Blackwell Publishing AsiaMelbourne, AustraliaJGHJournal of Gastroenterology and Hepatology0815 93192006 Blackwell Publishing Asia Pty LtdMarch 2006213499509Review Article

Pancreatitis in childrenA Nydegger

et al.

doi:10.1111/j.1440-1746.2006.04246.x

REVIEW

Childhood pancreatitis
Andy Nydegger,* Richard T L Couper, and Mark R Oliver*,,
*Department of Gastroenterology and Clinical Nutrition, Royal Childrens Hospital, Department of Paediatrics, University of Melbourne, Murdoch Childrens Research Institute, Melbourne, Victoria, Department of Gastroenterology and Clinical Nutrition, Womens and Childrens Hospital and Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia

Key words acute pancreatitis, chronic pancreatitis, dagnostic imaging, genetic predisposition lipase. Accepted for publication 21 September 2005. Correspondence Assoc Professor MR Oliver, Department of Gastroenterology and Nutrition, Royal Childrens Hospital, Flemington Road, Parkville, Victoria 3052, Australia. Email: mark.oliver@rch.org.au

Abstract
Inammation of the pancreas has many presentations in children and adolescents. The etiology is often elusive, with a great number of cases being idiopathic. However, there have been a number of recent advances in the areas of cell biology, genetics and imaging technology, which should be highlighted. Herein is provided a review for the reader with particular emphasis on some of these newer advances.

Introduction
Acute and chronic pancreatitis in childhood cause occasional death and signicant morbidity globally, but our understanding of pancreatic inammation is rudimentary, thus limiting therapy. Recent advances in cell biology, genetics and imaging technology provide hope that improved understanding of pancreatitis will facilitate novel therapeutic strategies. Examples include the identication of genes predisposing patients to pancreatitis, the development of endoscopic ultrasound, and magnetic resonance cholangiopancreatography, which allows clinicians important anatomical information with minimal risk to the child.1,2 This review will highlight recent advances and summarize current knowledge in childhood pancreatitis.

Denitions and etiology

Acute pancreatitis is dened as the sudden onset of abdominal pain associated with a rise in acinar digestive enzymes in the blood or urine. There is complete restitution of pancreatic structure and function following an attack.3,4 Studies by Lopez, Werlin et al. and Oliver et al. have suggested that the number of new pediatric cases of acute pancreatitis diagnosed at childrens hospitals is increasing.57 This may be due to either a change in incidence or increased clinical awareness. In contrast with adults, in whom 80% of cases of acute pancreatitis are associated with alcoholism and biliary tract disease, the etiology in children is diverse (Table 1). The most common etiologies are trauma, multisystem disease, drugs,

infections, idiopathic and congenital anomalies of the pancreaticobiliary system.5,6,8,9 Lopez showed that in children younger than 3 years of age, pancreatitis was always associated with another disease,5 and recommended an exhaustive evaluation in children younger than the age of 4 years with pancreatitis.5 New drugs alter the frequencies of various causes. For example the use of Lasparaginase in leukemia regimens caused a marked increase in acute pancreatitis in childhood oncology clinics. Recurrent acute pancreatitis is seen in 10% of children after the initial acute episode. It is more likely in children with structural anomalies, idiopathic and familial causes.10 Chronic pancreatitis is an inammatory disorder that results in anatomical changes that include chronic inammatory cell inltration and gland brosis,11 with loss of exocrine (malabsorption) and endocrine function (diabetes mellitus). The more common childhood causes are outlined in Table 2. On face value these denitions appear straightforward and fulll our need to pigeonhole patient diagnosis but the reality is far more complex. For instance it is possible that acute pancreatitis acts as a primer that in susceptible children results in a process characterized by relapses and eventually the development of chronic injury.11,12 This would imply that there is signicant overlap in the underlying pathophysiology of these conditions.

