Chronic Pancreatitic Lancet

7/30/2019 Chronic Pancreatitic Lancet

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1184 www.thelancet.com Vol 377 April 2, 2011

Lancet 2011; 377: 118497

Published Online

March 11, 2011

DOI:10.1016/S0140-

6736(10)61852-1

Department of

Gastroenterology

(J M Braganza DSc)andDepartment of Radiology

(S H Lee FRCR),Manchester

Royal Infirmary, Manchester,

UK; Department of Education,

Lancashire Teaching Hospitals,

Preston, UK (R F McCloy FRCS);and University of Leedsand

Nuffi eld Hospital , Leeds, UK

(Prof M J McMahon FRCS)

Correspondence to:

Dr Joan M Braganza,

c/o Mrs Jenny Parr,

Core Technology Facility,

3rd Floor, Grafton Street,

Manchester M13 9NT, UK

[email protected]

IntroductionChronic pancreatitis is a progressive inflammatorydisorder in which pancreatic secretory parenchyma isdestroyed and replaced by fibrous tissue, eventuallyleading to malnutrition and diabetes. Two forms arerecogniseda large-duct calcifying type1 and a small-ductvariant.24 The disease is uncommon in Europe and theUSA; its prevalence in France is 26 per 100 000 people.5This prevalence is not dissimilar to the middle of threeestimates from Japan,6,7 but considerably lower than thefigure of 114200 per 100 000in south India.7

The main symptom of chronic pancreatitis is usuallypain, which occurs as attacks that mimic acute pancrea-

titis or as constant and disabling pain. Despite decades ofresearch, treatment of chronic pancreatitis remainsmostly empirical, and thus patients are repeatedlyadmitted to hospital and have interventional procedures,which strains medical resources.8 This absence ofprogress in treatment is a sign of uncertainty about howthe identified causative factors lead to the disease.Therefore, in this Seminar we focus on the patho-physiology and pathology of chronic pancreatitis beforedescribing clinical management.

DefinitionTraditionally, chronic pancreatitis has been classed asfundamentally different from acute pancreatitisthelatter is usually characterised by restoration of normalpancreatic histology after full clinical recovery.1 However,acute, recurrent acute, and chronic pancreatitis are nowregarded as a disease continuum.9,10 There are severalreasons for this change: recurrent acute pancreatitis candevelop into chronic pancreatitis;1012 there is an overlapin causative factors, both genetic and environmental;10,13experimental protocols can be modified to induce eachcondition;14 and the pancreatitis attack is stereotypedpatients have severe abdominal pain and increased blood

amylase, lipase, and trypsinogen.Pathophysiology and pathologyExperimental studies since the 1950s have shown that anattack of pancreatitis begins as pancreastasis,13 preventionof apical exocytosis in the pancreatic acinar cell (figure 1).15The acinar cell quickly releases newly synthesised enzymevia the basolateral membrane into lymphatics, by way ofthe interstitium, and directly into the bloodstream.16 Somezymogen granules also release their stored enzymebasolaterally.15 These events result in inflammation.17Findings from prospective clinical studies concur withthis pancreastasispancreatitis sequence.13,17

Experimental work has pinpointed a burst of reactive

oxygen species (ROS) as the trigger of so-calledpancreastasis18 and as the potentiator of inflammation byactivating signalling cascades that convert the damagedacinar cell into a factory for chemokines and cytokines.19,20ROS serve several physiological roles, including in signaltransduction,13,21 but an excess of ROS compared withantioxidant capacity (electrophilic stress) is potentially verydamaging. The exocytosis blockade seems to be caused bydisruption of the methionine trans-sulphuration pathwaythat produces essential methyl and thiol (principallyglutathione) moieties.17,22 This problem also occurs inclinical acute or acute-on-chronic pancreatitis.2325

In patients who develop large-duct chronic pancreatitis,studies in the quiescent phase of the disease show thatthe composition of pancreatic fluid changes in a manner

Chronic pancreatitis

Joan M Braganza, Stephen H Lee, Rory F McCloy, Michael J McMahon

Chronic pancreatitis is a progressive fibroinflammatory disease that exists in large-duct (often with intraductalcalculi) or small-duct form. In many patients this disease results from a complex mix of environmental (eg, alcohol,cigarettes, and occupational chemicals) and genetic factors (eg, mutation in a trypsin-controlling gene or the cysticfibrosis transmembrane conductance regulator); a few patients have hereditary or autoimmune disease. Pain inthe form of recurrent attacks of pancreatitis (representing paralysis of apical exocytosis in acinar cells) or constantand disabling pain is usually the main symptom. Management of the pain is mainly empirical, involving potentanalgesics, duct drainage by endoscopic or surgical means, and partial or total pancreatectomy. However, steroidsrapidly reduce symptoms in patients with autoimmune pancreatitis, and micronutrient therapy to correctelectrophilic stress is emerging as a promising treatment in the other patients. Steatorrhoea, diabetes, localcomplications, and psychosocial issues associated with the disease are additional therapeutic challenges.

Search strategy and selection criteria

We searched PubMed and the Cochrane library (to August,

2010) for reviews on chronic pancreatitis. We used Google

scholar for specific searches, with chronic pancreatitis as the

key phrase combined with epidemiology, pathology,

aetiology, gene mutations, pathogenesis,

classification, diagnosis, pancreatic function tests,

pancreatic imaging tests, treatment of pain, pancreatic

enzyme therapy, micronutrient therapy, antioxidant

therapy, endoscopic treatment, or surgical treatment. We

selected the most up-to-date articles but did not disregard

commonly referenced older publications. We also examined

the reference lists of identified papers and selected those that

we judged to be relevant. Review articles and book chapters

are cited to give readers more details and references than this

Seminar can accommodate.


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www.thelancet.com Vol 377 April 2, 2011 1185

that, for uncertain reasons, facilitates protein depositsthe precursors to calcium carbonate stones.1 (1) There isan early increase in secretion of enzyme and calcium, buta decrease in the serine protease inhibitor Kazal type 1(SPINK 1), bicarbonate, and citrate.1 (2) Concentrations offree radical oxidation products are raised in the pancreaticfluid,26 which suggests ongoing electrophilic stress, andin an apparent attempt to compensate, concentrations ofthe natural antioxidants27 lactoferrin and mucin areincreased.1,2,28 (3) Concentrations are altered of twosecretory stress proteins29 (increased concentration ofpancreatitis associated protein [PAP]/regIII, which isactivated by electrophilic stress; and variable concentrationof pancreatic stone protein [PSP]/reg, formerly called

lithostatin;1 figure 1) that tend to form fibrous latticesupon partial digestion by trypsin. (4) There is an increaseof GP-2, which is a secreted component of zymogengranule membranes (analogous to the renal cast protein).30(5) Concentrations of lysosomal enzymes are increased inductal fluid, and traces of trypsin appear.31 Moreover, themethionine metabolic pathway remains fractured.3234

On histology, the defining triad of stable disease(irrespective of main causes or location)35 is acinar loss,mononuclear cell infiltration, and fibrosis. The earlylesions are distributed in patches; thus, normal findingson needle biopsy are unreliable. An unusual form of so-called groove (paraduodenal) pancreatitis has beenidentified.11 Each inflammatory attack can cause foci offat necrosis that seem to lead to both pseudocysts and

fibrosis.11 Nerves show breaching of the perineuriumadjacent to inflammatory foci, while the expression ofnociceptive chemicals in nerve endings is increased.36

Immunocytochemistry gives valuable insights into thedevelopment of chronic pancreatitis. Acinar cells,which are hyperplastic at disease outset,2 showstrong expression of cytochrome P450 (CYP) mono-oxygenases,3739 as do proliferated islets of Langerhans,3739and hepatocytes (figure 2).37,38 After birth, CYP enzymesare mainly located in the liver. CYP metabolisesenvironmental lipophilic chemicals (xenobiotics). In thefirst phase, the enzyme uses ROS to hydroxylate thesubstrate, which then usually undergoes second-phaseconjugation reactions, often with glutathione and

catalysed by glutathione transferases. So-called enzymeinduction might be accompanied by expansion of theendoplasmic reticulum so that, at least initially, the cellsecretes more of its normal products. However, thisdefence reaction backfires if first-phase processing (eg, byCYP2E1, CYP1A, and CYP3A1 isoforms) produces areactive xenobiotic metabolite. Cell injury depends onwhether or not there is enough by way of defences toROS and reactive xenobiotic species: antioxidant enzymes(including the selenium-dependent glutathione peroxi-dase), glutathione transferases, glutathione, and ascorbicacid (the bioactive form of vitamin C, which can substitutefor glutathione).32,40 Immunochemistry shows that thesedefence mechanisms are insuffi cient to meet theincreased oxidant load in acinar cells,32,37 which therefore

Figure 1: Schematic representation of disturbances in the pancreatic acinar cell during experimental acute pancreatitis

See text for a full description. The constitutive pathway at the basolateral pole normally transports a small fraction of newly synthesised enzyme, as do two pathways at the

apical pole. E=amylase, lipase, trypsinogen, and other precursor proteases, and pro-phospholipase A2. RER=rough endoplasmic reticulum. GC=Golgi complex. ZG=zymogen

granules. L=lysosomes. ZG-L=miniscule fraction of zymogens activated by co-localisation with lysosomal enzymes. D=centripetal dissolution of granules.

PAP/regIII=pancreatitis associated protein. PSP/reg=pancreatic stone protein/islet regenerating protein. MC=mast cell. PMN=polymorphonuclear cell. MO=monocyte.

Ph-PLA2=phospholipase A2 from phagocytes and mast cell. Adapted from Braganza.13

E

ZG

Nucleus Nucleus Nucleus

ZG-L

ZG ZG D

ZG-LL

Constitutivepathways

Normal Pancreastasis Pancreatitis

Constitutivepathway

GCRER

GC

PAP/regIII

PSP/reg

RERRER ZG

MC PMN

MO

Ph-elastasePh-PLA

2

Foci of gland digestion

E

EE


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show signs of electrophilic stress, such as excess lipo-

fuscin and cytoplasmic microvesiculation.

