1 severe CFTR mutation.everal CP patients, however, were transheterozygous forCFTR alteration and a SPINK1 or PRSS1 variant, illu-inating the significance of the combination of muta-

ions in different genes in disease pathogenesis.98,99

Alcoholic PancreatitisThe association between alcohol abuse and pan-

reatitis is well established, but individual susceptibilityo alcohol varies widely and only a minority of heavyrinkers develop CP. Increasing evidence portends thatdditional environmental or genetic cofactors are neces-ary, which are mostly unknown. Several studies investi-ating PRSS1, pancreatitis associated protein, �1-antit-ypsin, CFTR, cytokeratin 8, major histocompatibilityomplex antigens, and alcohol metabolizing or detoxify-ng enzymes have yielded negative or conflicting results.

Since xenobiotic-mediated cellular injury is thought tolay a role in the pathogenesis of alcoholic CP, geneticariations reducing the activity of detoxifying biotrans-ormation enzymes have also been examined. Recently, aow detoxification activity allele of the UDP-glucurono-yltransferase 1A7, UGT1A7*3, was linked to pancreaticancer and alcoholic CP.100 However, a subsequent studyould not confirm these findings.101

In a large multicenter study, an association betweenutated SPINK1 and alcoholic CP was described: the34S mutation was found in 16 of 274 (5.8%) patientsith alcoholic CP, but only in 4 of 540 (0.8%) healthy

ontrol individuals and 1 of 98 (1.0%) alcoholic controlsithout CP.102 Subsequent studies have reported an34S frequency in alcohol-related CP of around 6%.ost recently, the protective PRSS2 variant, G191R (see

elow), was reported to be significantly less common inatients with alcoholic CP compared with healthy con-rols (5 of 609 [0.8%] vs 220 of 6459 [3.4%]; P � .0001).85

In summary, recent advances in the field of genetics ofP have substantially improved our understanding of theisease (Figure 2). For a long time, hereditary pancreatitisas thought to be a rare disorder. However, the findings
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o-called idiopathic CP indicate that cases of inherited CPre much more common than originally envisioned.hese data challenge the differentiation between “hered-

tary” and “idiopathic” pancreatitis. Different mutationsn different genes might lead to different phenotypicresentations and inheritance patterns, and even theame mutation in the same gene might have differentonsequences depending on the individual’s geneticackground and environmental factors. The discovery ofPINK1 mutations in other types of CP such as tropicalalcific pancreatitis and alcohol-induced CP further blurshe borders between the particular CP subtypes. It isnticipated that the identification of other genes involvedn the pathogenesis of inherited CP will also enhance ournowledge about more common types of CP such aslcoholic or tropical CP. Future research most likely willeveal a very complex interaction between various envi-onmental and genetic factors, with flowing transitionsmong these subtypes (Figure 3).

Current Concept of the Pathogenesis ofChronic PancreatitisThe clinical and experimental evidence (largely

ased on alcohol-related studies) has led to the followingoncept for the pathogenesis of CP (Figure 4).

The pancreas may be rendered susceptible to autodi-estive injury, either because of abnormal trypsin activa-ion/inactivation mechanisms (as in hereditary, meta-olic, and tropical pancreatitis) or because of the effectsf toxins such as ethanol (via its metabolites and itsetabolic by-products) on digestive and lysosomal en-

yme content within the acinar cell and on the stability of

igure 2. Role of digestive enzymes in pancreatitis. (A) Normal pancrearenchyma is inhibited by SPINK1 and also by mesotrypsin or trypsin

rom activating the pancreatic enzyme cascade and autodigestion. (Broteases and their inhibitors within the pancreatic parenchyma, resultutodigestion and inflammation. Mutations in CFTR also may disturb thcidification or by defective apical trafficking of zymogen granules, thereepresent products of mutated genes. AP, activation peptide. Modified

he organelles that contain these enzymes. An appropri- h

te trigger factor (environmental or genetic) then stimu-ates overt pancreatic necrosis. Repeated episodes ofcute necroinflammation (regardless of etiology) and theelease of proinflammatory cytokines leads to the activa-ion of pancreatic stellate cells (PSCs). PSCs also arectivated directly by ethanol (via its metabolite acetalde-yde and the subsequent generation of oxidant stress).ersistent activation of PSCs leads to an imbalance be-ween extracellular matrix protein synthesis and degra-ation, eventually resulting in pancreatic fibrosis, a car-inal feature of CP.

