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Seminar

Pancreatitis
R M S Mitchell, M F Byrne, J Baillie In the past decade, our understanding of the genetic basis, pathogenesis, and natural history of pancreatitis has grown strikingly. In severe acute pancreatitis, intensive medical support and non-surgical intervention for complications keeps patients alive; surgical drainage (necrosectomy) is reserved for patients with infected necrosis for whom supportive measures have failed. Enteral feeding has largely replaced the parenteral route; controversy remains with respect to use of prophylactic antibiotics. Although gene therapy for chronic pancreatitis is years away, our understanding of the roles of gene mutations in hereditary and sporadic pancreatitis offers tantalising clues about the disorder’s pathogenesis. The division between acute and chronic pancreatitis has always been blurred: now, genetics of the disorder suggest a continuous range of disease rather than two separate entities. With recognition of pancreatic intraepithelial neoplasia, we see that chronic pancreatitis is a premalignant disorder in some patients. Magnetic resonance cholangiopancreatography and endoscopic ultrasound are destined to replace endoscopic retrograde cholangiopancreatography for many diagnostic indications in pancreatic disease. Two entities of pancreatitis exist: acute and chronic. We discuss the pathogenesis, diagnosis, and treatment of each type of this disorder. Although risk factors for acute pancreatitis have been known for some time, the pathophysiology is only now being elucidated. Most patients with this disorder have minimum organ dysfunction, and recovery is uneventful. However, 10–15% of patients develop systemic inflammatory response syndrome (SIRS), leading to a fulminant course with pancreatic necrosis and multiorgan failure. SIRS seems to be caused by activation of an inflammatory cascade mediated by cytokines, immunocytes, and the complement system. Inflammatory cytokines cause macrophages to migrate into tissues distant to the pancreas, including the lungs and kidneys. Immunocytes attracted by cytokines released from macrophages release more cytokines, free radicals, and nitric oxide.1,2 Some of these cytokines are implicated in disease progression—eg, interleukin 1 and tumour necrosis factor (TNF); interleukins 6 and 8 are useful for monitoring course of disease.3 Administration of an antagonist of interleukin 1 or anti-TNF has reduced severity and improved survival in rats with acute pancreatitis.4,5 Although administration of interleukin 10 has been similarly effective in animals,6,7 its use in patients after endoscopic retrograde cholangiopancreatography (ERCP) has produced conflicting results.8 Despite showing early promise in animals and people, the platelet-activating factor antagonist lexipafant probably has a clinically insignificant effect on SIRS or mortality in severe acute pancreatitis.9 Inappropriate activation of the proteolytic enzyme trypsin is thought to be the initial step in development of pancreatitis. Trypsinogen is activated through hydrolysis of an N-terminal peptide called trypsinogen-activating
Lancet 2003; 361: 1447–55
Division of Gastroenterology, Duke University Medical Center, Durham, NC, USA (R M S Mitchell MBBCh, M F Byrne MD, Prof J Baillie MBChB) Correspondence to: Prof John Baillie, Box 3189 Duke South, Duke University Medical Center, Durham, NC 27710, USA (e-mail: baill001@mc.duke.edu)

Pathogenesis of acute pancreatitis

peptide. In rats, this peptide has been used to localise the site of activation of trypsinogen within the pancreatic acinar cell to small cytoplasmic vacuoles.10,11 Several different mechanisms prevent pancreatic autodigestion by activated trypsin. These include: production of serine protease inhibitor Kazal type 1 (SPINK1; also known as pancreatic secretory trypsin inhibitor [PSTI]), which reversibly inhibits activated trypsin; trypsin-activated trypsin-like enzymes—eg, mesotrypsin—that degrade trypsinogen; and bicarbonate-rich secretions, which are affected by abnormal production of cystic fibrosis transmembrane conductance receptor (CFTR). SPINK1 inhibits up to 20% of potential trypsin within the pancreas in the event that trypsinogen becomes prematurely activated. The N34S mutation in SPINK1, identified by Chen and colleagues,12 has been reported in people with familial pancreatitis and in children with idiopathic chronic pancreatitis,13,14 and in 2% of control populations.13–15 Since SPINK1 mutations are much more common than pancreatitis, this protein probably acts as a disease modifier, rather than causing pancreatitis by itself. In 1996, Whitcomb and colleagues16 identified the third exon of the cationic trypsinogen gene on chromosome 7q35 as the gene that causes hereditary pancreatitis. This disorder is autosomal dominant, and 80% of individuals with the susceptibility gene develop recurrent acute pancreatitis; all those with penetrance (about 80%) develop chronic pancreatitis, and up to 40% of those with hereditary pancreatitis could go on to develop pancreatic cancer.17,18 The clinical and pathological features of these patients are identical to those of individuals with sporadic pancreatitis. The first mutation identified consisted of an arginine to histidine substitution at codon 122 (R122H); this mutation causes a conformational change in the

Search strategy and selection criteria
We did a Medline search of reports published in English, with the keywords acute pancreatitis, chronic pancreatitis, hereditary pancreatitis, idiopathic pancreatitis, CFTR, SPINK, cationic trypsinogen, pancreatic cancer. We reviewed the Cochrane database with respect to enteral versus parenteral feeding in acute pancreatitis. To evaluate treatments for acute and chronic pancreatitis, we concentrated on data from prospective randomised clinical trials.