41

Fibrosis is a sign that interstitial stellate cells areactivated in chronic pancreatitis; these cells play acentral part in disease progression by regulating thesynthesis and degradation of extracellular matrixproteins.42,43 Findings from histochemistry suggest acausal influence of two factorsan increase in lipidperoxidation products caused by an excess of ROS inadjacent acini,44 and the release of mast celldegranulation products,45 transforming growth factor 1in particular.46 The two factors are linked in that ROSand their oxidation products are natural activators ofmast cells.17 Activation of stellate cells is increased bycytokines from infiltrating leucocytes and the injured

acinar cell.43 The end stage of chronic pancreatitis isidentified by loss of all secretory tissue, disappearanceof inflammatory cells, and intense fibrosis. This

progression resembles that from chronic active hepatitis

to liver cirrhosis.

2,12,47

The table summarises the histological features ofordinary chronic pancreatitis compared with features ofthree variants in which the lesions are diffuse. Thepancreatic lesion in cystic fibrosis is a diffuse form ofchronic pancreatitis wherein inflammatory stigmatadisappear by birth,48 except in patients with mildmutations in the cystic fibrosis transmembraneconductance regulator gene (CFTR), who might haverecurrent attacks.49 Uniform lesions also occur upstreamof an obstructed duct1,11,48 and in autoimmunepancreatitis.50,51 The latter can involve the whole or partof the gland and has two subtypes. Characteristics ofthe more common type-1 autoimmune pancreatitis are

a dense lymphoplasmacytic infiltrate with predominantlyIgG4+ cells, periductal swirling sclerosis, and obliterativevenulitis. In the type-2, duct-destructive form, hordes

Ordinary* Cystic fibrosis Obstructive Autoimmune

Lesions

Distribution Patchy Diffuse Diffuse Diffuse

Extent of gland Variable Total Total Total or focalDuct system

Main duct Irregularly dilated Minimally dilated Smoothly dilated Constricted

Protein plugs All ducts Intralobular and interlobular No No

Calcifying tendency Yes No No No

Epithelium destroyed (Groove form) No No Yes (type 2)

Neutrophils No No No Yes (type 2)

Inflammatory cells Mononuclear No No Plasmalymphacytic

Fibrosis Mainly perilobular Perilobular, intralobular Perilobular, intralobular Perilobular, intralobular, periductal

Pseudocyst Frequent No No No

*Excludes the small-duct variant (as in at least 30% of cases) wherein characteristic features are focal acinar cell damage and tubular complexes.3 Groove pancreatitis is similar

to the ordinary form, except for prominent destruction of ductal epithelium and cysts.1,11 The earliest lesions occur in utero.48 Diffuse lesions occur upstream from the

obstruction.1,11 See text for subtypes.

Table: Main histological features of chronic pancreatitis subtypes (at diagnosis in stable disease)

Figure 2: Immunolocalisation of cytochrome P4503A1 in surgical material from a 27-year-old woman with calcific chronic pancreatitis

The patient drank little alcohol, smoked 40 cigarettes a day, and worked as a forecourt attendant at a car and lorry-fuelling station. (A)Thepancreatectomy fragment

shows that the enzyme (brown stain) is strongly expressed in acinar cells (A) but absent from epithelium of dilated ducts (D) or expanded stroma (S). (B) The needle

biopsy fragment of the liver showed that the enzyme is strongly expressed across the liver lobule (H) and weakly expressed in bile duct epithelium (D). Reproduced

with permission from Foster et al.37

BAD

D

H

H

D

50 m

S

A

A

50 m


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of neutrophils infiltrate the wall of the duct, accompanied

by lymphocytes and plasma cells.

51

CausesPanel 1 lists causative factors of chronic pancreatitis. Inadults, excluding those with cystic fibrosis, 9095% ofpatients are regarded as having alcoholic or idiopathicdisease. Infective causes are rare.52 The connection betweenchronic pancreatitis and drugs (eg, valproate) is mostlyanecdotal. Studies from Italy,53 China, and Japan54 reportan association with gallstones in about 30% of patients.

AlcoholicAlcohol has long been regarded as the leading cause ofchronic pancreatitis in Europe, the USA, Brazil, Mexico,

and South Africa, and is now regarded as the main causeof the disease also in Australia and South Korea.7However, excess alcohol was the predominant factor inonly 34% of cases of chronic pancreatitis in a recentmulticentre study from Italy53 and in 44% of cases in anaudit from the USA,55 with another study reporting thatAfrican-Americans are at particular risk.56 Whether thesenew data reflect differences in the definition of alcoholicdisease55 or a genuine change in the cause of chronicpancreatitis is not clear.57

Experimental studies have shown that, although thepancreas processes ethanol effi ciently (via a non-oxidativeroute that produces fatty acid ethyl esters, and byoxidation via the acetaldehyde pathway), its metabolitesinjure acinar cells and activate stellate cells in vitro.42,58However, prolonged ethanol feeding does not inducechronic pancreatitis.58,59 Hence, the finding of a latentinterval of 15 years or more in patients who consumed150 g or more of ethanol per dayas most recently notedin India60is unsurprising. Moreover, less than 10% ofpeople who drink alcohol in excess develop the disease.61Collectively, these findings suggest that other factorsinteract to amplify ethanol toxicity in vivo.

In animal models, small doses of ethanol induceCYP2E1, thus increasing the toxicity from other chemicalsto which the animal is simultaneously exposed.62,63 Theseresults might rationalise the old observation that there is

no threshold for the pancreatic toxicity of ethanol,1 butrecent data suggest there is a threshold at 60 g per day.55

Moreover, CYP2E1 is the main pathway that metabolisesethanol upon chronic excessive ingestion,63 but thispathway releases ROS.64

Idiopathic6070% of cases of chronic pancreatitis in India andChina are labelled as idiopathic, as are around half thecases in Japan.7 Tropical pancreatitis is a form ofidiopathic pancreatitis that affects young people andhas a propensity to diabetes and large calculi.65 Thisdisease is mainly reported in developing countries ofAsia, Africa, and Central America, where severemalnutrition and cyanogenic glycosides in cassava

(manioc) were implicated. The classic description oftropical pancreatitis was from Kerala, south India;66however, hospital admission statistics revealed a declinein the disease by six times between 1962 and 1987,66without a change in cassava consumption. Instead, thedecline coincided with the introduction of electricity inthis province, which removed the dependence ontraditional lighting (see below). At present, tropicalpancreatitis accounts for just 38 % of cases of chronicpancreatitis in India.60

Other toxic causesCigarette smoke has emerged as a strong independentrisk factor for chronic pancreatitis;55,67 the link was verified

Panel 1: Causative factors

Toxic

Xenobiotics

Alcohol

Cigarette smoke

Occupational volatile hydrocarbons

Drugs: valproate, phenacitin, thiazide, oestrogen,

and azathioprine

Endogenous

Hypercalcaemia, hyperparathyroidism

Hyperlipidaemia, lipoprotein lipase deficiency

Chronic renal failure

Infection or infestation

HIV, mumps virus, coxsackie virus Echinococcus, Cryptosporidium

Genetic*

CFTR mutation

PRSS1 mutation

SPINK1 mutation

Obstruction of main pancreatic duct

Cancer

Post-traumatic scarring

Post-duct destruction in severe attack

Recurrent acute pancreatitis

Autoimmune

Miscellaneous

Gall stones

After transplant

After irradiation

Vascular disease

Idiopathic

Early or late onset

Tropical

CFTR=cystic fibrosis transmenbrane conductance regulator. PRSS1=protease serine

cationic trypsinogen. SPINK1=serine protease inhibitor Kazal. *Other, less common

mutations have been described.


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by inhalation toxicology experiments.68,69 A case-control

study from the UK identified occupational volatilehydrocarbons as another independent risk factor.70 Thisconnection is upheld by descriptive studies from Chennai,India,71 and Soweto, South Africa,72 which also reportedregular contact with kerosene or paraffi n, respectively, incookers, heaters, or lamps in patients with chronicpancreatitis (potentially relevant to Kerala, see above).Toxic damage to the pancreas by petrochemicals has beendocumented in lower vertebrates.40 Moreover, the simplestanimal model of chronic pancreatitis, which develops viaan acute phase, involves just one parenteral injection ofdibutyltin (which has many industrial uses) and the injuryis amplified by alcohol.73

All these findings reinforce the pathological evidence

(figure 2) that the pancreas is a versatile but alsovulnerable xenobiotic-metabolising organ.40 Inhaledxenobiotics that survive the pulmonary circulation wouldpose the biggest threat (figure 2A) by striking thepancreas directly via its rich arterial supply.

AutoimmuneAutoimmune pancreatitis (24% of cases57) can be partof a multisystem disease (type 1) or can affect thepancreas alone (type 2).50,51 Aberrant human leucocyteantigen DR-1 expression on pancreatic ductal cellsmight present autoantigens to lymphocytes. Proposedpancreas-specific antigens include lactoferrin,28 carbonicanhydrase, SPINK1, and a peptide that is present inacinar cells that has homology to aminoacid sequencesin the plasminogen-binding protein ofHelicobacter pylori74(which might represent molecular mimicry)51 and alsoin ubiquitinprotein ligase74 (a cofactor for steroidhormone receptors and an important peptide in theintracellular protein degradation pathway).75

GeneticNormally, if trypsinogen becomes prematurely activatedwithin the pancreas, it is inhibited by SPINK1 and thenself-destructs or is degraded by trypsin-activated pro-teases;31 the potent inhibitor gluthathione is available ifall else fails.76 Hereditary pancreatitis is a rare condition

that is caused by a gain-of-function mutation (autosomaldominant, 80% penetrance) in the cationic trypsinogengene (PRSS1),9,10,42 which produces a degradation-resistant form of trypsin.77 A transgenic mouse modelof chronic pancreatic injury has proved this link.78 ThePRSS1 mutation is not associated with alcoholic ortropical chronic pancreatitis.79 By contrast, a loss-of-function mutation in SPINK1 is strongly associatedwith idiopathic disease7982 but is thought to be apredisposing or modifying factor rather than beingdirectly causative.42,79,80 Mutations in other genes thatcould increase the threat from trypsin have also beendescribed, 79 as has a loss-of-function mutation in thePRSS2 gene (encoding anionic trypsinogen), whichprotects against pancreatitis.79,80

Idiopathic chronic pancreatitis is associated with a

mutation in the CFTR gene.

