Seminar

Chronic pancreatitis
Joan M Braganza, Stephen H Lee, Rory F McCloy, Michael J McMahon
Lancet 2011; 377: 118497 Published Online March 11, 2011 DOI:10.1016/S01406736(10)61852-1 Department of Gastroenterology (J M Braganza DSc) and Department of Radiology (S H Lee FRCR), Manchester Royal Inrmary, Manchester, UK; Department of Education, Lancashire Teaching Hospitals, Preston, UK (R F McCloy FRCS); and University of Leeds and Nueld 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 jenny.parr@manchester.ac.uk

Chronic pancreatitis is a progressive broinammatory disease that exists in large-duct (often with intraductal calculi) 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 cystic brosis transmembrane conductance regulator); a few patients have hereditary or autoimmune disease. Pain in the form of recurrent attacks of pancreatitis (representing paralysis of apical exocytosis in acinar cells) or constant and disabling pain is usually the main symptom. Management of the pain is mainly empirical, involving potent analgesics, duct drainage by endoscopic or surgical means, and partial or total pancreatectomy. However, steroids rapidly reduce symptoms in patients with autoimmune pancreatitis, and micronutrient therapy to correct electrophilic stress is emerging as a promising treatment in the other patients. Steatorrhoea, diabetes, local complications, and psychosocial issues associated with the disease are additional therapeutic challenges.

Introduction
Chronic pancreatitis is a progressive inammatory disorder in which pancreatic secretory parenchyma is destroyed and replaced by brous tissue, eventually leading to malnutrition and diabetes. Two forms are recogniseda large-duct calcifying type1 and a small-duct variant.24 The disease is uncommon in Europe and the USA; its prevalence in France is 26 per 100 000 people.5 This prevalence is not dissimilar to the middle of three estimates from Japan,6,7 but considerably lower than the gure of 114200 per 100 000 in south India.7 The main symptom of chronic pancreatitis is usually pain, which occurs as attacks that mimic acute pancreatitis or as constant and disabling pain. Despite decades of research, treatment of chronic pancreatitis remains mostly empirical, and thus patients are repeatedly admitted to hospital and have interventional procedures, which strains medical resources.8 This absence of progress in treatment is a sign of uncertainty about how the identied causative factors lead to the disease. Therefore, in this Seminar we focus on the pathophysiology and pathology of chronic pancreatitis before describing clinical management.

Denition
Traditionally, chronic pancreatitis has been classed as fundamentally dierent from acute pancreatitisthe latter is usually characterised by restoration of normal pancreatic histology after full clinical recovery.1 However, acute, recurrent acute, and chronic pancreatitis are now regarded as a disease continuum.9,10 There are several reasons for this change: recurrent acute pancreatitis can develop into chronic pancreatitis;1012 there is an overlap in causative factors, both genetic and environmental;10,13 experimental protocols can be modied to induce each condition;14 and the pancreatitis attack is stereotyped patients have severe abdominal pain and increased blood amylase, lipase, and trypsinogen.

Pathophysiology and pathology

Experimental studies since the 1950s have shown that an attack of pancreatitis begins as pancreastasis,13 prevention of apical exocytosis in the pancreatic acinar cell (gure 1).15 The acinar cell quickly releases newly synthesised enzyme via the basolateral membrane into lymphatics, by way of the interstitium, and directly into the bloodstream.16 Some zymogen granules also release their stored enzyme basolaterally.15 These events result in inammation.17 Findings from prospective clinical studies concur with this pancreastasispancreatitis sequence.13,17 Experimental work has pinpointed a burst of reactive oxygen species (ROS) as the trigger of so-called pancreastasis18 and as the potentiator of inammation by activating signalling cascades that convert the damaged acinar cell into a factory for chemokines and cytokines.19,20 ROS serve several physiological roles, including in signal transduction,13,21 but an excess of ROS compared with antioxidant capacity (electrophilic stress) is potentially very damaging. The exocytosis blockade seems to be caused by disruption of the methionine trans-sulphuration pathway that produces essential methyl and thiol (principally glutathione) moieties.17,22 This problem also occurs in clinical acute or acute-on-chronic pancreatitis.2325 In patients who develop large-duct chronic pancreatitis, studies in the quiescent phase of the disease show that the composition of pancreatic uid changes in a manner
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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 specic searches, with chronic pancreatitis as the key phrase combined with epidemiology, pathology, aetiology, gene mutations, pathogenesis, classication, 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 identied 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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Normal