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3-dimensional structure of the trypsinogen-SPINK1 complex and might impair activity of the SPINK1 defence mechanism against activated trypsin.16,19 Further mutations—eg, A16V, K23R, N291, N29T, R122C—have been identified in close proximity to the cationic trypsinogen gene, which seem to confer susceptibility to hereditary pancreatitis. These gene defects could enhance trypsin activity by promotion of autoactivation of trypsinogen or reduction of degradation of active trypsin.16,20 Many of these mutations have been noted in patients with idiopathic chronic pancreatitis that has no obvious hereditary basis.16,21–25

Acute pancreatitis is an acute inflammatory process of the pancreas, with variable involvement of peripancreatic tissues and remote organ systems.26 A range of morphological findings exists, from interstitial oedema in mild disease to confluent areas of necrosis and haemorrhage in severe disease. In severe acute pancreatitis, multiorgan failure is the usual cause of early death. Local complications of severe disease include pseudocyst, abscess, and pseudoaneurysm formation. Although overall mortality of acute pancreatitis ranges from 2% to 10%,27 in 80% of patients the disorder is mild and self-limiting, with minimum mortality. In severe disease, however, the mortality rate can be as high as 25% in the presence of infected pancreatic necrosis.28 Sepsis is the usual cause of late mortality in severe acute pancreatitis. Gallstones are the leading cause of acute pancreatitis in developed countries; including microlithiasis, gallstones can account for more than 90% of cases worldwide. Alcohol abuse is typically cited as a close second to gallstones; however, whether acute alcoholic pancreatitis ever arises in the absence of chronic injury to the gland is hotly debated. Infrequent—but not rare—causes of the disorder include: drug reaction (usually idiosyncratic); pancreatic and ampullary tumours; hypertriglyceridaemia; hypercalcaemia (almost always due to hyperparathyroidism); hypothermia; congenital anomalies of pancreatic and biliary anatomy (eg, choledochocele); trauma (including iatrogenic damage, such as ERCP); and infectious or parasitic organisms. Rare causes include bites of certain spiders, scorpions, and the Gila Monster lizard. Cases without obvious cause are referred to as idiopathic. The roles of sphincter of Oddi dysfunction, pancreas divisum, and bile crystals or sludge are less clear. Advances in radiology and intensive medical management have led to a shift away from early surgery for pancreatic necrosis to treatment of local complications by endoscopic29 or percutaneous30 methods, which is considered by some—including us—to have improved survival.31

Risk factors and presentation of acute pancreatitis

either CT or ultrasound of the pancreas and biliary tree leads to the correct diagnosis in 81–95% of patients.33,34 Amplification of time from onset of pain to measurement,35 alcohol as the primary causal factor,36 and presence of hypertriglyceridaemia37 all reduce the sensitivity of serum amylase estimation. Serum lipase concentration rises within 4–8 h of an episode of acute pancreatitis, peaks at 24 h, and returns to normal after 8–14 days,38 making it a useful diagnostic method in patients presenting late (eg, >24 h from onset of pain). Lipase estimation is also more sensitive than that of amylase in alcohol-induced acute pancreatitis. Although amplification of serum lipase concentration is not specific to this disorder, a value greater than three times the upper limit of normal excludes most non-pancreatic causes. Other pancreatic enzymes, such as P-isoamylase, macroamylases, immunoreactive trypsinogen, and elastase are generally not considered useful for diagnosis of acute pancreatitis. Prediction of the severity of an attack at the time of admission can be difficult. Several prognostic scoring systems, with clinical, laboratory, and radiological criteria, have been proposed.39–41 Failure of pancreatic parenchyma to enhance during the arterial phase of intravenous contrastenhanced CT indicates necrosis, which predicts a severe attack, especially if more than 50% of the gland is involved. The so-called Balthazar Score predicting severity of acute pancreatitis is based on CT appearances, including presence or absence of necrosis.42 Development of the Atlanta Classification for severity has allowed comparison between trials and methodologies, and a more rational approach to prediction of severity. This classification defines severe acute pancreatitis on the basis of standard clinical manifestations, a score of 3 or more with Ranson criteria, or a score of 8 or more with APACHE II criteria, and evidence of organ failure and intrapancreatic pathological findings—ie, necrosis or interstitial pancreatitis.43 Other markers, such as obesity, concentration of serum C-reactive protein (CRP), neutrophil elastase, pancreatitis-associated peptide, interleukins 6, 8, 1, 10, and soluble TNF receptors, could have use in early prediction of severity. CRP concentration has independent prognostic value. A peak of more than 210 mg/L on day 2–4, or more than 120 mg/L at the end of the first week, could be as predictive as the multiple factor scoring systems.44 Urinary trypsinogen activation peptide, which is released during activation of trypsinogen to trypsin, has been shown to accurately predict severity of acute pancreatitis 24 h after onset, and might be an appropriate single marker for severity assessment in clinical practice.45 Enteral nutrition Patients with mild acute pancreatitis can usually begin oral refeeding within a few days of onset of their pain. In severe disease attributable to reduced oral intake and presence of a catabolic state, poor nutrition is a common and serious problem.43,46–48 Early nutritional support may aid recovery.49 One of the goals of this therapy is to avoid stimulation of the pancreas.50 Traditionally, this goal has been achieved by total parenteral nutrition; however, this method is expensive, and carries a risk of sepsis and metabolic disturbances.49,51 Enteral feeding has been shown to be safe, as effective as total parenteral nutrition, and well tolerated in severe acute pancreatitis.52,53 Enteral nutrition is less expensive than parenteral feeding, helps to maintain mucosal function, and limits absorption of endotoxins and cytokines from the gut.54,55 Pancreatic stimulation can be avoided by placement of the enteral feeding tube distal to
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Establishment of severity