80,82,83

Patients can have oneabnormal recessive allele, but possession of two confersa 40 times increased risk of developing idiopathic chronicpancreatitis, which rises to 500 times in patients whoalso have a SPINK1 mutation.83 Some patients withapparent idiopathic chronic pancreatitis who have CFTRmutations have an atypical form of cystic fibrosis.80 Threeoverlooked aspects of CFTR function have been reviewedrecently.32 CFTR is present in the luminal pole of acinarcells where it might facilitate membrane recycling andexocytosis, like it does elsewhere. CFTR transportsbicarbonate and glutathionewhich facilitate thesolubility of mucins in secretionsacross the luminalmembrane of ductal cells adjacent to the centroacinar

space. CFTR is inactivated by electrophilic stress but isprotected by thiols and ascorbic acid. Moreover, CFTR ismislocalised to the cytoplasm of ductal cells in patientswith chronic pancreatitis; this misplacement is correctedin autoimmune disease by steroids, which also reduceinflammation, restore bicarbonate and enzyme secretion,and regenerate acinar cells.84

Mutations in CFTR and SPINK1 have also beendescribed in patients with hypertriglyceridaemia orhyperparathyroidism who develop pancreatitis.32 Atpresent, molecular deficits that contribute to chronicpancreatitis have been identified in less than 10% ofalcoholic chronic pancreatitis and around 50% ofcases overall.79

PathogenesisThere is no agreement as to how these diverse causativefactors lead to chronic pancreatitis. There are manyhypotheses about the pathogenesis of the disease,43 whichfall into five main categories.

Ductal theoryOne hypothesis suggests that ducts are the primary targetof the disease: theories centre on the primacy of calcifyingprotein deposits (protein plug hypothesis),1 stagnation ofpancreatic juice, reflux of noxious bile and duodenal juice(facilitated by passage of gallstones), and primary auto-

immune attack.

Acinar theoryAnother hypothesis suggests that acini are the primarytarget: alcohol is thought to injure acinar cells directly(toxic metabolite hypothesis) or by increasing the cellssensitivity to cholecystokinin (CCK) or via CYP2E1, whilealso activating stellate cells, especially in the presence ofendotoxin.42,58 Another suggestion is that the disease iscaused by cyanide toxicity of the pancreas.

Two-hits theoryTwo so-called hits are additionally suggested as causingthe disease: variations include a duct-to-acinar sequence,vice versa, or double acinar hits. The last of these is the


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most popular theory and incorporates the idea that

recurrent necrosis leads to periductal fibrosis.

11

The firstattack of pancreatitis is taken to represent autodigestioncaused by unregulated trypsin activity in the acinar cell. Ifthis attack is severe enough to recruit macrophages(sentinel acute pancreatitis event hypothesis), subsequentdamage to the gland (by alcohol or electrophilic stress)leads to fibrosis via macrophage-primed stellate cells.

Electrophilic stress theoryThe electrophilic stress theory is the pancreatic equivalentof paracetamol or carbon tetrachloride hepatotoxicity,which results from insuffi cient protection by glutathioneagainst electrophilic attack (via CYP) on keymacromoleculesnot least, enzymes in the methionine

trans-sulphuration pathway towards glutathione. How-ever, in chronic pancreatitis electrophilic stress fromtoxic metabolitesand, thereby, recurrent pancrea-stasisdevelops over many years as a result of repetitiveexposures to multiple xenobiotics.41 Previous dietaryinsuffi ciency of micronutrients, especially methionineand ascorbic acid, facilitates the problem.41,85 The diversionof free radical oxidation products into the interstitiumcauses mast cells to degranulate, leading to inflammation,activation of nociceptive axon reflexes, and fibrosis.41 Therealisation that compromised availability of methyl andthiol (glutathione) moieties underlies chronic pancreatitishas allowed an extension of the electrophilic stressconcept to chronic pancreatitis that is associated withgene mutations.32 Thus, the daily exposure of acinar cellsto traces of trypsin in people with PRSS1 or SPINK1mutations is expected to strain glutathione reserves. Ofparticular note, those with a CFTR mutation would beleft vulnerable not only to pancreastasis but also tointraductal calcifying protein plugs (large duct disease)when the residual CFTR protein is immobilised byelectrophilic stress.32

Multiple-cause theoryThe final hypothesis states that different causative factorslead to damage via different pathways: this conceptincorporates the other theories while noting that

pancreatic ischaemia can aggravate the disease.43

Clinical featuresAlcoholic chronic pancreatitis presents in the fourth orfifth decade of life and mainly affects men.86 Idiopathicdisease has early-onset (second decade) and late-onset(sixth decade) forms, which have equal gender distri-bution.12,86 Hereditary disease manifests at around 10 years87and tropical pancreatitis at between 20 and 30 years,65whereas the more common type-1 form of autoimmunedisease affects men in the sixth decade.51

Presenting features of chronic pancreatitis usually fallinto one of four groups: apparent acute or recurrent acutepancreatitis (the true diagnosis of chronic pancreatitis issuspected when attacks recur after cholecystectomy);

constant pain; symptoms and signs of local complications

of the disease (eg, pseudocyst, obstruction of adjacentorgans, or vascular thrombosis); or complaints that suggestexocrine or endocrine pancreatic failure, or both, by whichstage pancreatic calculi are often present. These featuresform the basis for the most recent classification system(figure 3).47 In alcoholic disease, the interval from firstattack to steatorrhoea (signifying >95% loss of acini) isaround 13 years, which is substantially shorter than inearly-onset idiopathic disease12,86 or hereditary pancreatitis(26 years).12 Pancreatic calculi appear earliest in tropicalpancreatitis,65 and earlier in alcoholic than idiopathicdisease.86 Diabetes might precede, begin at the same timeas, or start after steatorrhoea.65,88

Pain is the over-riding symptom in all but 1015% of

cases of chronic pancreatitis; these cases are usually elderlypatients with idiopathic disease12,86 or patients withautoimmune pancreatitis who might present withsteatorrhoea, diabetes, or jaundice.50,51 The pain is wearyingand occurs in episodes that last about 1 week, or is constant.It starts in the epigastrium and moves through to the dorsalspine or localises to the left hypochondrium, radiating tothe left infrascapular region. The pain is sometimesassociated with nausea and vomiting and can be partiallyeased by sitting up and leaning forward or by application oflocal heat or other counterirritants to the dorsal spine orepigastrium. The pain can be so severe that patients fearfood and lose weight. Most,12,86,89 but not all,88 studies havereported that pain diminishes markedly once the diseaseburns out (which suggests that viable acini are a prerequisitefor pancreatic pain). However, by then patients often havebecome addicted to narcotic analgesics, which could causethem to lose their jobs, homes, or families.88,90

Panel 2 lists factors that might contribute to pain inpatients with chronic pancreatitis:36 mast cell degranulationproducts and hydrogen sulphide are plausible mediatorsof the pancreatic component.91,92 The intensity of the paincontrasts with the absence of specific signs in

Figure 3: Proposal for a clinically based classification system for

chronic pancreatitis

For example, a patient may be described as having chronic pancreatitis(idiopathic), stage B, bile duct.47

Attacks of apparentacute pancreatitis

Pain

Cause

Pancreatic failure

Clinicalcriteria

Complications Bile duct stricture Duodenal stricture Vascular stricture Portal hypertension Pseudocyst Pancreatic fistula Pancreatic ascites Rare, eg, colonic

stricture

B Intermediate

C End stage1 endocrine2 exocrine3 both

A Early


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uncomplicated disease. Erythema ab igne is a useful

pointer for diagnosis of chronic pancreatitis in thesepatients, as is meteorism in patients whose pain has led todependence on narcotic analgesics (figure 4). An epigastricswelling suggests a pseudocyst, inflammatory mass, orcancer. Patients with multisystem involvement usuallyhave the autoimmune form of chronic pancreatitis.