Pancreastasis

Pancreatitis PAP/regIII PSP/reg

Constitutive pathways

ZG L

ZG ZG-L

ZG

D ZG-L

GC RER RER ZG

GC

RER Ph-elastase Ph-PLA2

Nucleus Constitutive pathway E

Nucleus

Nucleus MO

MC

PMN Foci of gland digestion

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

that, for uncertain reasons, facilitates protein deposits the precursors to calcium carbonate stones.1 (1) There is an early increase in secretion of enzyme and calcium, but a decrease in the serine protease inhibitor Kazal type 1 (SPINK 1), bicarbonate, and citrate.1 (2) Concentrations of free radical oxidation products are raised in the pancreatic uid,26 which suggests ongoing electrophilic stress, and in an apparent attempt to compensate, concentrations of the natural antioxidants27 lactoferrin and mucin are increased.1,2,28 (3) Concentrations are altered of two secretory stress proteins29 (increased concentration of pancreatitis associated protein [PAP]/regIII, which is activated by electrophilic stress; and variable concentration of pancreatic stone protein [PSP]/reg, formerly called lithostatin;1 gure 1) that tend to form brous lattices upon partial digestion by trypsin. (4) There is an increase of GP-2, which is a secreted component of zymogen granule membranes (analogous to the renal cast protein).30 (5) Concentrations of lysosomal enzymes are increased in ductal uid, and traces of trypsin appear.31 Moreover, the methionine metabolic pathway remains fractured.3234 On histology, the dening triad of stable disease (irrespective of main causes or location)35 is acinar loss, mononuclear cell inltration, and brosis. The early lesions are distributed in patches; thus, normal ndings on needle biopsy are unreliable. An unusual form of socalled groove (paraduodenal) pancreatitis has been identied.11 Each inammatory attack can cause foci of fat necrosis that seem to lead to both pseudocysts and
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brosis.11 Nerves show breaching of the perineurium adjacent to inammatory foci, while the expression of nociceptive chemicals in nerve endings is increased.36 Immunocytochemistry gives valuable insights into the development of chronic pancreatitis. Acinar cells, which are hyperplastic at disease outset,2 show strong expression of cytochrome P450 (CYP) monooxygenases,3739 as do proliferated islets of Langerhans,3739 and hepatocytes (gure 2).37,38 After birth, CYP enzymes are mainly located in the liver. CYP metabolises environmental lipophilic chemicals (xenobiotics). In the rst phase, the enzyme uses ROS to hydroxylate the substrate, which then usually undergoes second-phase conjugation reactions, often with glutathione and catalysed by glutathione transferases. So-called enzyme induction might be accompanied by expansion of the endoplasmic reticulum so that, at least initially, the cell secretes more of its normal products. However, this defence reaction backres if rst-phase processing (eg, by CYP2E1, CYP1A, and CYP3A1 isoforms) produces a reactive xenobiotic metabolite. Cell injury depends on whether or not there is enough by way of defences to ROS and reactive xenobiotic species: antioxidant enzymes (including the selenium-dependent glutathione peroxidase), glutathione transferases, glutathione, and ascorbic acid (the bioactive form of vitamin C, which can substitute for glutathione).32,40 Immunochemistry shows that these defence mechanisms are insucient to meet the increased oxidant load in acinar cells,32,37 which therefore
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show signs of electrophilic stress, such as excess lipofuscin and cytoplasmic microvesiculation.41 Fibrosis is a sign that interstitial stellate cells are activated in chronic pancreatitis; these cells play a central part in disease progression by regulating the synthesis and degradation of extracellular matrix proteins.42,43 Findings from histochemistry suggest a causal inuence of two factorsan increase in lipid peroxidation products caused by an excess of ROS in adjacent acini,44 and the release of mast cell degranulation products,45 transforming growth factor 1 in particular.46 The two factors are linked in that ROS and their oxidation products are natural activators of mast cells.17 Activation of stellate cells is increased by cytokines from inltrating leucocytes and the injured acinar cell.43 The end stage of chronic pancreatitis is identied by loss of all secretory tissue, disappearance of inammatory cells, and intense brosis. This

progression resembles that from chronic active hepatitis to liver cirrhosis.2,12,47 The table summarises the histological features of ordinary chronic pancreatitis compared with features of three variants in which the lesions are diuse. The pancreatic lesion in cystic brosis is a diuse form of chronic pancreatitis wherein inammatory stigmata disappear by birth,48 except in patients with mild mutations in the cystic brosis transmembrane conductance regulator gene (CFTR), who might have recurrent attacks.49 Uniform lesions also occur upstream of an obstructed duct1,11,48 and in autoimmune pancreatitis.50,51 The latter can involve the whole or part of the gland and has two subtypes. Characteristics of the more common type-1 autoimmune pancreatitis are a dense lymphoplasmacytic inltrate with predominantly IgG4+ cells, periductal swirling sclerosis, and obliterative venulitis. In the type-2, duct-destructive form, hordes

B H

D S A

D
50 m 50 m

Figure 2: Immunolocalisation of cytochrome P4503A1 in surgical material from a 27-year-old woman with calcic 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) The pancreatectomy 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

Ordinary* Lesions Distribution Extent of gland Duct system Main duct Protein plugs Calcifying tendency Epithelium destroyed Neutrophils Inammatory cells Fibrosis Pseudocyst Irregularly dilated All ducts Yes (Groove form) No Mononuclear Mainly perilobular Frequent Patchy Variable

Cystic brosis

Obstructive

Autoimmune

Diuse Total Minimally dilated No No No No Perilobular, intralobular No

Diuse Total Smoothly dilated No No No No Perilobular, intralobular No

Diuse Total or focal Constricted No No Yes (type 2) Yes (type 2) Plasmalymphacytic Perilobular, intralobular, periductal No

Intralobular and interlobular 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 Diuse 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)

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of neutrophils inltrate the wall of the duct, accompanied by lymphocytes and plasma cells.51

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 deciency 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 brosis transmenbrane conductance regulator. PRSS1=protease serine cationic trypsinogen. SPINK1=serine protease inhibitor Kazal. *Other, less common mutations have been described.

Causes
Panel 1 lists causative factors of chronic pancreatitis. In adults, excluding those with cystic brosis, 9095% of patients are regarded as having alcoholic or idiopathic disease. Infective causes are rare.52 The connection between chronic pancreatitis and drugs (eg, valproate) is mostly anecdotal. Studies from Italy,53 China, and Japan54 report an association with gallstones in about 30% of patients.