Diagnosis of Chronic PancreatitisThe diagnosis of CP relies on relevant symp-

oms, imaging modalities to assess pancreatic struc-ure, and assessment of pancreatic function. The diag-ostic gold standard of early stage disease would be andequate surgical biopsy, which is rarely available.owever, because the primary lesions of early stage CP

re usually focal, fine-needle biopsy examinations may

igure 3. Influence of different environmental and genetic factors onhe pathogenesis of chronic pancreatitis. ACP, alcoholic chronic pancre-titis; TCP, tropical calcific pancreatitis; ICP, idiopathic pancreatitis; HP,

ypsin resulting from autoactivation of trypsinogen within the pancreaticsecond-line defense). This defense mechanism prevents the pancreascreatitis. Mutations in PRSS1 or in SPINK1 lead to an imbalance ofan inappropriate activation of pancreatic zymogens with subsequent

cate balance between proteases and antiproteases, by intrapancreaticilitating the intrapancreatic activation of digestive enzymes. Dark boxesWitt et al.85

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ield false-negative results. In the absence of definiteigns of CP, it often is difficult to differentiate earlytage disease from recurrent acute pancreatitis. For aefinitive diagnosis, a careful history and follow-upay be necessary. It is important that the assessment

f a patient with painful CP includes upper gastroin-estinal endoscopy, abdominal ultrasonography, andndoscopic retrograde cholangiopancreatographyERCP) or magnetic resonance cholangiopancreatogra-hy (MRCP) in order to detect a potentially reversibleause of pain (eg, peptic ulcer, pseudocyst, commonile duct stricture).The correlation between structural and functional im-

airment of the pancreas in CP is often poor.103 Patientsith severe exocrine insufficiency may have a largelyormal pancreatic structure and vice versa. In general,dvanced stages of CP may be diagnosed easily by imag-ng procedures such as ultrasound, computerized tomog-aphy (CT), magnetic resonance tomography, and mag-etic resonance cholangiopancreatography (MRCP). Inontrast, the diagnosis of early disease presents a consid-rable challenge.

The biochemical, structural, and functional parame-ers used to assist in the diagnosis of CP are discussed

igure 4. Current concept of the pathogenesis of chronic pancreatitis.rreversible pancreatic damage. (1) An acinar cell that is susceptible toffects of ethanol and its metabolites on subcellular organelles includingynthesis [increased mRNA] and impaired secretion) and destabilizactivation/deactivation processes. In the presence of an appropriate trig

s activated by cytokines released during pancreatic necroinflammationxcessive extracellular matrix protein production. (3) A pancreatic ducrogression. AC, acetaldehyde; CE, cholesteryl esters; L, lysosome; ZG,

elow: o

Serum ParametersIn patients presenting with pain, levels of pancre-

tic enzymes (mainly lipase) are determined in order todentify an acute episode of the disease. In patients with-ut acute attacks, reduced serum trypsinogen, lipase, ormylase levels may be found; however, the sensitivities ofhese tests are less than 60%, so none of them per se areelpful in diagnosing CP.104

Imaging ProceduresSeveral imaging procedures are available for the

valuation of CP. Transabdominal ultrasound andomputerized tomography are the most commonlysed techniques, whereas endoscopic retrogradeholangiopancreatography (ERCP), endoscopic ultra-onography (EUS), and MRCP usually are restricted topecialized centers.

Abdominal X-rayPlain abdominal x-ray has lost its place in the

odern diagnostic imaging paradigm. Nonetheless, inome cases, calcification on an abdominal x-ray whenssociated with steatorrhea can clinch the diagnosis and

e major elements of the pancreas are implicated in the development ofdigestive injury for the following reasons (depending on cause): (a) theased digestive and lysosomal enzyme content (secondary to increasedf lysosomes and zymogen granules; (b) impairment of trypsinogenctor, overt acinar cell injury is initiated. (2) A pancreatic stellate cell thatdirect effects of ethanol, its metabolites, and oxidant stress, leading toblocked by protein precipitation, which may further facilitate diseasegen granule.