Ordinary chronic pancreatitis has a high mortality

ratenearly 50% within 2025 years of disease onset,

12

as a result of complications of an attack, coexistingdisease, or the effects of alcoholism. Patients withchronic pancreatitis have an increased risk of pancreaticcancer,93 which accounts for 3% of deaths.86 Althoughthe risk of pancreatic cancer is especially high in patientswith hereditary pancreatitis,87 they do not have a highermortality risk than the general population.94Autoimmunepancreatitis also does not affect long-term survival.95

DiagnosisRoutine laboratory tests might reveal incipient diabetes,type-1 hyperlipidaemia, or hypercalcaemia in patientswith suspected chronic pancreatitis. If type-1 auto-

immune disease is a possibility, serology will showraised concentrations of -globulin, IgG (IgG4 pre-dominantly), and various antibodies, including anti-lactoferrin, anti-carbonic anhydrase, rheumatoid factor,and anti-nuclear antibody.50,51 An abnormal liver functionprofile suggests alcoholic liver disease, non-alcoholicsteatohepatitis,96 sclerosing cholangitis,50,51,96 metastasesfrom superimposed pancreatic cancer, gallstones, or,most commonly, constriction of the intrapancreatic bileduct, which occurs early in autoimmune pancreatitis,50,51but is late otherwise.47

Confirmation of the diagnosis of (non-calcific) chronicpancreatitis is by histology of a wedge biopsy or resectedspecimen of pancreas. However, this is impractical. Areduction in bicarbonate with or without enzymecontent of duodenal aspirates after intubation andhormonal stimulation (by secretin with or without CCKor its analogue caerulein), and abnormalities in thepancreatic duct system on endoscopic retrogradecholangio pancreatography (ERCP) are the most effi cientalternative diagnostic techniqueswith the formersubstantially better at detecting small-duct disease thanthe latter.2,4 However, the secretory test is available inonly a few centres worldwide (and whether or not an

Figure 4: Clinical features in chronic pancreatitis

(A)Erythema ab igne across the upper abdomen in a young patient with recurrent pancreatitis despite cholecystectomy for multiple gallstones (vertical scar). (B) Plainabdominal radiograph shows heavy calcification in the pancreatic head (arrow) and a loaded colon in a patient with abdominal distension who was addicted to opiates.

A B

Panel 2: Pain in chronic pancreatitis

Caused by the disease

Active inflammation*

Altered nociception

Neurogenic inflammation*

Visceral nerve sensitisation* Central nerve sensitisation

Psychological

Hypertension

Ductal or tissue via increased cholecystokinin

Tissue ischaemia

Caused by complications

Inflammatory mass in head of gland

Obstruction of bile duct or duodenum

Pseudocyst

Cancer of the pancreas

Caused by treatment

Opiate gastroparesis or constipation

Caused by unrelated problems

Peptic ulcer

Gall stones

Mesenteric ischaemia

Small-bowel stricture

Somatic (eg, surgical scar)

*Mast cell degranulation products and hydrogen sulphide are potential mediators

(see text).


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endoscopic secretory test is as good is unclear).97

Moreover, ERCP for diagnosis has largely beenabandoned in favour of magnetic resonancecholangiopancreatography (MRCP) because ERCP canprecipitate pancreatitis in up to 4% of patients.9

There is no non-invasive test that can substitute for thehormonal test for chronic pancreatitis.2 By contrast,sophisticated imaging methods have rapidly developed,such that the traditional ultrasound scan to visualise thepancreas itself is virtually obsolete (but see figure 5). Therepertoire of imaging techniques is impressive:multidetector CT (MDCT; figure 5); MRI;97 MRCP(figure 6), which provides excellent images of the mainpancreatic duct98 but not always of the side-branchchanges as shown by ERCP; secretin-enhanced MRCP,

which also shows duodenal filling by pancreatobiliarysecretions99 and is more accurate than standard MRCP inidentifying small-duct disease;100 endoscopic ultrasound(EUS),101,102 which identifies both parenchymal and ductalalterations (figure 6; now classified as the Rosemontcriteria),102 but which is observer-dependent and tends tooverdiagnose the disease;67 diffusion-weighted MRI;103and PET.104 The last two imaging techniques have notbeen properly assessed in chronic pancreatitis, whereasthe role of EUS continues to advance.

No investigation algorithm is suitable worldwide,because much depends on available resources andexpertise, but a battery of tests should not be used fordiagnosis of suspected chronic pancreatitis because thiswill generate many false positive outcomes and causedistress to the patient.2 Figure 7 presents a sequentialscheme for diagnosis of the disease, on the basis ofwhether or not the secretin test is available. This schemerecognises that an abdominal radiograph will showpancreatic calculi (nearly 100% specificity; figure 4) in atleast 30% of patients overall and in most patients withtropical pancreatitis. This stepwise approach isunnecessary in a patient who presents with fatty stoolsafter a long history of pancreatitis attacks or pain. In thisevent, any of the following tests is probably suffi cient fordiagnosis: acid steatocrit (high value) on a spot stoolsample (which obviates the need for the traditional 3-day

faecal fat test);105 faecal elastase (low);105 recovery in expiredair of C (low) from a C-labelled mixed triglycerideload;106 or serum trypsinogen (low).4 However, a CT scanis needed to identify the disease type.

Imaging tests show distinctive changes in type-1autoimmune pancreatitis. Both ultrasound and MDCTtypically show a diffusely enlarged sausage-shaped gland(figure 5). ERCP shows long or multiple strictures of thepancreatic duct and sometimes a long stricture in thedistal bile duct or sclerosing cholangitis.50,51 Findingsfrom one study suggest that MRCP cannot replace ERCPfor the diagnosis of autoimmune disease.107 Theseimaging features are suffi cient to make the diagnosis in apatient with an increased concentration of IgG4 in serum.If diagnostic doubt exists (as in a patient with type-2

disease, for which there are no serum markers), atherapeutic trial of steroids or histology (of core biopsy orresected specimen), or both might be needed.50,51

There are two diffi cult diagnostic issues that must beaddressed. First, how can one distinguish between aninflammatory mass of ordinary chronic pancreatitis, focalautoimmune disease, and pancreatic adenocarcinoma

with upstream chronic pancreatitis? Raised IgGconcentrations can occur in all three settings and existingtumour markers are not specific enough to distinguishbetween them, although new molecular markers are beingdeveloped.108 EUS or MDCT-guided core biopsy can beused to confirm autoimmune pancreatitis, or a simpleneedle biopsy might identify tumour cells. F-fluoro-deoxyglucose PET with CT facilitates the identification ofcancer,104 but increased uptake is also a feature ofautoimmune pancreatitis (as is increased uptake ofgallium).50,51 A pancreatectomy specimen might have to beused as the final diagnostic test, as it is for detecting anintraductal papillary mucinous tumour in a patient whohas suspected idiopathic large-duct disease.109 Second,should the clinician start a search for genetic mutations?

Figure 5: Examples of ultrasound and multidetector images in patients with chronic pancreatitis

(A)Transabdominal ultrasound scan showing a uniformly swollen, hypoechoic pancreas (arrowed), typical ofautoimmune pancreatitis. (B)Multidetector CT showing pancreatic calculi in an atrophic pancreas (long arrow)

and a pseudocyst at the tail of the pancreas (short arrow).

A B

Figure 6: Examples of three-dimensional magnetic resonance cholangiopancreatogram and endoscopicultrasound in patients with chronic pancreatitis

(A) Three-dimensional magnetic resonance cholangiopancreatogram shows a minimally dilated biliary tree and

moderately dilated irregular main pancreatic duct. (B)Endoscopic ultrasound scan shows a minimally dilated

pancreatic duct in the head of pancreas (arrowed) consistent with mild chronic pancreatitis: the distal common

bile duct appears normal (arrow head).

A B


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A recent review gives valuable guidance.80PRSS1 mutationtesting for diagnostic purposes is acceptable insymptomatic young individuals or in those with a familyhistory of pancreatitis, but counselling and clinical follow-up are needed if the result is positive. There is no indicationfor SPINK1 mutation testing. At present there is norationale for CFTR mutation testing in the setting ofpancreatitis alone. Instead, a sweat test should be done ifatypical cystic fibrosis is suspected, and patients should bereferred to a specialist clinic when sweat chlorideconcentration is borderline (4059 mmol/L) or abnormal(>60 mmol/L). However, the vulnerability of CFTR toelectrophilic stress potentially explains both false positive

sweat tests and abnormal nasal potential difference studiesin a variety of conditions (eg, severe malnutrition).32

TreatmentTreatment goalsThe goals of treatment for chronic pancreatitis are torelieve acute or chronic pain, calm the disease process toprevent recurrent attacks, correct metabolic consequencessuch as diabetes or malnutrition, manage complicationswhen they arise, and address psychosocial problems.Endoscopic treatment, surgery, or both, are only neededwhen optimum medical treatment fails to relieve pain(figure 8) and to deal with specific complications (figure 3).A detailed discussion of complications is beyond thescope of this Seminar.

When providing treatment to control the pain

associated with chronic pancreatitis, the patients fearsand misconceptions about the disease should beaddressed sympathetically. Time should be spentdiscussing the disease with the patient at the first clinicvisit, with particular attention paid to circumstancessurrounding the first attack. Patients should be advisedto avoid alcohol and cigarettes, although there is noevidence that abstinence from alcohol slows the diseaseand the effect of alcohol on pain is debated.67,89 A dietaryassessment should be done (see later). Where warranted,the help of a psychologist or pain therapy specialistshould be sought, and the primary-care practitionermust also be briefed on treatment strategy. Continuity ofcare is important to gain the patients trust and to

minimise the risk of addiction to narcotics.

AnalgesicsRegular analgesics are superfluous in patients withsporadic attacks but are needed in those with backgroundpain. Use of analgesics should broadly follow WHOguidelines for cancer pain.110 Briefly, analgesictreatment begins with paracetamol or a non-steroidalanti-inflammatory drug, or both, followed by a mildopioid such as tramadol, perhaps coupled with aneuroleptic antidepressant. Narcotic analgesics shouldbe avoided if possible. A simple pain diary with a 10 cmvisual analogue scale is useful, as is a baseline quality-of-life assessment. Analgesia devices to deliver morphinethat are controlled by the patient should not be used,even in an attack. Such drugs can worsen pain byinducing mast cell degranulation111 and (possibly thereby17)cause gastroparesis4 and constipation (figure 4).