Alcoholic
Alcohol has long been regarded as the leading cause of chronic pancreatitis in Europe, the USA, Brazil, Mexico, and South Africa, and is now regarded as the main cause of the disease also in Australia and South Korea.7 However, excess alcohol was the predominant factor in only 34% of cases of chronic pancreatitis in a recent multicentre study from Italy53 and in 44% of cases in an audit from the USA,55 with another study reporting that African-Americans are at particular risk.56 Whether these new data reect dierences in the denition of alcoholic disease55 or a genuine change in the cause of chronic pancreatitis is not clear.57 Experimental studies have shown that, although the pancreas processes ethanol eciently (via a non-oxidative route that produces fatty acid ethyl esters, and by oxidation via the acetaldehyde pathway), its metabolites injure acinar cells and activate stellate cells in vitro.42,58 However, prolonged ethanol feeding does not induce chronic pancreatitis.58,59 Hence, the nding of a latent interval of 15 years or more in patients who consumed 150 g or more of ethanol per dayas most recently noted in India60is unsurprising. Moreover, less than 10% of people who drink alcohol in excess develop the disease.61 Collectively, these ndings suggest that other factors interact to amplify ethanol toxicity in vivo. In animal models, small doses of ethanol induce CYP2E1, thus increasing the toxicity from other chemicals to which the animal is simultaneously exposed.62,63 These results might rationalise the old observation that there is no threshold for the pancreatic toxicity of ethanol,1 but recent data suggest there is a threshold at 60 g per day.55 Moreover, CYP2E1 is the main pathway that metabolises ethanol upon chronic excessive ingestion,63 but this pathway releases ROS.64

Idiopathic
6070% of cases of chronic pancreatitis in India and China are labelled as idiopathic, as are around half the cases in Japan.7 Tropical pancreatitis is a form of idiopathic pancreatitis that aects young people and has a propensity to diabetes and large calculi.65 This disease is mainly reported in developing countries of Asia, Africa, and Central America, where severe malnutrition and cyanogenic glycosides in cassava
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(manioc) were implicated. The classic description of tropical pancreatitis was from Kerala, south India;66 however, hospital admission statistics revealed a decline in the disease by six times between 1962 and 1987,66 without a change in cassava consumption. Instead, the decline coincided with the introduction of electricity in this province, which removed the dependence on traditional lighting (see below). At present, tropical pancreatitis accounts for just 38 % of cases of chronic pancreatitis in India.60

Other toxic causes

Cigarette smoke has emerged as a strong independent risk factor for chronic pancreatitis;55,67 the link was veried
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by inhalation toxicology experiments.68,69 A case-control study from the UK identied occupational volatile hydrocarbons as another independent risk factor.70 This connection is upheld by descriptive studies from Chennai, India,71 and Soweto, South Africa,72 which also reported regular contact with kerosene or paran, respectively, in cookers, heaters, or lamps in patients with chronic pancreatitis (potentially relevant to Kerala, see above). Toxic damage to the pancreas by petrochemicals has been documented in lower vertebrates.40 Moreover, the simplest animal model of chronic pancreatitis, which develops via an acute phase, involves just one parenteral injection of dibutyltin (which has many industrial uses) and the injury is amplied by alcohol.73 All these ndings reinforce the pathological evidence (gure 2) that the pancreas is a versatile but also vulnerable xenobiotic-metabolising organ.40 Inhaled xenobiotics that survive the pulmonary circulation would pose the biggest threat (gure 2A) by striking the pancreas directly via its rich arterial supply.

Autoimmune
Autoimmune pancreatitis (24% of cases57) can be part of a multisystem disease (type 1) or can aect the pancreas alone (type 2).50,51 Aberrant human leucocyte antigen DR-1 expression on pancreatic ductal cells might present autoantigens to lymphocytes. Proposed pancreas-specic antigens include lactoferrin,28 carbonic anhydrase, SPINK1, and a peptide that is present in acinar cells that has homology to aminoacid sequences in the plasminogen-binding protein of Helicobacter pylori74 (which might represent molecular mimicry)51 and also in ubiquitinprotein ligase74 (a cofactor for steroid hormone receptors and an important peptide in the intracellular protein degradation pathway).75

Idiopathic chronic pancreatitis is associated with a mutation in the CFTR gene.80,82,83 Patients can have one abnormal recessive allele, but possession of two confers a 40 times increased risk of developing idiopathic chronic pancreatitis, which rises to 500 times in patients who also have a SPINK1 mutation.83 Some patients with apparent idiopathic chronic pancreatitis who have CFTR mutations have an atypical form of cystic brosis.80 Three overlooked aspects of CFTR function have been reviewed recently.32 CFTR is present in the luminal pole of acinar cells where it might facilitate membrane recycling and exocytosis, like it does elsewhere. CFTR transports bicarbonate and glutathionewhich facilitate the solubility of mucins in secretionsacross the luminal membrane of ductal cells adjacent to the centroacinar space. CFTR is inactivated by electrophilic stress but is protected by thiols and ascorbic acid. Moreover, CFTR is mislocalised to the cytoplasm of ductal cells in patients with chronic pancreatitis; this misplacement is corrected in autoimmune disease by steroids, which also reduce inammation, restore bicarbonate and enzyme secretion, and regenerate acinar cells.84 Mutations in CFTR and SPINK1 have also been described in patients with hypertriglyceridaemia or hyperparathyroidism who develop pancreatitis.32 At present, molecular decits that contribute to chronic pancreatitis have been identied in less than 10% of alcoholic chronic pancreatitis and around 50% of cases overall.79

Pathogenesis
There is no agreement as to how these diverse causative factors lead to chronic pancreatitis. There are many hypotheses about the pathogenesis of the disease,43 which fall into ve main categories.

Genetic
Normally, if trypsinogen becomes prematurely activated within the pancreas, it is inhibited by SPINK1 and then self-destructs or is degraded by trypsin-activated proteases;31 the potent inhibitor gluthathione is available if all else fails.76 Hereditary pancreatitis is a rare condition that is caused by a gain-of-function mutation (autosomal dominant, 80% penetrance) in the cationic trypsinogen gene (PRSS1),9,10,42 which produces a degradationresistant form of trypsin.77 A transgenic mouse model of chronic pancreatic injury has proved this link.78 The PRSS1 mutation is not associated with alcoholic or tropical chronic pancreatitis.79 By contrast, a loss-offunction mutation in SPINK1 is strongly associated with idiopathic disease7982 but is thought to be a predisposing or modifying factor rather than being directly causative.42,79,80 Mutations in other genes that could increase the threat from trypsin have also been described,79 as has a loss-of-function mutation in the PRSS2 gene (encoding anionic trypsinogen), which protects against pancreatitis.79,80
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Ductal theory
One hypothesis suggests that ducts are the primary target of the disease: theories centre on the primacy of calcifying protein deposits (protein plug hypothesis),1 stagnation of pancreatic juice, reux of noxious bile and duodenal juice (facilitated by passage of gallstones), and primary autoimmune attack.