Pathophysiology
Acinar cell injury (drugs, metabolic disorders and infection) and premature activation of trypsinogen to trypsin in the pancreas, due
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Table 1 Etiology of acute pancreatitis in children Acute pancreatitis Drugs Salicylates Paracetamol Cytotoxic drugs (i.e. L-asparaginase) Corticosteroids Immunosuppressives (particularly azathioprine and 6-MP) Thiazides Sodium valproate Tetracycline (particularly if aged) Erythromycin Gallstones Choledochal cyst Pancreatic duct obstruction Congenital anomalies of pancreas (especially pancreas divisum) Enteric duplication cysts EpsteinBarr virus Mumps Measles Cytomegalovirus Inuenza A Mycoplasma Leptospirosis Malaria Rubella Ascariasis Cryptosporidium Blunt injury (handle bar, child abuse, etc.) ERCP -1 antitrypsin deciency Hyperlipidemias Hypercalcemia Scorpion, Gila monster, tropical marine snakes Refeeding pancreatitis Hemolyticuremic syndrome Reyes syndrome Kawasaki disease Inammatory bowel disease HenochSchonlein purpura SLE

Table 2 Etiology of chronic pancreatitis in children Chronic pancreatitis Chronic pancreatitis in childhood Cystic brosis Fibrosing pancreatitis Hereditary chronic pancreatitis Tropical calcic pancreatitis Inborn errors of metabolism (particularly branched chain aminoacidemias) Idiopathic Hyperlipidemias Partial lipodystrophy Wilsons disease Hemochromatosis 1 antitrypsin deciency

Chronic hereditary pancreatitis diagnosed mainly in adult life

Periampullary obstruction

Infections

a sentinel event the acute injury must be sufciently severe to attract monocytes and to cause inltration, differentiation and proliferation of pancreatic stellate cells. For brosis to occur there must be recurrent acinar injury resulting in chemocytokine release that then stimulates stellate cells.14 Recent developments in molecular biology and in our understanding of inammation have advanced our insight into the pancreatic process. They are the discovery of mutations in the cationic trypsinogen gene, cystic brosis transmembrane conductance regulator (CFTR), pancreatic secretory trypsin inhibitor (also known as SPINK 1) and the action of cytokines.

Trauma Metabolic

Cationic trypsinogen gene

Cationic trypsinogen (UniGene name: protease, serine 1: PRSS1) accounts for 65% of trypsinogen, and is one of the most abundant molecules produced by acinar cells.2 Two other forms of trypsinogen are produced by the human pancreatic acinar cell: (i) anionic trypsinogen, which accounts for approximately 30% of potential trypsin activity; and (ii) mesotrypsinogen, which is responsible for 5% of activity. Normally, trypsinogen is converted to trypsin in the duodenum as a result of activation by brush border-derived enterokinase. In turn, trypsin will activate other pancreatic enzymes (except amylase and lipase) that result in luminal digestion of nutrients. Genetic defects in the cationic trypsinogen gene (PRSS1) result in gain of function either by enhancing activation or preventing inactivation within the acinus, leading to pancreatic autodigestion.15 The most common hereditary pancreatitis-causing mutations in PRSS1 are R122H15 and N29I,16 but several other rare mutations in the PRSS1 gene have been identied, including mutations in codon 16, codon 22, and 23.2,17 The codon 122 mutations cause substitution of arginine with another amino acid. The most common variant is a histidine substitution: R122H. The N29I mutation in codon 29 causes a clinical syndrome identical to the R122H mutation.18 This discovery of genetic mutations associated with hereditary pancreatitis supports the hypothesis that intrapancreatic activation of pancreatic zymogens is central to the pathogenesis of acute pancreatitis.15,19,20 The mutant trypsin in hereditary pancreatitis is resistant to lysis, remains active, and causes autodigestion of the pancreas and episodes of acute pancreatitis. Median age at onset of disease is 11 years in patients with the N29I mutation and

Toxin Miscellaneous Inammatory/ systemic disease

ERCP, endoscopic retrograde cholangiopancreatography; 6-MP, 6-mercaptopurine; SLE, systemic lupus erythematosus.

either to obstruction of ductal ow (structural) or failure in feedback control (hereditary), underpins the genesis of pancreatitis. This results in an aggressive immune response, which is the cause of the pathological process that we identify clinically as pancreatitis. Other factors that modulate and contribute include ischemia reperfusion injury. Although other factors may contribute, this represents the most likely common pathway.10 Chronic pancreatitis can occur as a result of repeated episodes of acute inammation; the so-called necrosisbrosis hypothesis of Comfort et al.13 This does not explain why some patients with hereditary or alcoholic pancreatitis progress to a chronic process without evidence of signicant necrosis. Whitcomb has proposed a sentinel acute pancreatitis event (SAPE), which acts as an a priori step toward the development of chronic pancreatitis. To be
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10 years in those with the R122H.18 Approximately half of patients with hereditary pancreatitis develop chronic pancreatitis,21 and the cumulative incidence of pancreatic cancer was reported to be as high as 40% by age 70 years.22 Perhaps the most important question in these patients is what triggers acute attacks and also whether there are comorbid genes, which contribute to the temporal course.