Steroids and enzyme therapyTreatment with steroids is associated with rapid reliefof symptoms in autoimmune pancreatitis.50,51 Thestarting dose is 3040 mg per day of prednisolone,which is tapered over 3 months while monitoringserum IgG concentrations and imaging findings. Long-term maintenance with 5075 mg per day ofprednisolone is recommended to prevent relapses.50

Recurrences, which typically occur in type-1 disease,95favour the development of pancreatic calculi.112

In patients with small-duct disease, pancreatic acinarcells are suggested to be under constant stimulation byCCK because subnormal delivery of pancreatic proteasesinto the duodenum allows improved survival of a CCK-releasing peptide from the duodenal mucosa.4 Hence,the following potential treatments have been successfullytested:4 oral pancreatic enzymes (non-enteric coated, twotrials), subcutaneous octreotide (one trial), and oraldosing with the CCK-A receptor antagonist loxiglumide(one trial). However, this issue is contentious,113,114and theexplanation that these measures allow the pancreas torest4 is at odds with the finding that the exocytosisapparatus is already paralysed in an attack (figure 1) and

Figure 7: Algorithm for the diagnosis of chronic pancreatitis

Suspected chronic

pancreatitis

Plain radiograph for calculi

Multidetector CT

Secretin test available?

Secretin test

Magnetic resonancecholangiopancreatographyafter secretin stimulation

Endoscopic ultrasound

Reconsider other diagnosesRe-test at intervalsTherapeutic trial of

micronutrients?

Positive

Positive

Positive

Positive

Positive

Negative

Negative

Negative

Negative

Negative

Large-ductdisease

Chronicpancreatitis

Suspected small-ductdisease

Yes

No


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hindered thereafter.32 Other explanations might be that

such treatments act by blunting an effect of CCK on painpathways in the CNS36 or by ameliorating electrophilicstress (see later).115

Micronutrient therapyMicronutrient therapy is designed to supply methyl andthiol moieties that are essential for the exocytosisapparatus (figure 1) while protecting it againstelectrophilic attack, as by CYP-derived ROS or reactivexenobiotics species (figure 2).32 Findings from sixclinical trials have reported that micronutrient therapycontrols pain and curbs attacks in patients with chronicpancreatitis.116122 Of these trials, three weredescriptive116118 and three were placebo-controlled.119122

However, the different ways of expressing outcomeprecludes a meta-analysis.123 The study with the highestpower (80%) to detect a difference between treatmentand placebo was from Delhi:122 after 6 months treatment(which included pancreatic enzymes in all patients)there was a greater reduction in the number of painfuldays per month and in the use of analgesic tablets inthe treatment group than in the placebo group;substantially more patients became pain free, andbiochemical markers of electrophilic stress werelowered by active treatment.

Studies from Manchester, UK, suggested that themicronutrient therapy formulation should includemethionine and vitamin C,124 with the need for seleniumassessed by measuring blood concentrations. Vitamin Eand carotene were included in the first trial becausethere was no commercial preparation that did not includethem,119 and three of the other five trials also used thisprotocol.116,121,122 Improvement, as judged by the number ofattacks, admission episodes, pain diaries, pain intensity,or permutations and combinations of these factors,occurred by 1012 weeks.119,121,122 In the UK, the micro-nutrient therapy preparation Antox (Pharma Nord,Morpeth, UK) is a convenient means of dosing because itcontains all the desired items. A starting regimen of twotablets of Antoxthree times per day provides daily dosesof 288 g methionine (but up to 4 g might initially be

needed in some patients),125 720 mg vitamin C, 300 gorganic selenium, and 210 mg vitamin E (which isunnecessary until steatorrhoea develops).126 This treat-ment has no significant side-effects now that carotenehas been withdrawn because of cosmetic problems:125one patient (of >300) developed schizophrenia when on4 g of methionine daily but, of note, this patient had astrong family history of psychiatric disease.125

Patients should also be given dietary advice onantioxidant-rich foods to aid the long-term managementof the disease. It should be stressed that culinarypracticeseg, frying vegetables at high temperature (asin south India41)could compromise the bioavailability ofantioxidants, notably of ascorbic acid.32 Blood monitoringis essential to ensure that plasma and erythrocyte

glutathione levels have increased and that concentrationsof the prescribed micronutrients are not excessive,because this would compromise the physiological roles ofROS.127,128 Very recent reports indicate the need to keeptrack of blood homocysteine, and concentrations of

vitamins (B6, B12, folic acid) that serve as cofactors ofenzymes that govern homocysteine removaleither byfacilitating its transmethylation back to methionine, or byensuring its passage along the transsulphuration pathwaytowards glutathione.32,34,41,129 Of particular interest, elevatedhomocysteine has been recorded in people at Soweto(South Africa) who drank more than 100 g alcohol per dayfor many years130a group that is traditionally regardedas being at high risk of chronic pancreatitis.55

Treatment for 10 weeks is recommended before anyinvasive procedure in patients with chronic pancreatitis,to calm the disease process. Full treatment is usuallyneeded for 6 months, followed by a gradual dose reductionguided by biochemical data and patients symptoms.125 Werecorded treatment failure in 10% of patients, usually

Figure 8: Algorithm for the management of painful chronic pancreatitis

Note that the solid mass in autoimmune pancreatitis is often in the head of pancreas and suggests cancer,

but that ducts are usually constricted. *Procedures include thoracic splanchnicectomy, coeliac plexus block,

and neurostimulation.

Painful chronic pancreatitis

Exclude non-pancreatic painConservative treatment for 10 weeks

Non-narcotic analgesia

Alcohol and cigarette avoidanceDietary assessmentPsychosocial issuesMicronutrient treatmentPancreatic enzyme treatment

Cyst or pseudocyst

Suspectedautoimmune

pancreatitis

Trial of steroids

Endoscopicdrainage

CT guided or endoscopicultrasound-guided biopsy

Cancerconfirmed

Doubtpersists

Pancreatectomy

Treatment

noteffective

Treatmentnot effective

Suspectedcancer

Neuralmanipulation*

Treatmenteffective

Treatmenteffective

Treatmenteffective

Treatmenteffective

Solid mass Endoscopic or surgicalduct drainage

Treatmentnoteffective

Treatmenteffective

Treatment

noteffective

Pancreatic mass No mass

Largeduct disease Smallduct disease


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because of non-compliance (eg, in patients who misuse

alcohol) or a large cyst or pseudocyst;

125

otherwise,symptom control was achieved by choline supplements toboost methyl supply.32 Moreover, micronutrient therapyhas no effect on painful conditions that might bemisdiagnosed as chronic pancreatitis (unpublished); oncevalidated, this finding could form the basis for a therapeutictrial when the diagnosis remains equivocal after fulltesting (figure 7). Finally, there is increasing evidence tosupport the idea that a daily micronutrient supplementmight abort the development of chronic pancreatitis ingroups or even populations at risk of the disease.32,130

Micronutrient treatment is better at controlling painand improving quality of life than conventionaltreatment.131 Moreover, long-term micronutrient

treatment might curb disease progression.82 Excludingtypical autoimmune pancreatitis, which can be treatedwith steroids, micronutrient treatment has been effectiveirrespective of cause (including mutations in PRSS1,118CFTR,82 and SPINK182), disease duration,131 or ductalanatomy (large-duct calcifying or small-duct disease),and also when there is an inflammatory calcified mass.132By contrast, the antioxidants allopurinol and curcuminhave been ineffective for treatment of chronic pancreatitisin clinical trials.32 Two multicentre trials of Antox arein progress (Current Controlled Trials numbersISRCTN21047731 and ISRCTN44912429).

Treatment of steatorrhoea and diabetesThe treatment of pancreatic steatorrhoea usually beginswith 30 000 IU of lipase per meal in an acid-resistantenzyme preparation. In patients who do not respond tothis treatment, a low-fat diet (5075 g per day), doseincrease, gastric proton-pump inhibitor, or a combinationthereof should be recommended.67 A check on fat-solublevitamin status is advisable.126 The main aim in thetreatment of diabetes in patients with chronic pancreatitisis to prevent hypoglycaemia caused by deficiency ofglucagon; simple insulin regimens are preferable.

Endoscopic treatmentOf the many potential indications for endoscopic

treatment of chronic pancreatitis,133 two are undisputed.First, EUS can be used to facilitate transmural drainage ofpseudocysts that are not connected tothe pancreatic ductsystem, and endoscopically placed transpapillary stents inthe duct are useful when they do134 or when a duct leakleads to pancreatic ascites or pleural effusion.135 Second,endoscopic stenting of the bile duct is a useful temporarymeasure in patients with a distal duct stricture.

Limited comparative data suggest that surgery is moreeffective136 and has a more durable effect in controllingpain137 than endoscopic dilatation or stenting of thepancreatic duct. Findings from a randomised clinicaltrial showed that extracorporeal shock-wave lithotripsywith or without endoscopic clearance of stone fragmentswas equally effective at reducing pain over the subsequent

2 years in patients with intraductal calculi;138 however,

lithotripsy can occasionally precipitate acute pancrea-titis.133 Thoracoscopic splanchnicectomy can provide goodinitial pain relief, but pain recurs by 15 months in morethan 50% of patients.139

SurgeryHistorically, around 50% of patients with chronicpancreatitis referred to surgical clinics require an operationcompared with around 25% on long-term follow-up in aspecialist medical clinic.88 Micronutrient treatment seemsto substantially reduce the need for surgery.82,125,132 Theobjectives of surgery are to decompress obstructed ducts(to relieve pain) and at the same time to preserve pancreatictissue as well as adjacent organs (to preserve function),

while recognising that the head of the pancreas constitutesthe so-called pacemaker of chronic pancreatitis. Thesimplest operationlateral pancreatico jejunostomyprovides immediate pain relief in many patients but paintends to recur with the passage of time. Distal pancrea-tectomy, like pancreaticojejunostomy, does not address theproblem of disease in the head of the pancreas, which cancontinue to deteriorate. Moreover, distal pancreatectomycan result in removal of the functionally most active part ofthe gland. Pan creaticoduodenectomy gives good painrelief, but is a major operation. It is indicated in groovepancreatitis if there is duodenal obstruction or whenneoplasia cannot be ruled out preoperatively.140

Duodenum-preserving head resection combined, whenappropriate, with lateral pancreaticojejunostomy hasbeen a major advance: only 87% of patients continued tohave pancreatic pain at a median of 57 years follow-up,whereas 93% of patients had pancreatic painpreoperatively.141 The operation was simplified by carvingout an inverted cone from the pancreatic head, allowingthe cavity and the distal duct to drain into a jejunal loop,thus removing the complex mass of obstructed ducts andinflammatory tissue that frequently lies within the headof the gland.142 A further simplification made thisoperation suitable for patients in whom there was little inthe way of duct dilatation: a so-called ice-cream scoop istaken out of the pancreatic head to leave a thin rim of

pancreas laterally and posteriorly. Pain improved in55% of patients after 41 months of follow-up.143

A precise assessment of the merits of the differentoperations for painful chronic pancreatitis has beenconfounded by an absence of agreement aboutindications for surgery, details of the surgicaltechniques, and methods used to measure outcomes.144However, there is no doubt that the safety of conser-vative operations (eg, lateral pancreaticojejunostomycombined with limited excision of the head of thegland) has improved: operative mortality, about 5% withtraditional resection of the head of pancreas, has fallento 03% and morbidity has been halved.145 There seemsto be little if any advantage to be gained from totalpancreatectomy with islet transplant.146


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Conclusions

Chronic pancreatitis remains a challenging disease.Resective surgery continues to be the definitive treatmentfor persistent pain, but is not ideal in a chronicinflammatory process. Micronutrient treatment mightoffer a viable alternative.