Treatment strategies in acute pancreatitis

Diagnosis of acute pancreatitis

Diagnosis of acute pancreatitis can be difficult, as shown by the many cases diagnosed at autopsy.32 The clinical history of upper-abdominal pain and vomiting are characteristic of several acute disorders. The signs of Cullen and GreyTurner (periumbilical and flank bruising, respectively) are rare, and can arise in any disease that causes retroperitoneal haemorrhage. A rise in concentration of serum amylase is expected in acute pancreatitis, but this increase is not always seen. Although normoamylasaemia has been said to arise in up to 30% of cases, by definition, the denominator cannot be known. We feel that normoamylasaemic pancreatitis probably arises in fewer than 10% of cases, some of which undoubtedly show the rapid urinary clearance of amylase and missed (transient) amplification of serum amylase. Combination of the serum amylase value with results of 1448

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the Treitz ligament. Unfortunately, proximal migration of the feeding tube and subsequent pancreatic stimulation can aggravate acute pancreatitis, and severe ileus preventing enteral feeding is common in the early stages of disease.56 Partial ileus (manifest by reduced but not absent bowel sounds) should not be deemed a contraindication to enteral feeding; in this setting, patients frequently tolerate continuous low-volume nasojejunal infusion. In our institution, we favour laparoscopic or combined endoscopic-radiologic jejunostomy tube placement once patients have shown that they can tolerate nasoenteral feedings for 5–7 days. Results of a randomised study of nasogastric versus nasojejunal feeding in severe acute pancreatitis suggested that nasogastric feeding may also be safe, since little difference in pain, analgesic requirements, serum CRP concentrations, or clinical outcome was reported between the two methods.57 Enteral feeding by nasojejunal tube or percutaneous jejunostomy has largely replaced total parenteral nutrition in the management of patients with severely catabolic acute pancreatitis.58 Antibiotics Use of antibiotics in severe acute pancreatitis remains contentious: there is concern that their routine use is leading to a rise in drug-resistant or unusual organisms in pancreatic sepsis, and possibly even increased mortality when antibiotics are used inappropriately.59 Results of studies in the 1970s showed no benefit from routine antibiotic prophylaxis.60–62 However, the studies were probably underpowered, because patients with mild acute pancreatitis, who have a low morbidity and mortality, were included. In severe disease, secondary infection of necrotic pancreatic parenchyma is the leading cause of late mortality (figure 1).63 In the past decade, three randomised studies comparing antibiotics with no antibiotics in acute necrotising pancreatitis have been done. Pederzoli and colleagues64 randomly allocated 74 patients with necrotising pancreatitis from six centres in Italy either imipenem 0·5 g every 8 h for 2 weeks or no antibiotic. Oral antibiotics were used after the 2-week period if recovery was prolonged. In the imipenem group, a significant reduction in pancreatic and nonpancreatic sepsis was noted, but not in surgical intervention, multiorgan dysfunction, or death. In a Finnish study,65 60 patients with acute necrotising pancreatitis were randomly allocated cefuroxime 4·5 g daily or no antibiotic. A significant reduction in septic complications and death was seen in the antibiotic group. However, two patients in the no antibiotic group died very early in the course of their