Pancreatic secretory trypsin inhibitor gene Kazal type 1

Another mechanism to protect the pancreas from autodigestion, besides the self-inactivating capability of trypsin, is the serine protease inhibitor SPINK1 by inhibition of prematurely activated trypsinogen.23 This inhibitor acts as the rst line of defence against the prematurely activated trypsinogen but because of the 1:5 stoichiometric disequilibrium between SPINK1 and trypsinogen, the former is capable of inhibiting only 20% of potential trypsin. This gene may be particularly relevant in tropical pancreatitis, an idiopathic form of pancreatitis seen in southern Asia and parts of Africa. It has been suggested that malnutrition, together with cassava intake, plays an important role in the pathogenesis24 but is not the primary etiology.11 Rossi et al. showed that SPINK1 mutations are also clearly associated with a subtype of tropical pancreatitis, bro-calculous pancreatic diabetes.25 It has been suggested that the SPINK1 mutations alone do not cause pancreatitis, but act as a disease modier or as part of a complex trait by lowering the threshold for initiating pancreatitis or possibly worsening the severity of pancreatitis caused by other genetic and/or environmental factors such as diet.26,27 For example, intake of poorly prepared cassava was once thought to be associated with tropical pancreatitis. The SPINK1 mutations are relatively common, being present in approximately 2% of the general population.26,28 However, the frequency of SPINK1 mutations in populations with idiopathic chronic pancreatitis is markedly increased (approximately 25%), proving that these mutations are clearly associated in some way with pancreatitis.26,29

develop are poorly understood, but gut-derived endotoxin and inammatory mediators may be key.34 It is important to mention that cytokines themselves do not induce pancreatitis but rather mediate the progression of pancreatitis.35 Cellular immune responses therefore are the major determinants of severity.11 The most important step for the development of severe pancreatitis seems to be the activation of the T-helper cell type 1 (Th1) response. CD40 is a member of the tumor necrosis factor (TNF) receptor family expressed by a variety of cells, including B lymphocytes, T lymphocytes, and monocytes. Pancreatic production of pro-inammatory cytokines, such as TNF-, interleukin (IL)-1, IL-6, and IL-8 modulates local injury, systemic inammatory response, and distant organ failure, which, along with pancreatic necrosis, determines the outcome from acute pancreatitis. Inhibition of TNF- or IL-1 ameliorates experimental pancreatitis and inhibition of CD40 may be useful as well.36 The invading leukocytes, macrophages, acinar cells, and distant organs produce the cytokines. The TNF-, interleukins (IL-1, -6, and -8) released from granulocytes and macrophages also enter the portosystemic circulation and act on Kupffer cells in the liver that produce more cytokines and acute phase proteins.35 The net effect is an amplication of cytokine release and a concomitant upregulation of their receptors in the target organs.37 Saluja and Steer suggest that the severity of pancreatitis and associated distant organ damage is determined by events taking place subsequent to acinar cell injury. Their studies indicate that chemokines, plateletactivating factor, and substance P, acting via neurokinin-1 (NK-1) receptors, are pro-inammatory, whereas complement factor 5a (C5a), which is generally considered as an inammatory mediator, may be protective.38 Other factors determining the severity include free radicals, pancreatic glutathione, ischemia, chemokines and neurokines. The mode of acinar cell death and degree of apoptosis correlate with the severity of pancreatitis.37 Because the onset of cytokine production follows immediately after the onset of pancreatitis and peaks after 3648 h, cytokine antagonist therapy may represent a potential therapeutic target and therefore is of intense interest.11

Cystic brosis transmembrane conductance gene

In 1998, two groups reported an association between idiopathic chronic pancreatitis and CFTR mutations.30,31 Several mild pancreatic sufcient CFTR mutations were found to be associated with idiopathic pancreatitis. Overall, the data would suggest that patients with two severe mutations have classical cystic brosis (CF), those with a single mutation are carriers and those who are compound heterozygotes with one severe and one mild mutation are at risk of developing pancreatitis. Because there are more than 1200 mutations, less common alleles are difcult to search for routinely; it is also possible that a less severe mutation may, when coupled with another susceptibility gene such as SPINK 1, result in acute pancreatitis