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Transabdominal UltrasonographyTransabdominal ultrasonography is an inexpen-

ive technique representing the first procedure usuallyerformed in patients with suspected CP. Duct alter-tions, calcification, and cysts and are detected with highensitivity by this modality. Other complications of pan-reatitis such as duodenal or gastric distention and bileuct dilatation also may be demonstrated. In patientsith excessive abdominal gas or acute pancreatitis asso-

iated with ileus, the view is often limited, making therocedure highly related to the investigator’s skills. Nev-rtheless, sonography is a simple technique and, in theands of experienced investigators, remains a usefulethod for rapid and reliable diagnosis.

Endoscopic RetrogradeCholangiopancreatography (ERCP)ERCP is regarded as the gold standard for the

etection of CP. Typical alterations of pancreatic ductsbserved on ERCP are dilatations, stenoses, and abnor-alities of the side branches. The duct structure also may

e used to stage the disease according to the Cambridgelassification.105 However, Cambridge stage I is oftenuestioned as a reliable finding indicating CP. The most

mportant role of ERCP is the identification of structuralbnormalities such as duct stenosis, stones, or cysts thatay be amenable to interventional treatment and, the

xclusion, if possible, of pancreatic cancer. It is to beoted that ERCP eventually may be superseded by aoninvasive alternative, namely MRCP, for the diagnosisf CP.

Endoscopic Ultrasonography (EUS) andMagnetic ResonanceCholangiopancreaticography (MRCP)The role of endosonography for diagnosing early

tage CP is not well defined. The technique is regarded ashe most sensitive procedure to detect the disease. Thir-een criteria, such as reduced or increased echogenicity,ncreased lobulation, and alteration of small and largeucts, have been described.106 It is accepted that thebsence of these criteria reliably rules out CP, whereas theresence of 5 or 6 criteria strongly indicates the diagno-is.107 The significance of less than 5 criteria, however, isnclear. Apart from interobserver variability, one has toake into account the fact that a nonhomogeneous echotructure is not a specific sign for CP but also can be seenn the normal pancreas, especially in the elderly.108 Thereave been 2 follow-up studies of patients with suspectedP with a normal ERCP, but with alterations on EUS.ne study showed no alterations on ERCP during a

ollow-up period of 12–38 months,109 whereas the otheruggested a rapid progression of disease because ductalhanges were observed on ERCP after a mean follow-uperiod of 18 months in 22 of 38 patients.110 The latter
nding indicates a surprisingly rapid progression to CP. a
t present, it is still unclear what criteria may be used toiagnose mild CP reliably in patients with a normalRCP. MRCP is regarded as useful in patients at high riskf developing post-ERCP pancreatitis, with a low proba-ility of ductal alterations, or inaccessibility of the pan-reatic duct as a result of pancreatic or gastric surgery.111

Diagnosis of Pancreatic Cancer in ChronicPancreatitisAs noted earlier, patients with CP have an in-

reased risk of developing pancreatic cancer.21 Currently,o imaging procedure can reliably detect a malignantumor reliably in patients with CP. A recent study re-orted that 2-(18)F)-fluoro-2-deoxy-D-glucose positronmission tomography can differentiate between neoplas-ic and inflammatory pancreatic tumors at a sensitivity of1% and a specificity of 87%.112 However, whether-(18)F)-fluoro-2-deoxy-D-glucose positron emission to-ography is superior to traditional imaging techniques

uch as CT or magnetic resonance imaging (MRI) isuestionable because the latter also have been reported tolassify CP and pancreatic cancer correctly in 90% ofatients.