Acinar theory
Another hypothesis suggests that acini are the primary target: alcohol is thought to injure acinar cells directly (toxic metabolite hypothesis) or by increasing the cells sensitivity to cholecystokinin (CCK) or via CYP2E1, while also activating stellate cells, especially in the presence of endotoxin.42,58 Another suggestion is that the disease is caused by cyanide toxicity of the pancreas.

Two-hits theory
Two so-called hits are additionally suggested as causing the 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 brosis.11 The rst attack of pancreatitis is taken to represent autodigestion caused by unregulated trypsin activity in the acinar cell. If this attack is severe enough to recruit macrophages (sentinel acute pancreatitis event hypothesis), subsequent damage to the gland (by alcohol or electrophilic stress) leads to brosis via macrophage-primed stellate cells.

Electrophilic stress theory

The electrophilic stress theory is the pancreatic equivalent of paracetamol or carbon tetrachloride hepatotoxicity, which results from insucient protection by glutathione against electrophilic attack (via CYP) on key macromoleculesnot least, enzymes in the methionine trans-sulphuration pathway towards glutathione. However, in chronic pancreatitis electrophilic stress from toxic metabolitesand, thereby, recurrent pancreastasisdevelops over many years as a result of repetitive exposures to multiple xenobiotics.41 Previous dietary insuciency of micronutrients, especially methionine and ascorbic acid, facilitates the problem.41,85 The diversion of free radical oxidation products into the interstitium causes mast cells to degranulate, leading to inammation, activation of nociceptive axon reexes, and brosis.41 The realisation that compromised availability of methyl and thiol (glutathione) moieties underlies chronic pancreatitis has allowed an extension of the electrophilic stress concept to chronic pancreatitis that is associated with gene mutations.32 Thus, the daily exposure of acinar cells to traces of trypsin in people with PRSS1 or SPINK1 mutations is expected to strain glutathione reserves. Of particular note, those with a CFTR mutation would be left vulnerable not only to pancreastasis but also to intraductal calcifying protein plugs (large duct disease) when the residual CFTR protein is immobilised by electrophilic stress.32

constant pain; symptoms and signs of local complications of the disease (eg, pseudocyst, obstruction of adjacent organs, or vascular thrombosis); or complaints that suggest exocrine or endocrine pancreatic failure, or both, by which stage pancreatic calculi are often present. These features form the basis for the most recent classication system (gure 3).47 In alcoholic disease, the interval from rst attack to steatorrhoea (signifying >95% loss of acini) is around 13 years, which is substantially shorter than in early-onset idiopathic disease12,86 or hereditary pancreatitis (26 years).12 Pancreatic calculi appear earliest in tropical pancreatitis,65 and earlier in alcoholic than idiopathic disease.86 Diabetes might precede, begin at the same time as, 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 elderly patients with idiopathic disease12,86 or patients with autoimmune pancreatitis who might present with steatorrhoea, diabetes, or jaundice.50,51 The pain is wearying and occurs in episodes that last about 1 week, or is constant. It starts in the epigastrium and moves through to the dorsal spine or localises to the left hypochondrium, radiating to the left infrascapular region. The pain is sometimes associated with nausea and vomiting and can be partially eased by sitting up and leaning forward or by application of local heat or other counterirritants to the dorsal spine or epigastrium. The pain can be so severe that patients fear food and lose weight. Most,12,86,89 but not all,88 studies have reported that pain diminishes markedly once the disease burns out (which suggests that viable acini are a prerequisite for pancreatic pain). However, by then patients often have become addicted to narcotic analgesics, which could cause them to lose their jobs, homes, or families.88,90 Panel 2 lists factors that might contribute to pain in patients with chronic pancreatitis:36 mast cell degranulation products and hydrogen sulphide are plausible mediators of the pancreatic component.91,92 The intensity of the pain contrasts with the absence of specic signs in

Multiple-cause theory
The nal hypothesis states that dierent causative factors lead to damage via dierent pathways: this concept incorporates the other theories while noting that pancreatic ischaemia can aggravate the disease.43
Attacks of apparent acute pancreatitis Pain Complications Bile duct stricture Duodenal stricture Vascular stricture Portal hypertension Pseudocyst Pancreatic stula Pancreatic ascites Rare, eg, colonic stricture A Early

Clinical features
Alcoholic chronic pancreatitis presents in the fourth or fth decade of life and mainly aects men.86 Idiopathic disease has early-onset (second decade) and late-onset (sixth decade) forms, which have equal gender distribution.12,86 Hereditary disease manifests at around 10 years87 and tropical pancreatitis at between 20 and 30 years,65 whereas the more common type-1 form of autoimmune disease aects men in the sixth decade.51 Presenting features of chronic pancreatitis usually fall into one of four groups: apparent acute or recurrent acute pancreatitis (the true diagnosis of chronic pancreatitis is suspected when attacks recur after cholecystectomy);
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Clinical criteria

B Intermediate

Cause

Pancreatic failure

C End stage 1 endocrine 2 exocrine 3 both

Figure 3: Proposal for a clinically based classication system for chronic pancreatitis For example, a patient may be described as having chronic pancreatitis (idiopathic), stage B, bile duct.47

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uncomplicated disease. Erythema ab igne is a useful pointer for diagnosis of chronic pancreatitis in these patients, as is meteorism in patients whose pain has led to dependence on narcotic analgesics (gure 4). An epigastric swelling suggests a pseudocyst, inammatory mass, or cancer. Patients with multisystem involvement usually have the autoimmune form of chronic pancreatitis.