Acute pancreatitis
Clinical diagnosis
Acute pancreatitis has a variable presentation in children and symptoms may range from mild abdominal pain to severe systemic involvement characterized by metabolic disturbances and shock. Severe disturbance occurs less commonly in children. Complications of this condition are both local and systemic (Table 3). Diagnosis is based on clinical symptoms and signs, accompanied by a threefold increase in either amylase or lipase. Abdominal pain is the most frequent symptom. The pain can be both sudden in onset or slow and gradual.9 Although the most common location is the epigastrium, pain can be located in either the right or left upper quadrant. The typical radiation of the pain to the back observed in adults is not seen in 6090% of children.39,40 Other accompanying symptoms are vomiting, anorexia, and nausea. Generally, food aggravates pain and vomiting.9 On examination the child may be ill, irritable, quiet, or all of these. They typically lie still because movement aggravates the pain and may on occasion get up on hand and knees in an attempt to alleviate
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Role of cytokines
Patients with severe acute pancreatitis have a high incidence of sepsis, multiple organ dysfunction syndrome (MODS), and death.32,33 The mechanisms whereby systemic complications

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pain. Tachycardia, fever, hypotension and abdominal signs such as guarding, rebound tenderness and decreased bowel sounds may be present. Grey Turners and Cullens discoloration of the anks and umbilicus, signs of a hemorrhagic pancreatitis, are seldom present in children. A diagnostic algorithm is shown (Fig. 1).

Laboratory investigations
Amylase Serum amylase rises within 212 h and, in uncomplicated cases, remains elevated for 25 days. Serum amylase levels greater than threefold normal levels (330 U/L) are considered signicant for diagnosis.5 The sensitivity and specicity of amylase in pediatric acute pancreatitis is less than in adults, which varies between 80% and 90%.9 Cox et al. were able to show that 40% of children had normal amylase levels with pancreatitis.41 Hyperamylasemia is non-specic and can be caused by other serious intra-abdominal disorders (appendicitis, intestinal obstruction, and acute cholecystitis), salivary gland disease (mumps and Sjogrens syndrome) and renal insufciency (poor renal clearance of amylase). Normally, 60% of serum amylase is salivary and the rest is pancreatic.9,42 If in doubt, pancreatic isoamylse can be measured. Macroamylasemia deserves comment because this can result in chronic elevation of serum amylase and is due to normal serum amylase being bound to an immunoglobulin to form a complex that is too large to be ltered by the kidney.43 Lipase The serum lipase level is usually elevated in acute pancreatitis and remains elevated for longer than serum amylase levels. Furthermore, lipase has greater sensitivity and specicity than

Table 3 Complications of acute pancreatitis Complication Local Edema/inammation Pancreatic necrosis Abscess Hemorrhage Fluid collections Pseudocyst Ductal rupture and stricture Extension to nearby organs Systemic Shock Pulmonary edema/effusions Hyperglycemia Hypocalcemia Multi-organ failure Renal failure Coagulopathy

History/physical consistent with diagnosis then confirm with lipase/amylase

Investigations will depend on suspected etiology

Trauma

Infection

Evidence of biliary obstruction

Medication

Uncertain

US/ CT

Viral serology or Bacterial cultures

US/CT or MRCP

Cease medication

LFTS Calcium Lipids US

Intact pancreatic duct

Pancreatic duct disrupted

Gallstone

Positive tests

Recurrent attacks (negative tests)

Conservative therapy

ERCP placed stent or surgery

Cholecystectomy vs sphincterotomy +/ursodeoxycholic acid

Treat cause

Consider more extensive testing including genetic studies and further imaging

Figure 1 Diagnostic algorithm for acute/recurrent pancreatitis. CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; LFT, liver function tests; MRCP, magnetic resonance cholangiopancreatography; US, ultrasound.