Functional StudiesThe secretin-cerulein test is regarded as the “gold

tandard” for the detection of exocrine pancreatic insuf-ciency.113 However, the procedure is only available in a

ew specialized centers and its protocol as well as itsvaluation is not well standardized. In addition, the tests time consuming and uncomfortable for the patient.herefore, less invasive alternatives have been developed

ncluding fecal elastase, lipase, or chymotrypsin; the pan-reolauryl test; the bentiromide test; and a variety ofreath tests using radiolabeled pancreatic substrates,sually triolein. However, none of these tests have beenble to meet clinical needs unequivocally. In mild oroderate pancreatic insufficiency, the sensitivity of these

ests is inadequate. It is only in severe disease that pan-reatic function tests show a high sensitivity114; however,he diagnosis of severe CP is usually obvious by other

eans, making a pancreatic function test unnecessary. Inatients with mild or moderate disease, pancreatic func-ion tests only achieve sensitivities of 50% and 65%–75%,espectively, and hence they are not very helpful in theiagnostic work-up of patients with recurrent pain ofnclear origin. Other MRI– derived tests have been de-cribed, but the majority of these studies did not assessatients with mild or moderate CP.115,116

Treatment of Chronic PancreatitisThe treatment of CP is mainly symptomatic and is

irected toward the cardinal features of pain, and exo-rine and endocrine insufficiency. A diagnosis of CP doesot necessarily require treatment because patients may be
symptomatic. However, if a precipitating factor such as

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n anatomic anomaly or a metabolic disease can be iden-ified, it may be treated by surgical or medical interven-ion. In general, the therapeutic strategies for CP includebstinence from alcohol and cigarette consumption, painelief, correction of exocrine and endocrine insufficiency,utritional support, and endoscopic or surgical interven-ion.

In alcoholic patients, the major goals of treatment areustained abstinence from alcohol and smoking, the im-rovement of compliance, and social re-integration. Mostlcoholic patients are heavy smokers and, clinically, it cane difficult to achieve abstinence from both alcohol andobacco. In a practical sense, the treating physician mayave to concede continued smoking as a trade-off forlcohol abstinence. Although the role of alcohol absti-ence in the reduction of pancreatic pain is somewhatnclear, there is evidence to indicate that deterioration ofancreatic function is slower in abstainers than in non-bstainers,9,20 and that abstainers have a better responseo pain therapy than nonabstainers. The role of smokings an causative factor in CP is controversial.64,117,118

onetheless, cigarette consumption contributes to thexcess mortality associated with the condition.

PainIn CP, abdominal pain is a serious clinical prob-

em leading to a markedly compromised quality of lifend, potentially, narcotic addiction. Treatment of painhould be started with conventional analgesics such ascetaminophen. If pain relief is not achieved, additionalrescription of opiates may be necessary. However, it is

mportant to be mindful of the well-known side effects ofpioids such as central nervous system depression, alter-tions of gastrointestinal motility, and induction of de-endence. Other, as yet unproven, strategies of pain relief

nclude inhibition of pancreatic enzyme secretion usingancreatic enzyme therapy and the use of antioxidants.nvasive approaches such as celiac plexus block, endo-copic procedures, and surgical drainage and resectionlso have been used as therapy for the pain of CP, butone of these procedures has ever been the subject ofontrolled trials either in comparison with medical ther-py or with no therapy.

Treatment of Exocrine InsufficiencyIn theory, pancreatic enzymes are indicated in

atients with steatorrhea (fecal fat �7 g/day) and weightoss. In clinical practice, however, measurement of fecalat rarely is performed, so that the decision for enzymeeplacement is based on an assessment of the patient’slinical state. The dose of pancreatic enzymes givenhould be high enough to treat steatorrhea, but a signif-cant increase of body weight is rarely achieved. Thesenzymes should be taken with meals in acid-protectedenteric-coated) formulations (except in patients after
astric surgery, ie, Kausch–Whipple resection). Approxi- t
ately 25,000 –50,000 U lipase/meal are recommended,ut a higher dose or combination with a proton pump

nhibitor may be required.

Treatment of DiabetesDiabetes in CP is classified as type IIIc.11 However,

he treatment is not different from patients with type Iiabetes. Due to the co-existing deficiency of glucagon,atients with CP have an increased risk of hypoglycemicvents. This is a particular problem in patients with poorompliance and/or continued alcohol consumption orutonomic neuropathy. In these patients, the therapeuticoal should be to avoid hypoglycemia by a simple insulinegimen. As indicated earlier, the survival of patients withlcoholic CP is limited. Approximately 50% of patientsill not live longer than 10 years after the initial diagno-

is and therefore will not benefit from aggressive insulinherapy. A more intensive insulin regimen is indicatednly in patients with good compliance and cessation oflcohol. Acarbose and insulin sensitizers are ineffective.