Contributors

All authors participated in writing this Seminar. All authors saw andapproved the final manuscript.

Conflicts of interest

We declare that we have no conflicts of interest.

Acknowledgments

We thank Prof J R Foster for the microphotographs (figure 2).

References1 Sarles H. Etiopathogenesis and definition of chronic pancreatitis.

Dig Dis Sci 1986; 11 (suppl): S91107.

2 Braganza JM. The pancreas. Recent Adv Gastroenterol1986;6: 25180.

3 Walsh TN, Rode J, Theis BA, Russell RCG. Minimal changechronic pancreatitis. Gut1992; 33: 156671.

4 Gupta V, Toskes PP. Diagnosis and management of chronicpancreatitis. Postgrad Med J2005; 81: 49197.

5 Lvy P, Barthet M, Mollard BR, Amouretti M,Marion-Audibert AM, Dyard F. Estimation of the prevalenceand incidence of chronic pancreatitis and its complications.Gastroenterol ClinBiol2006; 30: 83844.

6 Otsuki M. Chronic pancreatitis in Japan: epidemiology, prognosis,diagnostic criteria, and future problems.J Gastroenterol2003;38: 31526.

7 Garg PK, Tandon RK. Survey on chronic pancreatitis in theAsiaPacific region.J Gastroenterol Hepatol2004; 19: 9981004.

8 Spanier BWM, Dijkgraaf MGW, Bruno MJ. Trends and forecastsof hospital admissions for acute and chronic pancreatitis in the

Netherlands. Eur J Gasroenterol Hepatol2008; 20: 65358.9 Mitchell RMS, Byrne MF, Baillie J. Pancreatitis. Lancet2003;

361: 144755.10 Whitcomb DC. Mechanismsof disease: advances in understanding

the mechanisms leading tochronic pancreatitis.Nat Clin Pract Gastroenterol Hepatol2004; 1: 4652.

11 Klppel G. Chronic pancreatitis, pseudotumors and othertumor-like lesions. Mod Pathol2007; 20: S11331.

12 Ammann RW. Diagnosis and management of chronicpancreatitis: current knowledge. SwissMed Wkly2006;136: 16674.

13 Braganza JM. Evolution of pancreatitis. In: Braganza JM, ed.The pathogenesis of pancreatitis. Manchester: ManchesterUniversity Press, 1991: 1933.

14 Wallig M. Xenobiotic metabolism, oxidant stress and chronicpancreatitis: focus on glutathione. Digestion 1998;59 (suppl 4): 1324.

15 Gaisano HY, Gorelick FS. New insights into the mechanismsof pancreatitis. Gastroenterology2009; 136: 204044.16 Cook LJ, Musa OA, Case RM. Intracellular transport of pancreatic

enzymes. Scand JGastroenterol1996; 219 (suppl): 15.17 Braganza JM. Towards a novel treatment strategy for acute

pancreatitis: 1: reappraisal of the evidence on aetiogenesis.Digestion 2001; 63: 6991.

18 Sanfey H, Bulkley B, Cameron JL. The role of oxygen-derived freeradicals in the pathogenesis of acute pancreatitis. Ann Surg1984;200: 40513.

19 Dabrowski A, Boguslowicz C, Dabrowska M, Tribillo I,Gabryelewicz A. Reactive oxygen species activate mitogen-activatedprotein kinases in pancreatic acinar cells. Pancreas 2000;21: 37684.

20 Leung P, Chan YC. Role of oxidative stress in pancreaticinflammation. Antioxid RedoxSignal2009; 11: 13565.

21 Chavnov M, Petersen OH, Tepikin A. Free radicals andthe pancreatic acinar cells: role in physiology and pathology.

Philos Trans R Soc Lond B Biol Sci 2005; 360: 227384.

22 Capdevila A, Decha-Umphai W, Song K-H, Borchardt RT,Wagner C. Pancreatic exocrine secretion is blocked by inhibitors

of methylation. Arch Biochem Biophys 1997; 345: 4755.23 Mrtennson J, Bolin T. Sulphur amino acid metabolism in chronic

relapsing pancreatitis. Am J Gastroenterol1986; 81: 117984.24 Braganza JM, Scott P, Bilton D, et al. Evidence for early oxidative

stress in acute pancreatitis. Int J Pancreatol1995; 17: 6981.25 Rahman SH, Srinivasan AR, Nicolaou A. Transsulfuration defects

and increased glutathione degradation in severe acute pancreatitis.Dig Dis Sci 2009; 54: 67582.

26 Santini SA, Spada C, Bononi F, et al. Enhanced lipoperoxidationproducts in pure pancreatic juice: evidence for organ-specificoxidative stress in chronic pancreatitis. Dig LiverDis 2003;35: 88892.

27 Gutteridge JMC. Lipid peroxidation and antioxidants as biomarkersof tissue damage. ClinChem1995; 41: 181928.

28 Jin CX, Hayakawa T, Kitagawa M, Ishiguro H. Lactoferrinin chronic pancreatitis.JOP2009; 10: 23741.

29 Graf R, Schiesser M, Reding T, et al. Exocrine meets endocrine:

pancreatic stone protein and regenerating proteintwo sidesof the same coin.J Surg Res 2006; 133: 11320.30 Freedman SD, Sakamoto K, Venu RP. GP2, the homologue to the

renal cast protein uromodulin is a major component of intraductalplugs in chronic pancreatitis.J Clin Invest1993; 92: 8390.

31 Rinderknecht H. Pancreatic secretory enzymes. In: Go VLW,DiMagno EP, Gardner JD, Lebenthal E, Reber HA, Scheele GA, eds.The pancreas. Biology, pathobiology, and disease. 2nd edition.New York: Raven Press, 1993: 21952.

32 Braganza JM, Dormandy TL. Micronutrient therapy for chronicpancreatitis: rationale and impact. JOP2010; 11: 99112.

33 Syrota A, Dop-Ngassa M, Paraf A. C-L-methionine for evaluationof pancreatic exocrine function. Gut1981; 22: 90715.

34 Girish BN, Vaidyanathan K, Rao NA, Rajesh G, Reshmi S,Balakrishnan V. Chronic pancreatitis is associated withhyperhomocysteinemia and derangements in transsulfurationand transmethylation pathways. Pancreas 2010; 39: e1116.

35 Shrikhande SV, Martignoni ME, Shrikhande M, et al. Comparison

of histological features and inflammatory cell reaction in alcoholic,idiopathic and tropical chronic pancreatitis. Br J Surg2003;90: 156572.

36 Lieb II JG, Forsmark CE. Pain and chronic pancreatitis.Aliment Pharmacol Ther2009; 29: 70619.

37 Foster JR, Idle JR, Hardwick JP, Bars R, Scott P, Braganza JM.Induction of drug-metabolising enzymes in human pancreaticcancer and chronic pancreatitis.J Pathol1993; 169: 45763.

38 Wacke R, Kirchner A, Prail F, et al. Up-regulation of cytochromeP450 1A2, 2C9 and 2E1 in chronic pancreatitis. Pancreas 1998;16: 52128.

39 Standop J, Schneider M, Ulrich A, Bchler MW, Pour PM.Differences in immunohistochemical expression ofxenobiotic-metabolizing enzymes between normal pancreas, chronicpancreatitis and pancreatic cancer. Toxicol Pathol2003; 31: 50613.

40 Foster JR. Toxicology of the exocrine pancreas. In: Ballantyne B,Marrs T, Syversen T eds. General and applied toxicology, 3rd edn.

Chichester: John Wiley and Sons, 2009: 141155.41 Braganza JM. A framework for the aetiogenesis of chronicpancreatitis. Digestion 1998; 58 (suppl 4): 112.

42 Witt H, Apte MV, Keim V, Wilson JS. Chronic pancreatitis:challenges and advances in pathogenesis, genetics, diagnosis,and therapy. Gastroenterology2007; 132: 155773.

43 Stevens T, Conwell DL, Zuccaro G. Pathogenesis of chronicpancreatitis: an evidence-based review of past theories and recentdevelopments. Am J Gastroenterol2004; 99: 225670.

44 Casini A, Galli A, Pignalosa P, et al. Collagen type 1 synthesisedby pancreatic periacinar stellate cells (PSC) co-localizes with lipidperoxidation-derived aldehydes in chronic alcoholic pancreatitis.J Pathol2000; 192: 8189.