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amylase.44,45 It is considered as consistent with pancreatitis when elevated greater than threefold the normal levels.5 Lipase is also found in intestinal mucosa, stomach, adipose tissue, leukocytes, and breast milk and can be elevated in the serum of patients with other abdominal conditions.9 Neither concentration correlates with disease severity.46 Frank and Gottlieb showed that the proportion of adult patients with isolated hyperlipasemia was up to 32% in acute pancreatitis and 1184% in non-pancreatic abdominal pain.47 This occurred especially in alcoholic patients where gastric lipase may be elevated. Therefore in children the simultaneous measurement of both, amylase and lipase, still appears to have the highest sensitivity with 94%.47

admission white blood cell count (>18.5 109/L), admission lactic dehydrogenase (>2000 IU/L), 48-h trough Ca2+, 48-h trough albumin, 48-h uid sequestration, and 48-h rise in blood urea nitrogen (BUN). If each criterion is assigned a value of 1 point, then the outcome of patients with 02 points was 8.6% severe and 1.4% mortality; with 24 points, 38.5% severe and 5.8% mortality; and with 57 points, 80% severe and 10% mortality. They showed a better sensitivity versus Ranson and Glasgow scores (70% vs 30% and 35%, respectively) and a better negative predictive value (91% vs 85% and 85%).57

Chronic pancreatitis
Classication
The diagnosis of this condition is based on a combination of clinical features (abdominal pain, weight loss and diabetes mellitus) and functional (documented exocrine pancreatic insufciency) and imaging studies.2 In adult patients, pancreatic biopsy is considered the gold standard for diagnosis, but is rarely if ever performed in children. Three main classication systems for chronic pancreatitis have been utilized in adults, each building on the shortcomings of its predecessor. The rst is the Marseille classication, which relies heavily on the grading of biopsy specimens.5861 Later reviews of this classication attempt to link histopathology with etiology. The second was the Cambridge classication, which places a greater emphasis on the use of imaging to provide a grading and severity score.62,63 Both systems have aws including: (i) an inability to distinguish the different forms of chronic pancreatitis; and (ii) not distinguishing patients or functional abnormalities associated with specic etiologies. More recently the toxic, idiopathic, genetic, autoimmune, recurrent severe associated chronic pancreatitis and other (TIGAR-O) system has been developed and allows multiple risk factors to be assessed in an individual patient either as a risk factor or as an etiology.64 The perfect classication system remains elusive. In children with evidence of chronic pancreatitis we suggest the following investigations: (i) sweat test; (ii) gene testing for CFTR, cationic trypsinogen and SPINK 1 mutations; (iii) imaging to exclude a structural (congenital or acquired) etiology; and (iv) assessment for auto-immune causes.

Imaging
Imaging techniques will conrm the diagnosis of pancreatitis, and sometimes identify the cause, and also assess complications such as pseudocyst.48 Among the most useful and frequently used are abdominal ultrasound and computed tomography (CT). The two major sonographic ndings are increased pancreatic size and decreased pancreatic echogenecity,41,49 whereas a normal gland can be observed in mild cases.48 The published sensitivity for diagnosing acute pancreatitis by ultrasound (US) is not higher than 6267%50 but it is the most sensitive of the readily available methods for evaluating the biliary tract for clues to the cause of acute pancreatitis.51 Endoscopic ultrasound provides better images of the lower biliary tract than conventional US. Contrast-enhanced CT is the most useful imaging method for evaluating the severity and detecting complications but radiation exposure is high.9,52 It is indicated (i) when there is history of signicant blunt trauma or if one is concerned about other serious intra-abdominal disorders such as mesenteric infarction as a cause of severe pain; (ii) to stage severe pancreatitis (particularly to look for evidence of necrosis, which is often not noted for 4872 h after onset); and (iii) to determine if there are signicant intraabdominal complications of pancreatitis. Scanning should occur after the patient receives oral contrast to delineate bowel followed by i.v. contrast to identify areas of necrosis in the pancreas. Animal models have suggested that i.v. contrast can worsen experimental acute pancreatitis.36 However, Uhl et al. observed no deterioration of acute pancreatitis in 264 of 302 patients with severe acute pancreatitis, compared with 38 patients in whom an admission CT scan was not performed.52 In adults, magnetic resonance imaging (MRI) of the pancreas provides much the same information53 but experience in children is limited.9 Magnetic resonance imaging may well supersede other forms of imaging because it reduces a childs exposure to ionizing radiation.