illness, and 76% of patients in the no antibiotic group received an antibiotic at some point during their admission, factors that could have skewed results. In the smallest of the three studies, Delcenserie and colleagues66 randomly allocated 23 consecutive patients ceftazidime, amikacin, and metronidazole, or no antibiotic. The incidence of sepsis—but not mortality—was reduced in the antibiotic group. Results of a meta-analysis of these trials confirmed a reduction in mortality in patients with severe acute pancreatitis treated with antibiotics.67 Buchler and colleagues68 reported that of ten different antibiotics tested, only imipenem, ofloxacin, and ciprofloxacin showed adequate tissue penetration and bactericidal properties to be useful in infected pancreatic necrosis. Bassi and co-workers59 later randomly allocated 60 patients with necrotising acute pancreatitis either intravenous pefloxacin 400 mg twice daily or intravenous imipenem 500 mg three times daily, starting within 120 h of diagnosis and continuing for 2 weeks. Pancreatic—but not extrapancreatic—sepsis was reduced in the imipenem group, but mortality did not differ greatly between the two groups. The importance of early initiation of antibiotics is unclear, but in a study, early imipenem-cilastatin therapy seemed to substantially reduce the need for surgery and the overall number of major organ complications. Mortality was also lowered, but did not differ significantly.69 An alternative strategy for prevention of translocation of bacteria from the gut into the pancreatic bed is selective decontamination: conclusive data are absent, but some preliminary results have been reported from animals70 and work in human beings.71 At present, the standard of care dictates that patients with acute pancreatitis complicated by necrosis should receive a prophylactic, broad-spectrum antibiotic, typically imipenem. Therapeutic endoscopy in acute pancreatitis and its complications Of four prospective randomised trials that have been reported, the two most methodologically sound showed benefit from early ERCP for bile-duct clearance in acute gallstone (biliary) pancreatitis.72,73 Urgent ERCP is usually reserved for patients with acute cholangitis or progressive jaundice, to keep the yield at a maximum and thereby keep the number of unnecessary procedures to a minimum. Pseudocysts complicate acute pancreatitis in fewer than 5% of cases. Pseudocysts are peripancreatic fluid collections that develop a wall that does not have an epithelial layer; they take 4–6 weeks to mature. Pseudocyst fluid usually has high amylase concentrations and low amounts of tumour markers, such as CA19-9 and carcinoembryonic antigen. If acute pseudocysts are uncomplicated, asymptomatic, and not increasing in size on serial imaging, to withhold intervention is preferable, since many of these pseudocysts will resolve spontaneously. Otherwise, endoscopic, percutaneous, or surgical drainage is indicated. Reported success rates for endoscopic pseudocyst drainage vary between 70% and 94%.74,75 Predrainage ERCP to define pancreatic ductal anatomy is advisable. Endoscopic transpapillary stent placement is a treatment option when communication is shown between the pseudocyst and the pancreatic duct.76 Contraindications to endoscopic drainage of pancreatic pseudocysts include presence of an abscess or necrotic tissue within the cyst (a necroma), gastric or duodenal varices, coagulopathy, and excessive thickness (>1 cm) of the cyst wall. Use of endoscopic ultrasound to define safe access for endotherapy reduces the risk of life-threatening complications. Newer echoendoscopes allow direct pseudocyst drainage without the need for a separate endoscopic procedure.77 1449

Figure 1: Contrast-enhanced helical abdominal CT scan showing severe necrotising pancreatitis
Courtesy of Erik Paulson, Duke University Medical Center.

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Figure 2: Peroperative photograph showing the abdominal incision for necrosectomy
Courtesy of Douglas Tyler, Duke University Medical Center.

Percutaneous drainage is done under ultrasound or CT guidance, and is useful to drain symptomatic peripancreatic fluid collections, non-communicating pseudocysts, and abscesses. Although endoscopic therapy is an option, especially for patients unfit for surgery, data from our institution suggest that an operative approach is preferable for pseudocysts that communicate with the pancreatic duct.78 Surgery is also preferred when diagnosis of a pseudocyst is in doubt (eg, possible cystic neoplasm), when the pseudocyst is complex, and to manage fistulae. We are not aware of any randomised trial comparing endoscopic treatment with percutaneous or surgical decompression for pancreatic pseudocysts. Timing of surgery after acute pancreatitis In patients with mild gallstone pancreatitis, many surgeons choose to do cholecystectomy during the same admission to avoid risk of recurrence. In severe acute pancreatitis, cholecystectomy is typically delayed to allow resolution of the inflammatory process and await improvement in the patient’s nutritional state. Increasingly, only those with a high likelihood of choledocholithiasis undergo precholecystectomy ERCP. If an intraoperative cholangiogram shows a possible stone in the common bile duct, this stone is dealt with by next-day ERCP. Laparoscopic bile-duct exploration for stones avoids the need for subsequent ERCP, but is time-consuming and has not gained widespread acceptance. Opinion on timing of surgery to debride non-viable pancreas (necrosectomy) after acute pancreatitis is clearly changing, at least in the USA. In our institution, for example, necrosectomy is usually reserved for persistently febrile patients who fail to respond to broadspectrum antibiotics with or without percutaneous drainage of fluid collections over 72 h or more (figure 2). Pancreatitis complicates ERCP in 3% to more than 40% of cases:79,80 risk is dependent on patients’ factors, such as age, female sex, diameter of the common bile duct, previous post-ERCP pancreatitis, and technical factors, such as performance of biliary or pancreatic sphincterotomy or manometry, balloon dilation of the biliary sphincter, difficult (traumatic) cannulation, repeated injections into the pancreatic duct, and skill of the operator.79–81 A widely used classification of post-ERCP complications was proposed by Cotton.82 According to this classification, mild post-ERCP pancreatitis results in a hospital stay of 1–3 nights, moderate disease needs 4–10 nights, and severe disease leads to admission for more than 10 nights, or any surgical or radiological intervention, or death. About 90% 1450