45 Zimnoch L, Szynaka B, Puchalski Z. Mast cells and pancreaticstellate cells in chronic pancreatitis with differently intensifiedfibrosis. Hepatogastroenterology2002; 49: 113538.

46 Lindstedt KA, Wang Y, Shiota N, et al. Activation of paracrineTGF-beta1 signaling upon stimulation and degranulation of rat serosal

mast calls: a novel function for chymase. FASEB J2001; 15: 137788.


13/14

Seminar


47 Buchler MW, Martigone ME, Friess H, Malfertheiner P. A proposalfor a new clinical classification of chronic pancreatitis.

BMC Gastroenterol2009; 9: 93.48 Longnecker DS. Pathology and pathogenesis of diseases

of the pancreas. Am J Pathol1982; 107: 10321.49 OSullivan BP, Freedman SD. Cystic fibrosis. Lancet2009;

373: 1891904.50 Shimosegawa T, Kanno A. Autoimmune pancreatitis in Japan:

overview and perspective. JGastroenterol2009; 44: 50317.51 Park DH, Kim M-H, Chari S. Recent advances in autoimmune

pancreatitis. Gut2009; 58: 168089.52 Wagner ACC. Serological tests to diagnose chronic pancreatitis.

In: Buchler MW, Friess H, Uhl W, Malfertheiner P, eds. Chronicpancreatitis: novel concepts in biology and therapy. London:Blackwell, 2002: 21722.

53 Frulloni L, Gabrielli A, Pezzilli R, et al. Chronic pancreatitis: reportfrom a muticenter Italian survey (PanCronfAISP) on 893 patients.Dig Liver Dis 2009; 41: 31117.

54 Yan M-X, Li Y-Q. Gall stones and chronic pancreatitis: the black box

in between. Postgrad Med J2006; 82: 25458.55 Yadav D, Whitcomb DC. The role of alcohol and smoking

in pancreatitis. Nat RevGastroenterol Hepatol2010; 7: 13145.56 Yang AL, Vadhavkar S, Singh G, Omary MB. Epidemiology of

alcohol-related liver and pancreatic disease in the United States.Arch Intern Med2008; 168: 64956.

57 Pezzilli R. Etiology of chronic pancreatitis: has it changed in the lastdecade? World JGastroenterol2009; 15: 473740.

58 Pandol SJ, Rarity M. Pathobiology of alcoholic pancreatitis.Pancreatology2007; 7: 10514.

59 Li J, Guo M, Liu R, Wang R, Tang C. Does chronic ethanol intakecause chronic pancreatitis?: evidence and mechanism. Pancreas2008; 37: 18995.

60 Balakrishnan V, Unnikrishnan AG, Thomas V, et al. Chronicpancreatitis: a prospective nationwide study of 1086 subjects fromIndia.JOP2008; 9: 593600.

61 Dufour MC, Adamson MD. The epidemiology of alcohol-inducedpancreatitis. Pancreas 2003; 27: 28690.

62 Strubelt O. Interaction between ethanol and other hepatotoxicagents. Biochem Pharmacol1980; 29: 144549.

63 Lieber CS. The discovery of the microsomal ethanol oxidizingsystem and its physiological and pathological role. Drug Metab Rev2004; 36: 51112.

64 Gonzalez FJ. Role of cytochromes P450 in chemical toxicity andoxidative stress: studies with CYP2E1. Mutat Res 2005; 569: 10110.

65 Barman KK, Premalatha G, Mohan V. Tropical chronic pancreatitis.Postgrad Med J2003; 79: 60615.

66 Balakrishnan V. Tropical pancreatitisepidemiology, pathogenesisand aetiology. In: Balakrishnan V, ed. Chronic pancreatitis in India.Trivandrum: St Josephs Press, 1987: 8185.

67 Di Magno MJ, Wamsteker E-J, Lee A. Chronic pancreatitis.BMJ Best Practice 2010. http://bestpractice.bmj.com/best-practice/monograph/67/highlights.html (accessed Feb 12, 2011).

68 Wittel UA, Hopt UT, Batra SK. Cigarette smoke-induced pancreaticdamage: experimental data. Langenbecks Arch Surg2008;

393: 58188.69 Hao J-Y, Li G, Pang B. Evidence for cigarette smoke-induced

oxidative stress in the rat pancreas. Inhalation Toxicol2009;21: 100712.

70 McNamee R, Braganza JM, Hogg J, Leck I, Rose P, Cherry N.Occupational exposure to hydrocarbons and chronic pancreatitis:a case-referent study. Occup Environ Med1994; 51: 63137.

71 Braganza JM, John S, Padmayalam I, et al. Xenobiotics and tropicalpancreatitis. Int J Pancreatol1990; 7: 23145.

72 Jeppe CY, Smith MD. Transversal descriptive study of xenobioticexposures in patients with chronic pancreatitis and pancreaticcancer.JOP2008;9: 23539.

73 Merkord J, Weber H, Jonas L, Nizze H, Henninghausen G.The influence of ethanol on long-term effects of dibutyltindichloride (DBTC) in pancreas and liver of rats. Hum Exp Toxicol1998; 17: 14450.

74 Frulloni L, Lunardi C, Simone R, et al. Identification of a novel

antibody associated with aotuimmune pancreatitis. N Engl J Med2010; 361: 213542.

75 Ramamoorthy S, Nawaz Z. E6-associated protein is a dualfunction coactivator of steroid hormone receptors.

Nucl Recept Signal2008; 6: e006.76 Steven FS, Al-Habib A. Inhibition of trypsin and chymotrypsin

by thiols. Biochim Biophys Acta 1979; 568: 40815.77 Halangk W, Krger B, Ruthenbrger M, et al. Trypsin activity is

not involved in premature, intrapancreatic trypsinogen activation.Am J Physiol Gastrointest Liver Physiol2002; 282: G36774.

78 Archer H, Jura N, Keller J, Jacobson M, Bar-sag D. A mousemodel of hereditary pancreatitis generated by transgenicexpression of R122H trypsinogen. Gastroenterology2006;131: 184455.

79 Chen JM, Frec C. Chronic pancreatitis: genetics andpathogenesis. Annu Rev GenomicsHum Genet2009; 10: 6387.

80 Ooi CY, Gonska T, Durie PR, Freedman SD. Genetic testingin pancreatitis. Gastroenterology2010; 138: 220206.

81 Mahurkar S, Nageshwar Reddy D, Rao GV, Chandak GR. Geneticmechanisms underlying the pathogenesis of tropical calcificpancreatitis. World J Gastroenterol2009; 21: 25669.

82 Midha S, Khaguria R, Shastri S, Kabra M, Garg PK. Idiopathicchronic pancreatitis in India: phenotypic characterization andstrong genetic susceptibility due to SPINK1 and CFTR mutations.Gut2010; 59: 80007.

83 Cohn JA. Reduced CFTR function and the pathobiology ofidiopathic pancreatitis.J Clin Gastroenterol2005; 39: S7077.

84 Ko SB, Mizumo N, Yatabe Y, et al. Corticosteroids correct aberrantCFTR localization in the duct and regenerate acinar cells inautoimmune pancreatitis. Gastroenterology2010; 138: 198896.

85 Segal I. Pancreatitis in Soweto, South Africa: focus on alcohol.Digestion 1998; 59 (suppl 4): 2535.

86 Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ,DiMagno EP. The different courses of early and late-onsetidiopathic and alcoholic chronic pancreatitis. Gastroenterology1994; 107: 148187.

87 Rosendahl J, Bdeker H, Mssner J, Teich N. Hereditary chronicpancreatitis. Orphanet J Rare Dis 2007; 2: 1.

88 Lankisch PG, Lhr-Happe A, Otto J, Creutzfeldt W. Natural course

in chronic pancreatitis. Digestion 1993; 54: 14855.89 Bornman PC, Girdwood AH, Marks IN, Hatfield ARW, Kottler RE.

The influence of continued alcohol intake, pancreatic ducthold-up, and pancreatic insuffi ciency on the pain pattern inchronic noncalcific and calcific pancreatitis: a comparative study.Surg Gastroenterol1982; 1: 59.

90 Gardner TB, Kennedy AT, Gelrud A, et al. Chronic pancreatitisand its effect on employment and health care experience: resultsof a prospective American multicenter study. Pancreas 2010;39: 498501.

91 Hoogerwerf WA, Gondesen K, Xiao SY, Winston JH, Willis WD,Pasricha PJ. The role of mast cells in the pathogenesis of pain inchronic pancreatitis. BMC Gastroenterol2005; 5: 8.

92 Nishimura S, Fukushima H, Takahashi T, et al. Hydrogen sulfideas a novel mediator for pancreatic pain in rodents. Gut2009;58: 76270.

93 Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis

and the risk of pancreatic cancer. N Engl J Med1993; 328: 143337.94 Rebours V, Boutron-Ruault M-C, Jooste V, et al. Mortality rateand risk factors in patients with hereditary pancreatitis: uni- andmultidimensional analyses. Am J Gastroenterol2009; 104: 231217.

95 Sah RP, Chari ST, Pannala R, et al. Differences in clinical profileand relapse rate of type 1 versus type 2 autoimmune pancreatitis.Gastroenterology2010; 139: 14048.

96 Braganza JM. The role of the liver in exocrine pancreatic disease.Int J Pancreatol1988; 3: S1942.

97 Balci NC, Smith A, Momtahen AJ, et al. MRI and S-MRCPfindings in patients with suspected chronic pancreatitis:Correlation with endoscopic pancreatic function testing (Epft).JMagn Reson Imaging2010; 31: 60106.

98 Tamura R, Ushibashi T, Takahashi S. Chronic pancreatitis: MRCPversus ERCP for quantitative caliber measurement and qualitativeevaluation. Radiology2006; 238: 92028.

99 Czako L. Diagnosis of early-stage chronic pancreatitis bysecretin-enhanced magnetic resonance cholangiopancreatography.