Clinical features
Abdominal pain leads to signicant morbidity in chronic pancreatitis. It is most commonly described as epigastric, deep or penetrating towards the back and accompanied by nausea and vomiting. It is often relieved by sitting forward and may increase post-prandially. The natural history of the pain in the adult population is variable and incompletely studied. It may commence as intermittent attacks with periods of well-being and then become more continuous. Others may have little or no pain.6567 Over time there is a tendency for the pain to burn out.66 Steatorrhea and weight loss will not occur until pancreatic exocrine function has been reduced to around 2% of the normal output.68 Patients have characteristic bulky and oily stools, which may be accompanied by weight loss. In adults, the median time to the development of exocrine insufciency varies from 5.6 to 13.1 years and will occur in 5080% of patients.65,66 Diabetes mellitus has also been
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Scoring system
Several scoring systems are used in adults, but there is no universally accepted scoring system for predicting severity in acute pancreatitis in children. In adults, both the Ransons criteria and Glasgow score measure the severity and prognosis of acute pancreatitis,5456 but their disadvantage is that prognosis cannot be predicted until 48 h after admission.46 Recently, DeBanto et al. compared Ranson and Glasgow scores with a new scoring system developed for children, using age (<7 years), weight (23 kg),
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described in adults with chronic pancreatitis and is said to ultimately occur in 4070% of patients, with a median time to onset of 11.926.3 years.65,66 Because insulin and glucagon producing cells are destroyed in chronic pancreatitis, the diabetes in these patients can be particularly brittle. Pediatric data on the prevalence and incidence of exocrine and endocrine failure are limited. The complications of chronic pancreatitis are summarized in Table 4. Specic mention of the development of pancreatic adenocarcinoma should be made. The lifetime risk for this complication is quoted as 4%69 but the risk in patients with hereditary pancreatitis is said to approach 40%.22

Ultrasound Findings consistent with chronic pancreatitis include (i) dilation of the pancreatic duct; (ii) ductal stones; (iii) irregularities in gland margins/changes in echotexture; and (iv) pseudocysts. This test is said to have a sensitivity of 5080% and a specicity of 90%.72 Endoscopic ultrasound allows a highly detailed study of the pancreatic duct and parenchyma. When compared to ERCP there is agreement in 75% of patients.7375 This modality needs further assessment in children. Computed tomography

Functional testing
This refers to testing for pancreatic exocrine insufciency and is not specic to chronic pancreatitis, because positive tests can occur in children with other causes of pancreatic insufciency, such as ShwachmanDiamond syndrome. Current tests of exocrine function include small intestinal intubation tests to assess the secretory capacity of the pancreas. These tests are highly sensitive and specic but are invasive and time-consuming. Indirect tests detect abnormalities secondary to loss of pancreatic function such as malabsorption of fat and nitrogen. Although less expensive, these lack both sensitivity and specicity, and cannot adequately differentiate between mild and moderate exocrine pancreatic function. Improvements in both direct and indirect tests with appropriate standardization are required, so that we can determine when relapsing and chronic pancreatitis develop exocrine insufciency.70,71 A summary of direct versus indirect tests is presented in Table 5. We would advocate the use of simple indirect tests to assess patients for pancreatic insufciency. The use of fecal elastase and a 72-h fecal fat balance is adequate for most children.71

This test has a sensitivity and specicity of around 90% with a grading system devised by Forsmark that is applicable to adults with pancreatitis.76 Endoscopic retrograde cholangiopancreatography In the absence of tissue conrmation, ERCP is considered to be the gold standard in adult practice (although MRI may eventually supersede ERCP). The sensitivity and specicity approaches 90 100%.2 An ERCP grading system as part of the Cambridge classication has been validated in adults but not in children.62,63 Changes are graded as normal, equivocal, mild, moderate and severe on the appearance of the main pancreatic duct and side branches. Interpretation is subjective and there can be substantial inter- and intraobserver variation. Also similar morphological changes in the pancreatic duct can be produced by acute pancreatitis, and can remain for months after the resolution of the acute attack.76 Magnetic resonance imaging This is an evolving tool in the analysis of chronic pancreatitis. It has signicant advantages in that it is non-invasive and avoids ionizing radiation. Agreement between magnetic resonance cholangiopancreatography and ERCP is around 75%.77 The main problem with MRI is its inability to reveal the details of the small ducts, which can represent the early phases of chronic pancreatitis. As MRI technology improves, it is likely that this will be used more often for diagnosis and staging of chronic pancreatitis.