Panel 2: Pain in chronic pancreatitis Caused by the disease Active inammation* Altered nociception Neurogenic inammation* Visceral nerve sensitisation* Central nerve sensitisation Psychological Hypertension Ductal or tissue via increased cholecystokinin Tissue ischaemia Caused by complications Inammatory 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).

Ordinary chronic pancreatitis has a high mortality ratenearly 50% within 2025 years of disease onset,12 as a result of complications of an attack, coexisting disease, or the eects of alcoholism. Patients with chronic pancreatitis have an increased risk of pancreatic cancer,93 which accounts for 3% of deaths.86 Although the risk of pancreatic cancer is especially high in patients with hereditary pancreatitis,87 they do not have a higher mortality risk than the general population.94 Autoimmune pancreatitis also does not aect long-term survival.95

Diagnosis
Routine laboratory tests might reveal incipient diabetes, type-1 hyperlipidaemia, or hypercalcaemia in patients with suspected chronic pancreatitis. If type-1 autoimmune disease is a possibility, serology will show raised concentrations of -globulin, IgG (IgG4 predominantly), and various antibodies, including antilactoferrin, anti-carbonic anhydrase, rheumatoid factor, and anti-nuclear antibody.50,51 An abnormal liver function prole suggests alcoholic liver disease, non-alcoholic steatohepatitis,96 sclerosing cholangitis,50,51,96 metastases from superimposed pancreatic cancer, gallstones, or, most commonly, constriction of the intrapancreatic bile duct, which occurs early in autoimmune pancreatitis,50,51 but is late otherwise.47 Conrmation of the diagnosis of (non-calcic) chronic pancreatitis is by histology of a wedge biopsy or resected specimen of pancreas. However, this is impractical. A reduction in bicarbonate with or without enzyme content of duodenal aspirates after intubation and hormonal stimulation (by secretin with or without CCK or its analogue caerulein), and abnormalities in the pancreatic duct system on endoscopic retrograde cholangiopancreatography (ERCP) are the most ecient alternative diagnostic techniqueswith the former substantially better at detecting small-duct disease than the latter.2,4 However, the secretory test is available in only a few centres worldwide (and whether or not an
B

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) Plain abdominal radiograph shows heavy calcication in the pancreatic head (arrow) and a loaded colon in a patient with abdominal distension who was addicted to opiates.

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endoscopic secretory test is as good is unclear).97 Moreover, ERCP for diagnosis has largely been abandoned in favour of magnetic resonance cholangiopancreatography (MRCP) because ERCP can precipitate pancreatitis in up to 4% of patients.9 There is no non-invasive test that can substitute for the hormonal test for chronic pancreatitis.2 By contrast, sophisticated imaging methods have rapidly developed, such that the traditional ultrasound scan to visualise the pancreas itself is virtually obsolete (but see gure 5). The repertoire of imaging techniques is impressive: multidetector CT (MDCT; gure 5); MRI;97 MRCP (gure 6), which provides excellent images of the main pancreatic duct98 but not always of the side-branch changes as shown by ERCP; secretin-enhanced MRCP, which also shows duodenal lling by pancreatobiliary secretions99 and is more accurate than standard MRCP in identifying small-duct disease;100 endoscopic ultrasound (EUS),101,102 which identies both parenchymal and ductal alterations (gure 6; now classied as the Rosemont criteria),102 but which is observer-dependent and tends to overdiagnose the disease;67 diusion-weighted MRI;103 and PET.104 The last two imaging techniques have not been properly assessed in chronic pancreatitis, whereas the role of EUS continues to advance. No investigation algorithm is suitable worldwide, because much depends on available resources and expertise, but a battery of tests should not be used for diagnosis of suspected chronic pancreatitis because this will generate many false positive outcomes and cause distress to the patient.2 Figure 7 presents a sequential scheme for diagnosis of the disease, on the basis of whether or not the secretin test is available. This scheme recognises that an abdominal radiograph will show pancreatic calculi (nearly 100% specicity; gure 4) in at least 30% of patients overall and in most patients with tropical pancreatitis. This stepwise approach is unnecessary in a patient who presents with fatty stools after a long history of pancreatitis attacks or pain. In this event, any of the following tests is probably sucient for diagnosis: acid steatocrit (high value) on a spot stool sample (which obviates the need for the traditional 3-day faecal fat test);105 faecal elastase (low);105 recovery in expired air of C (low) from a C-labelled mixed triglyceride load;106 or serum trypsinogen (low).4 However, a CT scan is needed to identify the disease type. Imaging tests show distinctive changes in type-1 autoimmune pancreatitis. Both ultrasound and MDCT typically show a diusely enlarged sausage-shaped gland (gure 5). ERCP shows long or multiple strictures of the pancreatic duct and sometimes a long stricture in the distal bile duct or sclerosing cholangitis.50,51 Findings from one study suggest that MRCP cannot replace ERCP for the diagnosis of autoimmune disease.107 These imaging features are sucient to make the diagnosis in a patient with an increased concentration of IgG4 in serum. If diagnostic doubt exists (as in a patient with type-2
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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 of autoimmune pancreatitis. (B) Multidetector CT showing pancreatic calculi in an atrophic pancreas (long arrow) and a pseudocyst at the tail of the pancreas (short arrow).