of cases are mild. In a large multicentre study, Freeman and colleagues83 reported that 5·7% of outpatients needed admission for complications of ERCP (mostly pancreatitis): of these, 79% developed pain within 6 h of the procedure. Post-ERCP pancreatitis has a similar clinical picture to acute pancreatitis from other causes. How can post-ERCP pancreatitis be recognised before the patient is sent home? Narcotic analgesia used for endoscopy sedation frequently masks early signs and symptoms of the disease. Serum markers, such as 4-h amylase,84 interleukins 6 and 10,85 and serum and urinary trypsinogen 2 and trypsinogen 2 1 antitrypsin complex,86 have all proved helpful in identification of post-ERCP pancreatitis in clinical studies. However, at present, none of these markers is in widespread use for prediction of disease. Trials assessing use of pharmacological agents in prevention of post-ERCP pancreatitis have been largely disappointing. So far, only somatostatin,87 gabexate,88 octreotide,89 interleukin 10,90 and nafamostat have shown any benefit, although most of the studies remain to be validated elsewhere. Chronic pancreatitis is characterised by permanent damage of structure, function, or both because of progressive inflammation.91 The early stage of the disease is distinguished by recurrent bouts of acute pancreatitis, followed—generally many years later—by progressive pancreatic exocrine and endocrine insufficiency and sometimes calcification. In most patients, pain is the dominant symptom.92 Complications include pseudocyst formation, pancreatic stones and strictures, biliary strictures, duodenal stenosis, portal hypertension with varices, and an amplified risk of pancreatic cancer.93,94 In countries in Europe, around 70% of cases of chronic pancreatitis are thought to be caused by alcohol abuse. Less common causes include autoimmune disease, hypertriglyceridaemia, hyperparathyroidism, tropical pancreatitis, pancreas divisum, obstruction of the pancreatic duct by tumour, and genetic abnormalities.95 The remaining patients (10–30%) are classified as idiopathic.96,97 Chronic pancreatitis usually presents in the 5–7th decades of life, but some patients present before the age of 30 years.92 Historically, the progressive pancreatic failure of cystic
7p22.3

Cause and presentation of chronic pancreatitis

p

7p11.2 7q11.22

Post-ERCP pancreatitis

q

CFTR 7q31.2

7q36.3 Figure 3: Artist’s impression of the cystic fibrosis transmembrane conductance regulator gene on human chromosome 7q31
Reprinted with permission of the US Department of Energy Human Genome Program from http://www.ornl.gov/hgmis.

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Rights were not granted to include this image in electronic media. Please refer to the printed journal.

Patients with a compound heterozygote (severe/mildvariable) genotype for CFTR seem to be at greatest risk for pancreatitis, whereas their lung function is protected by residual CFTR function from the mild-variable mutation.102,103 In young patients with idiopathic chronic pancreatitis, the combination of two CFTR mutations and one SPINK1 mutation has been described.104 Because SPINK1 is present in acinar cells and CFTR in ductal epithelium, these genes could affect susceptibility to chronic pancreatitis independently.105 However, intrapancreatic protease activation attributable to the SPINK1 mutation could contribute to pathogenesis of CFTR-related pancreatitis.104 Imaging Because of the difficulty of obtaining pancreatic tissue for histological analysis in vivo, chronic pancreatitis is usually diagnosed by pancreatic imaging with or without dynamic tests of exocrine function. ERCP remains the gold standard for diagnosis and staging of the disease. With sensitivity in various series of 75–95%, and a specificity of 90% or more, ERCP has been the most sensitive imaging tool for diagnosing chronic pancreatitis during the past 30 years. However, it is invasive and carries significant morbidity (3% to 40%) and mortality (0·1–1·0%). Magnetic resonance cholangiopancreatography (MRCP), with or without secretin stimulation,106 is proving a useful alternative to ERCP in many circumstances (figure 5). With magnetic resonance technology, the pancreatic ductal anatomy and peripancreatic fluid collections are seen with heavily T2-weighted images; with different settings, with or without MRI contrast medium, the parenchyma can be assessed.107 Quality, sensitivity, and specificity of MRCP varies greatly between centres, and depends not only on the type of scanner but also on the interest and skill of the operator. At present, most clinicians use MRCP as an alternative to ERCP, helical CT scanning, or both in selected cases. We predict that in the near future, MRCP will be used in place of ERCP for most diagnostic reasons. Endoscopic ultrasound has emerged as a sensitive imaging technique in chronic pancreatitis. Wiersema and colleagues prospectively assessed several pancreatic ductal and parenchymal abnormalities seen at ultrasound compared with clinical, laboratory, and ERCP findings.108 Eight features on ultrasound were indicative of chronic pancreatitis: if three or more were present, sensitivity, specificity, and accuracy of endoscopic ultrasound was