NutritionThere is no such thing as a specific pancreatic diet.

bstinence from alcohol and the intake of smaller butore frequent meals is recommended. Restriction of fat

ntake is not advised if the pancreatic exocrine insuffi-iency is largely compensated by enzyme-replacementherapy. Restriction of dietary fat and administration of

edium-chain triglycerides (MCTs) is indicated only inases of severe maldigestion refractory to treatment since

CTs may worsen diarrhea in many patients. Deficien-ies of fat-soluble vitamins are found mainly in patientsho continue to drink; in these cases vitamin supplemen-

ation can be instituted.

Interventional Treatment of ComplicationsThere is a long-standing controversy concerning

he indication(s) for interventional (mainly endoscopic)herapy of complications of CP such as duct stones,ancreatic or biliary tract stenosis, or pseudocysts. Thereas been a profound lack of randomized controlled stud-

es, resulting in therapeutic decisions largely being maden the basis of technical skills available rather thancientific evidence. Many centers perform interventionalherapy only in symptomatic patients with recurrent painr acute attacks, associated with ductal dilatation proxi-al to the stenosis or an obstructive stone. Some evi-

ence exists that stenting a biliary stenosis is inferior tourgery; transitional stenting has been shown to be effec-ive only in patients with a mass in the head of theancreas obstructing the pancreatic duct.119 Interven-ional therapy is obligatory in patients with cyst-associ-ted pain, gastric compression, or biliary obstructionhen alternatives are absent (eg, if surgery is refused by

he patient or the surgeon).

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SurgeryIndications for surgery include complications

uch as common bile duct or duodenal obstruction, fail-re of endoscopic therapy in a patient with intractableain, or a suspected pancreatic cancer.120 Like endoscopicherapy, surgical procedures for pain in CP have nevereen subjected to randomized controlled trials compar-

ng them with medical therapy or no therapy. In patientsith pain and an inflammatory tumor of the head of theancreas, a duodenum-preserving resection of the head ishe method of choice in many centers.121 As an alterna-ive procedure, a longitudinal prancreaticojejunostomy

ay be considered if the main pancreatic duct is dilatedo 7 mm or more.122

SummaryIn summary, CP is characterized by progressive

nd ultimately irreversible pancreatic injury that mani-ests clinically as maldigestion and diabetes. Alcoholbuse is the most common association of CP in theestern world. Important advances have been made in

ecent years with respect to our understanding of theathogenesis of this disease, particularly related to theechanisms responsible for the development of pancre-

tic fibrosis (a cardinal feature of CP) after repeated acutettacks of pancreatic necroinflammation (the necrosis-brosis concept). The pancreatic stellate cell is now es-ablished as playing a central role in fibrogenesis, partic-larly when activated either directly by toxic factorsssociated with pancreatitis (such as ethanol, its metab-lites, or oxidant stress) or by cytokines released duringancreatic necroinflammation. Considerable research ef-ort also has been directed toward the genetic abnormal-ties that may predispose to CP. Mutations of severalandidate genes related to trypsinogen activation/inacti-ation and to CFTR function increasingly are being rec-gnized for their potential disease-modifier role in dis-inct forms of CP including alcoholic, tropical, anddiopathic pancreatitis. Treatment of uncomplicated CPs usually conservative, with the major aim being toffectively alleviate pain, maldigestion, and diabetes, and,onsequently, to improve the patient’s quality of life.urgical and endoscopic interventions are reserved foromplications such as pseudocysts, abscesses, and malig-ancies.

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Received January 29, 2007. Accepted February 28, 2007.Address requests for reprints to: Professor J. S. Wilson, MD, Southestern Sydney Clinical School, The University of New South Wales,

evel 2, Thomas and Rachel Moore Education Centre, Liverpool Hos-ital, Liverpool NSW 2031, Australia. e-mail: [email protected];fax: (61) 2-98283850.J.S.W. was the senior author; H.W., M.V.A., and V.K. contributed

qually to this article as co–first authors.

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