Figure 6: Examples of three-dimensional magnetic resonance cholangiopancreatogram and endoscopic ultrasound 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).

disease, for which there are no serum markers), a therapeutic trial of steroids or histology (of core biopsy or resected specimen), or both might be needed.50,51 There are two dicult diagnostic issues that must be addressed. First, how can one distinguish between an inammatory mass of ordinary chronic pancreatitis, focal autoimmune disease, and pancreatic adenocarcinoma with upstream chronic pancreatitis? Raised IgG concentrations can occur in all three settings and existing tumour markers are not specic enough to distinguish between them, although new molecular markers are being developed.108 EUS or MDCT-guided core biopsy can be used to conrm autoimmune pancreatitis, or a simple needle biopsy might identify tumour cells. F-uorodeoxyglucose PET with CT facilitates the identication of cancer,104 but increased uptake is also a feature of autoimmune pancreatitis (as is increased uptake of gallium).50,51 A pancreatectomy specimen might have to be used as the nal diagnostic test, as it is for detecting an intraductal papillary mucinous tumour in a patient who has suspected idiopathic large-duct disease.109 Second, should the clinician start a search for genetic mutations?
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Suspected chronic pancreatitis Positive

Plain radiograph for calculi Negative Multidetector CT Negative Suspected small-duct disease No

Positive

Large-duct disease

Secretin test available? Yes Secretin test Positive Negative

Magnetic resonance cholangiopancreatography after secretin stimulation Negative Endoscopic ultrasound Negative

Positive

When providing treatment to control the pain associated with chronic pancreatitis, the patients fears and misconceptions about the disease should be addressed sympathetically. Time should be spent discussing the disease with the patient at the rst clinic visit, with particular attention paid to circumstances surrounding the rst attack. Patients should be advised to avoid alcohol and cigarettes, although there is no evidence that abstinence from alcohol slows the disease and the eect of alcohol on pain is debated.67,89 A dietary assessment should be done (see later). Where warranted, the help of a psychologist or pain therapy specialist should be sought, and the primary-care practitioner must also be briefed on treatment strategy. Continuity of care is important to gain the patients trust and to minimise the risk of addiction to narcotics.

Analgesics
Positive

Reconsider other diagnoses Re-test at intervals Therapeutic trial of micronutrients?

Chronic pancreatitis

Figure 7: Algorithm for the diagnosis of chronic pancreatitis

A recent review gives valuable guidance.80 PRSS1 mutation testing for diagnostic purposes is acceptable in symptomatic young individuals or in those with a family history of pancreatitis, but counselling and clinical followup are needed if the result is positive. There is no indication for SPINK1 mutation testing. At present there is no rationale for CFTR mutation testing in the setting of pancreatitis alone. Instead, a sweat test should be done if atypical cystic brosis is suspected, and patients should be referred to a specialist clinic when sweat chloride concentration is borderline (4059 mmol/L) or abnormal (>60 mmol/L). However, the vulnerability of CFTR to electrophilic stress potentially explains both false positive sweat tests and abnormal nasal potential dierence studies in a variety of conditions (eg, severe malnutrition).32

Regular analgesics are superuous in patients with sporadic attacks but are needed in those with background pain. Use of analgesics should broadly follow WHO guidelines for cancer pain.110 Briey, analgesic treatment begins with paracetamol or a non-steroidal anti-inammatory drug, or both, followed by a mild opioid such as tramadol, perhaps coupled with a neuroleptic antidepressant. Narcotic analgesics should be avoided if possible. A simple pain diary with a 10 cm visual analogue scale is useful, as is a baseline quality-oflife assessment. Analgesia devices to deliver morphine that are controlled by the patient should not be used, even in an attack. Such drugs can worsen pain by inducing mast cell degranulation111 and (possibly thereby17) cause gastroparesis4 and constipation (gure 4).

Steroids and enzyme therapy

Treatment with steroids is associated with rapid relief of symptoms in autoimmune pancreatitis.50,51 The starting dose is 3040 mg per day of prednisolone, which is tapered over 3 months while monitoring serum IgG concentrations and imaging ndings. Longterm maintenance with 5075 mg per day of prednisolone is recommended to prevent relapses.50 Recurrences, which typically occur in type-1 disease,95 favour the development of pancreatic calculi.112 In patients with small-duct disease, pancreatic acinar cells are suggested to be under constant stimulation by CCK because subnormal delivery of pancreatic proteases into the duodenum allows improved survival of a CCKreleasing peptide from the duodenal mucosa.4 Hence, the following potential treatments have been successfully tested:4 oral pancreatic enzymes (non-enteric coated, two trials), subcutaneous octreotide (one trial), and oral dosing with the CCK-A receptor antagonist loxiglumide (one trial). However, this issue is contentious,113,114 and the explanation that these measures allow the pancreas to rest4 is at odds with the nding that the exocytosis apparatus is already paralysed in an attack (gure 1) and
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Treatment
Treatment goals
The goals of treatment for chronic pancreatitis are to relieve acute or chronic pain, calm the disease process to prevent recurrent attacks, correct metabolic consequences such as diabetes or malnutrition, manage complications when they arise, and address psychosocial problems. Endoscopic treatment, surgery, or both, are only needed when optimum medical treatment fails to relieve pain (gure 8) and to deal with specic complications (gure 3). A detailed discussion of complications is beyond the scope of this Seminar.
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hindered thereafter.32 Other explanations might be that such treatments act by blunting an eect of CCK on pain pathways in the CNS36 or by ameliorating electrophilic stress (see later).115