Diagnosis of chronic pancreatitis

Figure 4: Artist’s impression of the cystic fibrosis transmembrane conductance regulator protein
Reprinted with permission of The McGraw-Hill Companies. Taken from Lewis R. Human genetics: concepts and applications. Dubuque: Wm C Brown, 1994.

fibrosis has been judged a separate entity from chronic pancreatitis, but in terms of genetic predisposition, some cases of the disease might represent a forme fruste of cystic fibrosis (see below). Mutations in the CFTR gene, identified in 1989, have been associated with chronic pancreatitis (figure 3).98,99 CFTR mutations cause impairment of cyclic AMP (cAMP)regulated chloride channels of various organs, leading to inspissated secretions and blockage of ductal systems (figure 4). As well as the F508del mutation, more than 1000 other mutations of CFTR of varying severity are described (http://www.genet.sickkids.on.ca/cftr/). Some of the socalled mild mutations, such as R117H, cause pulmonary disease of reduced severity: patients with this mutation are generally pancreatic sufficient and have greatly improved survival compared with the typical cystic fibrosis phenotype.100 In the same issue of the New England Journal of Medicine in 1998, two independent groups reported an increased incidence of CFTR mutations in patients with chronic pancreatitis compared with controls.98,99 In 134 patients with disease of mixed cause, Sharer and colleagues99 noted 13·4% of patients with chronic pancreatitis carried one common CFTR mutation compared with 5·3% of controls. A 5T allele in intron 8, which reduces amounts of functional CFTR by decreasing mRNA levels, was seen twice as commonly as expected. Cohn and co-workers98 studied 27 patients with idiopathic pancreatitis and recorded common CFTR mutations in ten (37%), including one patient with two mutant alleles. None of the patients in either study fulfilled present criteria for diagnosis of phenotypic cystic fibrosis.101
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Pathogenesis of chronic pancreatitis

Figure 5: Normal magnetic resonance cholangiopancreatogram
The gallbladder, biliary tree and main pancreatic duct are clearly visible. Courtesy of Erik Paulson, Duke University Medical Center.

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80%, 86%, and 86%, respectively. Results of subsequent studies have confirmed these criteria in idiopathic recurrent pancreatitis109 and in high-risk groups, in which presence of pancreatic calcifications, number of criteria present, and history of alcohol abuse were also independently predictive of chronic pancreatitis.110 However, detection of subtle changes by endoscopic ultrasound might lead to overdiagnosis of the disease. The overall sensitivity of CT in diagnosis of chronic pancreatitis is 75–90%. It is especially useful for detection of focal pancreatic enlargement, parenchymal atrophy, calcification, pancreatic ductal dilatation, and pseudocysts. CT can also detect complications of chronic pancreatitis, including portal and splenic vein thrombosis, gastric varices, splenic enlargement, fluid collections, and biliary obstruction. Although transabdominal ultrasound is inexpensive and easily available, it is insensitive for detection of early disease. However, it is an excellent method for imaging fluid collections, such as pseudocysts, which are generally aspirated or drained under ultrasound guidance. Pancreatic function tests Aspiration and assay of duodenal contents after pancreatic stimulation by secretin-cholecystokinin or a Lundh test meal is judged by some the gold standard for diagnosis of pancreatic exocrine insufficiency. Critics of dynamic testing say that it rarely alters management: by the time a patient has grossly abnormal dynamic testing, their chronic pancreatitis is usually obvious clinically and radiologically. A niche role for dynamic testing could be investigation of patients with suspected minimum-change pancreatitis, for which subtle loss of exocrine function might suggest pancreatic injury not yet apparent on conventional imaging. Since standardisation of pancreatic function tests is difficult, these tests are rarely used outside major centres. Noninvasive tests, such as the bentiromide (PABA) test, faecal fat determination, and measurement of faecal pancreatic enzymes such as elastase and chymotrypsin, are limited by difficulties in collection, insensitivity for early chronic pancreatitis, and the occurrence of false-positive results. Pancreatic endocrine dysfunction is a late event in this disease; investigation beyond fasting blood glucose estimation and a glucose tolerance test has not proved clinically relevant.