Imaging studies
Four imaging procedures are used in children and adults with chronic pancreatitis and these include US (less frequently endoscopic ultrasonography), CT, endoscopic retrograde cholangiopancreatography (ERCP) and MRI.
Table 4 Complications of chronic pancreatitis Pancreatic pseudocyst Pseudoaneurysm Splenic vein thrombosis Common bile duct obstruction Duodenal obstruction Pancreatic stula Adenocarcinoma

Treatment of acute, relapsing and chronic pancreatitis

Treatment of acute pancreatitis is primarily supportive and aims at limiting exocrine pancreatic secretion and monitoring for acute and long-term complications.46 Most mild to moderate cases will settle if food and drink is withheld for 35 days. During this time it is necessary to maintain hydration by administering i.v. uids

Table 5 Tests of exocrine pancreatic function Direct tests Exogenoous hormonal stimulants (secretin and CCK) Nutrient stimulants (Lundh test meal, fatty acids, amino acids and hydrochloric acid) CCK, cholecystokinin. Indirect tests Stool (microscopy for fat globules, 72-h fecal fat balance, chymotrypsin and elastase) Breath tests (carbon-14-lipids, carbon-13-lipids and starch) Urinary and plasma markers (bentiromide, pancreolaryl, dual-label Schilling)

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and controlling pain with parenteral analgesia. In children with relapsing attacks of pancreatitis, we would advocate similar management and also include further investigations to exclude structural, metabolic and hereditary forms of pancreatitis as suggested in Fig. 1. In those who have chronic pancreatitis the management should be directed towards: (i) etiological investigations; (ii) adequate analgesia; (iii) providing appropriate long-term follow up with emphasis on monitoring and treatment of exocrine pancreatic insufciency and diabetes mellitus; and (iv) providing patient education with regard to avoidance of smoking and alcohol (both risk factors for the development of pancreatic adenocarcinoma). In patients with recalcitrant acute/relapsing and established chronic pancreatitis, other therapeutic options have been used to aid recovery, these include (i) enteral nutrition via a naso-jejunal feeding tube; (ii) antioxidants; (iii) pancreatic enzyme replacement; (iv) octreotide (OCT) and pancreatic protease inhibitors; (v) antibiotics; and (vi) surgery.

none while on treatment.81 This nding raises the possibility that supplementation with antioxidants may be benecial, because there is a known association between oxidative stress and activation of trypsinogen.82

Pancreatic enzymes
Discussions about enzyme therapy in patients with acute pancreatitis are based upon theory rather than evidence.83 However, in chronic pancreatitis, several studies have evaluated pain relief by oral pancreatic enzymes with varying success.8488 Physiological studies in pigs and rats have documented that pancreatic serine proteases can suppress exocrine pancreatic secretion. The enzymes work by suppressing the feedback mechanism in the duodenum that regulates the cholecystokinin (CCK) release.89 Briey, trypsin cleaves CCK-releasing peptide, which is thought to be derived from the proximal small intestine. This peptide results in CCK release and acinar drive. In the fasting state CCKreleasing peptide is thought to be largely destroyed by proteases. In the immediate post-prandial period, the serine proteases are competed for by dietary protein, allowing CCK-releasing protein to avoid digestion and promote CCK secretion. After the meal is digested there is a return to the fasting state. In chronic pancreatitis, because there can be some degree of exocrine insufciency the normal suppression of CCK-releasing peptide may be limited, resulting in acinar drive, and could contribute to inammation in the susceptible person. There have been at least six randomized controlled studies assessing the ability of orally administered pancreatic enzymes to decrease pain in chronic pancreatitis.8487,90,91 Two studies using non-enteric coated enzyme preparations reported some benet,84,85 while four others using enteric coated microsphere enzyme preparations did not show any improvement in chronic pancreatitic pain.86,87,90,91 These nding may possibly be explained by the fact that the feedback-sensitive part of the small bowel is proximally situated and that enzymes in enteric coated microspheres are released only distally.

Enteral versus parenteral nutrition

The results of several controlled studies in adult patients with acute pancreatitis support enteral nutrition.78 A recently completed meta-analysis of six studies with 263 participants compared outcomes in patients treated with enteral nutrition alone to those who received parenteral nutrition only. Enteral nutrition was associated with a lower incidence of infection, reduced surgical interventions to ameliorate pancreatitis and a reduced hospital stay. There were no signicant differences in mortality or non-infectious complications between the two groups of patients.78 Enteral nutrition (EN) costs less than parenteral nutrition (PN): PN is four times more expensive.79 Although there are sparse pediatric data, EN feeding has been widely adopted. A naso-jejunal feeding tube is placed either radiologically or endoscopically and the child is fed a highprotein and low-fat formula until he or she is ready to commence oral intake.