J Gastroenterol2007; 42 (suppl 17): 11317.


14/14

Seminar

100 Sai JK, Suyama M, Kubokawa Y, Watanabe S. Diagnosis of mildchronic pancreatitis (Cambridge classification): comparative study

using secretin injection-magnetic resonancecholangiopancreatography and endoscopic retrogradepancreatography. World J Gastroenterol2008; 14: 121821.

101 Kahl S, Glasbrenner B, Leodolter A, Pross M, Schulz HU,Malfertheiner P. EUS in the diagnosis of early chronic pancreatitis:a prospective follow-up study. Gastrointest Endosc2002; 55: 50711.

102 Catalano MF, Sahai A, Levy M, et al. EUS-based criteria for thediagnosis of chronic pancreatitis: the Rosemont classification.Gastrointest Endosc2009; 169: 125161.

103 Balci NC, Perman WH, Saglam S, Akisik F, Fattahi R, Bilgin M.Diffusion-weighted magnetic resonance imaging of the pancreas.Top Magn Reson Imaging2009; 20: 4347.

104 Kumar R, Kumari A, Garg P, et al. Role of F18-FDG PET-CTimaging in differentiating benign and malignant pancreatic lesionsand its comparison with CT/MRI/EUS.J Nucl Med2009;50 (suppl 2): 1755.

105 Girish BN, Rajesh G, Vaidyanathan K, Balakrishnan V. Fecalelastase1 and acid steatocrit estimation in chronic pancreatitis.Indian J Gastroenterol2009; 28: 20105.

106 Nakamura H, Morifuji M, Murakami Y, et al. Usefulness of a13C-labeled mixed triglyceride breath test for assessing exocrinefunction after pancreatic surgery. Surgery2009; 145: 16875.

107 Kamisawa T, Tu Y, Egawa N, Okamoto A, Kodama M, Kamata N.Can MRCP replace ERCP for the diagnosis of autoimmunepancreatitis? Abdom Imaging2009; 34: 38184.

108 Mendieta Zern H, Garcia Flores JR, Romero Prieto ML.Limitations in improving detection of pancreatic adenocarcinoma.Future Oncol2009; 5: 65768.

109 Pezzilli R. Intraductal papillary-mucinous tumor of the pancreas:the clinical research continues. JOP2004; 5: 5355.

110 WHO. Cancer pain relief and palliative care: report of a WHOexpert committee. Geneva: World Health Organization, 1990:technical report series 804.

111 Di Bello MG, Masini E, Ioannides C, et al. Histamine release fromrat mast cells induced by the metabolic activation of drugs of abuse

into free radicals. Inflamm Res 1998; 47: 12230.112 Kawa S, Hamano H, Ozaki Y, et al. Long-term follow-up of

autoimmune pancreatitis: characteristics of chronic disease andrecurrence. Clin Gastroenterol Hepatol2009; 7 (suppl 11): S1822.

113 Winstead NS, Wilcox CM. Clinical trials of pancreatic enzymereplacement for painful chronic pancreatitisa review.Pancreatology2009; 9: 34450.

114 Shafiq N, Rana S, Bhasin D, et al. Pancreatic enzymes for chronicpancreatitis. Cochrane Database Syst Rev2009; 4: CD006302.

115 Kotzampassi K, Paramythiotis D, Makedou A, Eleftheriadis E.Octreotide improves oxidative stress in sodiumtaurocholate-induced pancreatic injury. Annals Gastroenterol2004;17: 40206.

116 De las Heras-Castano G, Garcia de la Paz A, Fernandez MD,Fernndez Forcelledo JL. Use of antioxidants to treat pain inchronic pancreatitis. Rev Esp Enferm Dig2000; 92: 38185.

117 Dt P, Prcechtelov M, Novotn I, Soka V, akov A, Lata J.Changes of reactive oxidative substances in patients withmorphologically different degrees of chronic pancreatitisand effects of long-term therapy with natural antioxidants.Gastroenterologia Polska 2003; 10: 37983.

118 Uomo G, Talamini G, Rabitti PG. Antioxidant treatment inhereditary pancreatitis: a pilot study on three young patients.Dig Liver Dis 2001; 33: 5862.

119 Uden S, Bilton D, Nathan L, Hunt LP, Main C, Braganza JM.Antioxidant therapy for recurrent pancreatitis: placebo-controlledtrial. Aliment Pharmacol Ther1990; 4: 35771.

120 Uden S, Schofield D, Miller PF, Day JP, Bottiglieri T, Braganza JM.Antioxidant therapy for recurrent pancreatitis: biochemical profilesin a placebo-controlled trial. Aliment PharmacolTher1992; 6: 22940.

121 Kirk GR, White JS, McKie L, et al. Combined antioxidant therapyreduces pain and improves quality of life in chronic pancreatitis.J Gastrointest Surg2006; 10: 499503.

122 Bhardwaj P, Garg PK, Maulik S, Saraya A, Tandon RK, Acharya SK.A randomized controlled trial of antioxidant supplementation for

pain relief in patients with chronic pancreatitis. Gastroenterology2009; 136: 14959.

123 Monfared SSMS, Vahidi H, Abdolghaffari AH, Nikfar S,Abdollahi M. Antioxidant therapy in the management of acute,

chronic and post-ERCP pancreatitis: a systematic review.World JGastroenterol2010; 15: 448190.

124 Bilton D, Schofield D, Mei G, Kay PM, Bottiglieri T, Braganza JM.Placebo-controlled trials of antioxidant therapy in patients withrecurrent pancreatitis. Drug Invest1994; 8: 1020.

125 McCloy RF. Chronic pancreatitis at Manchester, UK. Focuson antioxidant therapy. Digestion 1998; 59 (suppl 4): 3648.

126 Dominguez-Muoz JE, Iglesias-Garcia J. Oral pancreatic enzymesubstitution therapy in chronic pancreatitis: is clinical response anappropriate marker for evaluation of therapeutic effi cacy?JOP2010;11: 15862.

127 Li T-S, Marbn E. Physiological levels of reactive oxygen species arerequired to maintain genomic stability in stem cells. Stem Cells2010; 28: 117885.

128 Gutteridge JMC, Halliwell B. Antioxidants: molecules, medicines,and myths. BiochimBiophys Res Commun 2010; 393: 56164.

129 Braganza JM, Odom N, McCloy RF, Ubbink JB. Homocysteine

and chronic pancreatitis. Pancreas 2010; 39: 130304.130 Segal I, Ally R, Hunt LP, Sandle LN, Ubbink JB, Braganza JM.Insights into the development of alcoholic chronic pancreatitis atSoweto, South Africa: a controlled cross-sectional study. Pancreas(in press).

131 Shah NS, Makin AJ, Sheen AJ, Siriwardena AK. Quality of lifeassessment in patients with chronic pancreatitis receivingantioxidant therapy. World J Gatroenterol2010; 16: 406671.

132 Sharer NM, Taylor PM, Linaker BD, Gutteridge JMC, Braganza JM.Safe and successful use of vitamin C to treat painful calcific chronicpancreatitis despite iron overload from primary haemochromatosis.Clin Drug Invest1995; 10: 31015.

133 Heyries L, Sahel J. Endoscopic treatment of chronic pancreatitis.World J Gastroenterol2007; 13: 612733.

134 Rosso E, Alexis N, Ghanesh P, et al. Pancreatic pseudocyst inchronic pancreatitis: endoscopic and surgical treatment. Dig Surg2003; 20: 397406.

135 Pai CG, Suvana D, Bhat G. Endoscopic treatment as first-line

therapy for pancreatic ascites and pleural effusion.JGastroenterol Hepatol2009; 24: 1198202.

136 Cahen DL, Gouma DJ, Nio Y, et al. Endoscopic versus surgicaldrainage of the pancreatic duct in chronic pancreatitis. N Engl J Med2007; 356: 67684.

137 Kowalczyk LM, Draganov PV. Endoscopic therapy for chronicpancreatitis: technical success, clinical outcomes, andcomplications. Curr Gastroenterol Rep 2008; 11: 11118.

138 Dumonceau J-M, Costamagna G, Tringali A, et al. Treatment forpainful calcified chronic pancreatitis: extracorporeal shock wavelithotripsy versus endoscopic treatment: a randomized controlledtrial. Gut2007; 56: 54552.

139 Baghdadi S, Abbas MH, Albouz F, Ammori BJ. Systematic reviewof the role of thoracoscopic splanchnicectomy in palliating the painof patients with chronic pancreatitis. Surg Endosc2008; 22: 58088.

140 Laverick JM, Gordon SR, Sutton JE, Suriawinata A, Gardner TB.A comprehensive, case-based review of groove pancreatitis. Pancreas2009; 38: e16975.

141 Beger HG, Bchler M, Bittner RR, Oettinger W, Roscher R.Duodenum-preserving resection of the head of the pancreas insevere chronic pancreatitis: early and late results. Ann Surg1989;209: 27378.

142 Ho HS, Frey CF. The Frey procedure: local resection of pancreatichead combined with lateral pancreaticojejunostomy. Arch Surg2001;136: 135358.

143 Mller MW, Friess H, Leitzbach S, et al. Perioperative and follow-upresults after central pancreatic head resection (Berne technique) ina consecutive series of patients with chronic pancreatitis. Am J Surg2008; 196: 36472.

144 Shah NS, Siriwardena AK. Variance in elective surgery for chronicpancreatitis.JOP2009; 10: 3036.

145 Andersen DK, Frey CF. The evolution of the surgical treatmentof chronic pancreatitis. Ann Surg2010; 251: 1832.

146 Garcea G, Weaver J, Phillips J, et al. Total pancreatectomy with andwithout islet cell transplantation for chronic pancreatitis: a series of

85 consecutive patients. Pancreas 2009; 38: 17.

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