pseudoaneurysm; an associated motility disorder; or development of malignancy. Amman and colleagues114 identified two different patterns of pain in a cohort of patients with alcoholic chronic pancreatitis: short episodes (<10 days) with long pain-free periods in between; and chronic persistent pain. Patients with chronic persistent pain had complications of chronic pancreatitis—eg, pseudocyst formation or biliary obstruction—and all underwent surgery. None of the patients with short episodes of pain needed surgery. Many patients with chronic pancreatitis and pain come to surgery for resection, ductal drainage procedures, or management of complications such as pseudocysts. Unfortunately, surgery is no guarantee of pain relief, especially in those patients who have become narcotic-dependent. Use of pancreatic enzymes for pain relief remains controversial; trials of non-enteric-coated enzyme preparations have generally produced better results than have those of enteric-coated preparations,115,116 particularly in patients with predominantly small duct disease. Pancreatic enzyme supplements with snacks and meals and avoidance of dietary fat and alcohol are still the main lifestyle modifications we recommend to patients with chronic pancreatitis. Coeliac plexus neurolysis (chemical destruction of the nerve plexus) has proved disappointing, especially in young adults and in patients who have previously undergone surgery.117 Endoscopic ultrasoundguided coeliac plexus neurolysis, with steroids (triamcinolone) and local anaesthetic (bupivacaine) rather than absolute alcohol, seems safer and more effective than the CT-guided alternative.118 In skilled hands, thoracoscopic sympathectomy can be very effective for intractable pain. Many patients with chronic pancreatitis become addicted to narcotic analgesics; such patients benefit from management in a dedicated pain clinic. Non-narcotic modulators of chronic pain, such as gabapentin, and selective serotonin reuptake inhibitors (eg, paroxetine), should be considered in difficult-to-manage pain syndromes associated with chronic pancreatitis. Exocrine and endocrine insufficiency A reduction in pancreatic enzyme output to less than 10% of normal is usually needed for maldigestion to occur.119 To ensure that an adequate dose of pancreatic enzymes reaches the duodenum, gastric acid must be suppressed by an H2receptor antagonist or proton-pump inhibitor. Enzyme supplements which have high lipase concentrations are effective, but have been associated with fibrosing smallbowel disease (diaphragm disease) and fibrosing colonopathy, especially in children with cystic fibrosis.120,121 Diabetes, usually insulin-dependent, eventually develops in 30–50% of patients with chronic pancreatitis,112 and can be difficult to manage, particularly in the presence of continuing alcohol use and maldigestion. Non-surgical versus surgical approaches to complications of chronic pancreatitis Symptomatic pseudocysts complicating chronic pancreatitis rarely resolve spontaneously.122 Management of pseudocysts should be multidisciplinary. If the pseudocyst communicates with the pancreatic ductal system, surgery could be the best option. If endoscopy if preferred, transpapillary drainage might be effective,76 although in practice results are variable and less predictable than the transgastric or transduodenal approach. If no communication is present between the pseudocyst and the pancreatic duct, endoscopic or percutaneous drainage frequently leads to resolution. Endoscopic clearance of main pancreatic duct stones and dilation of ductal strictures
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Treatment of chronic pancreatitis

The natural history of chronic pancreatitis is of episodic or intractable abdominal pain, and progressive exocrine and endocrine insufficiency. Pain is the main complaint of most patients with the disease,111 although a few with late-onset idiopathic chronic pancreatitis are fortunate enough never to have pain.97,112 Some patients with alcohol-induced disease gain pain relief as their pancreas progressively atrophies. Development or worsening of pain in chronic pancreatitis could signal the presence of complications, such as pseudocysts or biliary, duodenal, or colonic strictures.113 Chronic pancreatitis has been suggested to diminish over time, with relief of symptoms. To most clinicians managing the disease, the reality is that it is continuous but patients get used to their pain episodes and more adept at managing them without emergency room visits or admissions. Pain management Although the pathogenesis of pain in chronic pancreatitis is incompletely understood, it has been attributed in varying amounts to: increased intraductal pressure (so-called pancreatic hypertension); perineural inflammation (socalled pancreatic neuropathy); increased visceral nocioception; space occupying lesions, eg, a pseudocyst or 1452

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Normal

PanIN-1A tall columnar flat

PanIN-1B

PanIN-2

PanIN-3 mitoses, luminal nuclei papillae lack stromal core

mucinous cells nuclear changes papillary growth

Figure 6: PanIN progression series
PanIN 3 lesions are papillary and show budding and necrosis of clusters of epithelial cells. Reprinted from Clinical Cancer Research 2000; 6: 2969–72, with permission.