Painful chronic pancreatitis

Micronutrient therapy
Micronutrient therapy is designed to supply methyl and thiol moieties that are essential for the exocytosis apparatus (gure 1) while protecting it against electrophilic attack, as by CYP-derived ROS or reactive xenobiotics species (gure 2).32 Findings from six clinical trials have reported that micronutrient therapy controls pain and curbs attacks in patients with chronic pancreatitis.116122 Of these trials, three were descriptive116118 and three were placebo-controlled.119122 However, the dierent ways of expressing outcome precludes a meta-analysis.123 The study with the highest power (80%) to detect a dierence between treatment and 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 painful days per month and in the use of analgesic tablets in the treatment group than in the placebo group; substantially more patients became pain free, and biochemical markers of electrophilic stress were lowered by active treatment. Studies from Manchester, UK, suggested that the micronutrient therapy formulation should include methionine and vitamin C,124 with the need for selenium assessed by measuring blood concentrations. Vitamin E and carotene were included in the rst trial because there was no commercial preparation that did not include them,119 and three of the other ve trials also used this protocol.116,121,122 Improvement, as judged by the number of attacks, admission episodes, pain diaries, pain intensity, or permutations and combinations of these factors, occurred by 1012 weeks.119,121,122 In the UK, the micronutrient therapy preparation Antox (Pharma Nord, Morpeth, UK) is a convenient means of dosing because it contains all the desired items. A starting regimen of two tablets of Antox three times per day provides daily doses of 288 g methionine (but up to 4 g might initially be needed in some patients),125 720 mg vitamin C, 300 g organic selenium, and 210 mg vitamin E (which is unnecessary until steatorrhoea develops).126 This treatment has no signicant side-eects now that carotene has been withdrawn because of cosmetic problems:125 one patient (of >300) developed schizophrenia when on 4 g of methionine daily but, of note, this patient had a strong family history of psychiatric disease.125 Patients should also be given dietary advice on antioxidant-rich foods to aid the long-term management of the disease. It should be stressed that culinary practiceseg, frying vegetables at high temperature (as in south India41)could compromise the bioavailability of antioxidants, notably of ascorbic acid.32 Blood monitoring is essential to ensure that plasma and erythrocyte
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Non-narcotic analgesia Alcohol and cigarette avoidance Dietary assessment Psychosocial issues Micronutrient treatment Pancreatic enzyme treatment

Exclude non-pancreatic pain Conservative treatment for 10 weeks Treatment not eective

Treatment eective

Largeduct disease

Smallduct disease

Pancreatic mass

No mass

Cyst or pseudocyst

Solid mass

Endoscopic or surgical duct drainage

Treatment eective

Suspected autoimmune pancreatitis Treatment not eective Trial of steroids

Suspected cancer

Treatment not eective

Neural manipulation*

Treatment eective

Endoscopic drainage

CT guided or endoscopic ultrasound-guided biopsy

Treatment not eective

Treatment eective

Treatment eective

Cancer conrmed

Doubt persists

Pancreatectomy

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.

glutathione levels have increased and that concentrations of the prescribed micronutrients are not excessive, because this would compromise the physiological roles of ROS.127,128 Very recent reports indicate the need to keep track of blood homocysteine, and concentrations of vitamins (B6, B12, folic acid) that serve as cofactors of enzymes that govern homocysteine removaleither by facilitating its transmethylation back to methionine, or by ensuring its passage along the transsulphuration pathway towards glutathione.32,34,41,129 Of particular interest, elevated homocysteine has been recorded in people at Soweto (South Africa) who drank more than 100 g alcohol per day for many years130a group that is traditionally regarded as being at high risk of chronic pancreatitis.55 Treatment for 10 weeks is recommended before any invasive procedure in patients with chronic pancreatitis, to calm the disease process. Full treatment is usually needed for 6 months, followed by a gradual dose reduction guided by biochemical data and patients symptoms.125 We recorded treatment failure in 10% of patients, usually
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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 to boost methyl supply.32 Moreover, micronutrient therapy has no eect on painful conditions that might be misdiagnosed as chronic pancreatitis (unpublished); once validated, this nding could form the basis for a therapeutic trial when the diagnosis remains equivocal after full testing (gure 7). Finally, there is increasing evidence to support the idea that a daily micronutrient supplement might abort the development of chronic pancreatitis in groups or even populations at risk of the disease.32,130 Micronutrient treatment is better at controlling pain and improving quality of life than conventional treatment.131 Moreover, long-term micronutrient treatment might curb disease progression.82 Excluding typical autoimmune pancreatitis, which can be treated with steroids, micronutrient treatment has been eective irrespective of cause (including mutations in PRSS1,118 CFTR,82 and SPINK182), disease duration,131 or ductal anatomy (large-duct calcifying or small-duct disease), and also when there is an inammatory calcied mass.132 By contrast, the antioxidants allopurinol and curcumin have been ineective for treatment of chronic pancreatitis in clinical trials.32 Two multicentre trials of Antox are in progress (Current Controlled Trials numbers ISRCTN21047731 and ISRCTN44912429).

2 years in patients with intraductal calculi;138 however, lithotripsy can occasionally precipitate acute pancreatitis.133 Thoracoscopic splanchnicectomy can provide good initial pain relief, but pain recurs by 15 months in more than 50% of patients.139

Surgery
Historically, around 50% of patients with chronic pancreatitis referred to surgical clinics require an operation compared with around 25% on long-term follow-up in a specialist medical clinic.88 Micronutrient treatment seems to substantially reduce the need for surgery.82,125,132 The objectives of surgery are to decompress obstructed ducts (to relieve pain) and at the same time to preserve pancreatic tissue as well as adjacent organs (to preserve function), while recognising that the head of the pancreas constitutes the so-called pacemaker of chronic pancreatitis. The simplest operationlateral pancreaticojejunostomy provides immediate pain relief in many patients but pain tends to recur with the passage of time. Distal pancreatectomy, like pancreaticojejunostomy, does not address the problem of disease in the head of the pancreas, which can continue to deteriorate. Moreover, distal pancreatectomy can result in removal of the functionally most active part of the gland. Pancreaticoduodenectomy gives good pain relief, but is a major operation. It is indicated in groove pancreatitis if there is duodenal obstruction or when neoplasia cannot be ruled out preoperatively.140 Duodenum-preserving head resection combined, when appropriate, with lateral pancreaticojejunostomy has been a major advance: only 87% of patients continued to have pancreatic pain at a median of 57 years follow-up, whereas 93% of patients had pancreatic pain preoperatively.141 The operation was simplied by carving out an inverted cone from the pancreatic head, allowing the cavity and the distal duct to drain into a jejunal loop, thus removing the complex mass of obstructed ducts and inammatory tissue that frequently lies within the head of the gland.142 A further simplication made this operation suitable for patients in whom there was little in the way of duct dilatation: a so-called ice-cream scoop is taken out of the pancreatic head to leave a thin rim of pancreas laterally and posteriorly. Pain improved in 55% of patients after 41 months of follow-up.143 A precise assessment of the merits of the dierent operations for painful chronic pancreatitis has been confounded by an absence of agreement about indications for surgery, details of the surgical techniques, and methods used to measure outcomes.144 However, there is no doubt that the safety of conservative operations (eg, lateral pancreaticojejunostomy combined with limited excision of the head of the gland) has improved: operative mortality, about 5% with traditional resection of the head of pancreas, has fallen to 03% and morbidity has been halved.145 There seems to be little if any advantage to be gained from total pancreatectomy with islet transplant.146
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Treatment of steatorrhoea and diabetes