might have beneficial long-term results in some patients.123 About 50% of patients with chronic pancreatitis will undergo surgery at some stage in their disease for pain management or to manage their complications.96,124 In many cases, however, despite apparent technical success, no measurable improvement is seen in quality of life.125

References
1 Gukovskaya AS, Gukovsky I, Zaninovic V, et al. Pancreatic acinar cells produce, release, and respond to tumor necrosis factor-alpha: role in regulating cell death and pancreatitis. J Clin Invest 1997; 100: 1853–62. Norman JG, Fink GW, Franz MG. Acute pancreatitis induces intrapancreatic tumor necrosis factor gene expression. Arch Surg 1995; 130: 966–70. Leser HG, Gross V, Scheibenbogen C, et al. Elevation of serum interleukin-6 concentration precedes acute-phase response and reflects severity in acute pancreatitis. Gastroenterology 1991; 101: 782–85. Hughes CB, Grewal HP, Gaber LW, et al. Anti-TNF alpha therapy improves survival and ameliorates the pathophysiologic sequelae in acute pancreatitis in the rat. Am J Surg 1996; 171: 274–80. Tanaka N, Murata A, Uda K, et al. Interleukin-1 receptor antagonist modifies the changes in vital organs induced by acute necrotizing pancreatitis in a rat experimental model. Crit Care Med 1995; 23: 901–08. Kusske AM, Rongione AJ, Ashley SW, McFadden DW, Reber HA. Interleukin-10 prevents death in lethal necrotizing pancreatitis in mice. Surgery 1996; 120: 284–88. Rongione AJ, Kusske AM, Kwan K, Ashley SW, Reber HA, McFadden DW. Interleukin 10 reduces the severity of acute pancreatitis in rats. Gastroenterology 1997; 112: 960–67. Baillie J. Predicting and preventing post-ERCP pancreatitis. Curr Gastroenterol Rep 2002; 4: 112–19. Johnson CD, Kingsnorth AN, Imrie CW, et al. Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis. Gut 2001; 48: 62–69. Otani T, Chepilko SM, Grendell JH, Gorelick FS. Codistribution of TAP and the granule membrane protein GRAMP-92 in rat caeruleininduced pancreatitis. Am J Physiol 1998; 275: G999–G1009. Hofbauer B, Saluja AK, Lerch MM, et al. Intra-acinar cell activation of trypsinogen during caerulein-induced pancreatitis in rats. Am J Physiol 1998; 275: G352–62. Chen JM, Mercier B, Audrezet MP, Ferec C. Mutational analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene in hereditary and sporadic chronic pancreatitis. J Med Genet 2000; 37: 67–69. Witt H, Luck W, Hennies HC, et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000; 25: 213–16. Threadgold J, Greenhalf W, Ellis I, et al. The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease. Gut 2002; 50: 675–81. Truninger K, Witt H, Kock J, et al. Mutations of the serine protease inhibitor, Kazal type 1 gene, in patients with idiopathic chronic pancreatitis. Am J Gastroenterol 2002; 97: 1133–37. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996; 14: 141–45. Perrault J. Hereditary pancreatitis: historical perspectives. Med Clin North Am 2000; 84: 519–29.

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Chronic pancreatitis and risk of pancreatic cancer

Chronic pancreatitis, especially the hereditary form, has long been deemed a risk factor for development of pancreatic cancer. Traditional teaching holds that the disease is responsible for fewer than 5% of all pancreatic adenocarcinomas.126 However, this figure will probably be revised upwards as our understanding of the genetic basis of chronic pancreatitis and pancreatic cancer increases. The PanIN (pancreatic intraepithelial neoplasia) classification has been proposed to unify the various previous classifications of malignant precursors of pancreatic ductal adenocarcinoma (http://www.path.jhu. edu/pancreas). There are three categories: PanIN 1, 2, and 3. The classification describes a progression of lesions from mildly to strikingly atypical. PanIn 3 lesions can have an associated mass, although there is no invasion of the basement membrane (figure 6). All stages of PanIN lesion have been reported in chronic pancreatitis:127,128 these are presumed to be potential sites for future cancer development. To identify PanIn 3 lesions might be possible with endoscopic ultrasound before development of frank malignancy. Clinicians are, at present, suggesting that patients with established chronic pancreatitis undergo endoscopic ultrasound every year with fine-needle aspiration cytology or biopsy of suspicious masses in the pancreatic-duct wall. Those with dysplastic lesions or carcinoma in situ should be offered surgical resection as prophylaxis against developing what is presently an almost 100% fatal cancer. The logistics of providing yearly ultrasound for every patient with chronic pancreatitis are staggering, but to think that such screening might reduce the death toll from pancreatic adenocarcinoma is exciting.
Conflict of interest statement
None declared.

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Acknowledgments

RMSM’s advanced endosopy fellowship is supported by an unrestricted grant from Boston Scientific. The sponsor had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

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