The treatment of pancreatic steatorrhoea usually begins with 30 000 IU of lipase per meal in an acid-resistant enzyme preparation. In patients who do not respond to this treatment, a low-fat diet (5075 g per day), dose increase, gastric proton-pump inhibitor, or a combination thereof should be recommended.67 A check on fat-soluble vitamin status is advisable.126 The main aim in the treatment of diabetes in patients with chronic pancreatitis is to prevent hypoglycaemia caused by deciency of glucagon; simple insulin regimens are preferable.

Endoscopic treatment
Of the many potential indications for endoscopic treatment of chronic pancreatitis,133 two are undisputed. First, EUS can be used to facilitate transmural drainage of pseudocysts that are not connected to the pancreatic duct system, and endoscopically placed transpapillary stents in the duct are useful when they do134 or when a duct leak leads to pancreatic ascites or pleural eusion.135 Second, endoscopic stenting of the bile duct is a useful temporary measure in patients with a distal duct stricture. Limited comparative data suggest that surgery is more eective136 and has a more durable eect in controlling pain137 than endoscopic dilatation or stenting of the pancreatic duct. Findings from a randomised clinical trial showed that extracorporeal shock-wave lithotripsy with or without endoscopic clearance of stone fragments was equally eective at reducing pain over the subsequent
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Conclusions
Chronic pancreatitis remains a challenging disease. Resective surgery continues to be the denitive treatment for persistent pain, but is not ideal in a chronic inammatory process. Micronutrient treatment might oer a viable alternative.
Contributors All authors participated in writing this Seminar. All authors saw and approved the nal manuscript. Conicts of interest We declare that we have no conicts of interest. Acknowledgments We thank Prof J R Foster for the microphotographs (gure 2). References 1 Sarles H. Etiopathogenesis and denition of chronic pancreatitis. Dig Dis Sci 1986; 11 (suppl): S91107. 2 Braganza JM. The pancreas. Recent Adv Gastroenterol 1986; 6: 25180. 3 Walsh TN, Rode J, Theis BA, Russell RCG. Minimal change chronic pancreatitis. Gut 1992; 33: 156671. 4 Gupta V, Toskes PP. Diagnosis and management of chronic pancreatitis. Postgrad Med J 2005; 81: 49197. 5 Lvy P, Barthet M, Mollard BR, Amouretti M, Marion-Audibert AM, Dyard F. Estimation of the prevalence and incidence of chronic pancreatitis and its complications. Gastroenterol Clin Biol 2006; 30: 83844. 6 Otsuki M. Chronic pancreatitis in Japan: epidemiology, prognosis, diagnostic criteria, and future problems. J Gastroenterol 2003; 38: 31526. 7 Garg PK, Tandon RK. Survey on chronic pancreatitis in the AsiaPacic region. J Gastroenterol Hepatol 2004; 19: 9981004. 8 Spanier BWM, Dijkgraaf MGW, Bruno MJ. Trends and forecasts of hospital admissions for acute and chronic pancreatitis in the Netherlands. Eur J Gasroenterol Hepatol 2008; 20: 65358. 9 Mitchell RMS, Byrne MF, Baillie J. Pancreatitis. Lancet 2003; 361: 144755. 10 Whitcomb DC. Mechanisms of disease: advances in understanding the mechanisms leading to chronic pancreatitis. Nat Clin Pract Gastroenterol Hepatol 2004; 1: 4652. 11 Klppel G. Chronic pancreatitis, pseudotumors and other tumor-like lesions. Mod Pathol 2007; 20: S11331. 12 Ammann RW. Diagnosis and management of chronic pancreatitis: current knowledge. Swiss Med Wkly 2006; 136: 16674. 13 Braganza JM. Evolution of pancreatitis. In: Braganza JM, ed. The pathogenesis of pancreatitis. Manchester: Manchester University Press, 1991: 1933. 14 Wallig M. Xenobiotic metabolism, oxidant stress and chronic pancreatitis: focus on glutathione. Digestion 1998; 59 (suppl 4): 1324. 15 Gaisano HY, Gorelick FS. New insights into the mechanisms of pancreatitis. Gastroenterology 2009; 136: 204044. 16 Cook LJ, Musa OA, Case RM. Intracellular transport of pancreatic enzymes. Scand J Gastroenterol 1996; 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 free radicals in the pathogenesis of acute pancreatitis. Ann Surg 1984; 200: 40513. 19 Dabrowski A, Boguslowicz C, Dabrowska M, Tribillo I, Gabryelewicz A. Reactive oxygen species activate mitogen-activated protein kinases in pancreatic acinar cells. Pancreas 2000; 21: 37684. 20 Leung P, Chan YC. Role of oxidative stress in pancreatic inammation. Antioxid Redox Signal 2009; 11: 13565. 21 Chavnov M, Petersen OH, Tepikin A. Free radicals and the pancreatic acinar cells: role in physiology and pathology. Philos Trans R Soc Lond B Biol Sci 2005; 360: 227384.

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