Antioxidants
Damage by oxygen radicals may contribute to pain in both acute and chronic pancreatitis. Free radicals are generated naturally and are involved in signal transduction, apoptosis, cytokine production, chemotaxis, proteolysis, and phagocytosis. Most biologically important free radicals are either oxygen or nitrogen derived. Their potential to damage the bodys own cells is balanced by their short half-life and the presence of inhibitors such as catalase, superoxide dismutase, or glutathione peroxidase, and scavenger antioxidants such as -tocopherol, -carotene, or ascorbate. The problem arises when the balance between activation and inactivation is disrupted by either increased generation of free radicals or decreased generation or supply of scavengers.11 Mathew et al. have shown antioxidant deciencies in children with hereditary pancreatitis. The children presented with lower vitamin E and selenium levels and higher activities of the antioxidant enzyme superoxide dismutase, compared with asymptomatic relatives or unrelated controls.80 Uden et al. conducted a 20-week double-blind cross-over trial in 28 adult patients who required either tablets providing daily doses of 600 g organic selenium, 9000 IU beta carotene, 0.54 g vitamin C, 270 IU vitamin E and 2 g methionine (20 patients) or placebo (eight patients). Six patients had an attack while on placebo but

Octreotide and pancreatic protease inhibitors

Octreotide is a synthetic cyclic long-acting octapeptide analog of somatostatin (SS). It has a half-life of approximately 90 min when given subcutaneously,92 compared to 3 min for native SS.93 Both SS and OCT inhibit many physiological functions including gastrointestinal motility, secretion of gastric acid, pepsin and intrinsic factor, intestinal secretion of water and electrolytes, splanchnic blood ow, pancreatic enzyme secretion, and gallbladder contractility. Of the protease inhibitors gabexate mesilate is the most widely studied. All these agents have been used in severe acute and chronic pancreatitis to control pain but the evidence for routine clinical use of these agents is weak. A meta-analysis conducted by Andriulli et al. assessed the effects of SS, OCT and gabexate mesilate on patients with mild to severe acute pancreatitis and found that antisecretory agents, such as SS and OCT, reduced mortality but not complications, whereas gabexate mesilate did not reduce mortality but did reduce complications.94 Subsequent to this, the results of a large multicenter trial refuted these conclusions with regard to OCT. In that study, Uhl et al. assessed the use of OCT in 302 patients from 32 hospitals all fullling the criteria
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for moderate to severe acute pancreatitis.95 Patients were randomly assigned to one of three treatment groups: placebo; 100 g and 200 g (OCT) administered by s.c. injections three times a day for 7 days. The primary outcome was mortality and 15 typical complications of acute pancreatitis. Treatment was not benecial. But do these agents reduce acute pancreatitis in patients (adult) undergoing ERCP? The risk of developing pancreatitis following ERCP is estimated as 3% of diagnostic and 5% of therapeutic ERCP.96 Andriulli et al. conducted a meta-analysis of 28 clinical trials with the aim of evaluating the efcacy of SS, OCT and gabexate mesilate in the treatment of post-ERCP pancreatitis.97 They concluded that pancreatic injury after ERCP can be prevented with the administration of either SS or gabexate mesilate. This would suggest that these agents may be used prophylactically; but the cost-effectiveness is yet to be determined. It is fair to say that all the aforementioned data on OCT, SS and gabexate mesilate apply to pancreatitis in adults and that there are few data relevant to children.

case series,105 and a decision with regard to surgery in children is often based on adult experience. Endoscopic therapy refers to stent placement and is useful only if there is an identiable dominant stricture with evidence of pancreatic duct obstruction.106109 Surgical options include drainage procedures such as a lateral pancreaticojejunostomy and are useful for large duct strictures in the distal half of the pancreas. In this operation, the pancreatic duct is opened longitudinally and anastomosed to a defunctionalized limb of small bowel, which is then connected with a Roux-en-Y limb. At the time any ductal strictures can be excised and pancreatic stones removed. This procedure has a low morbidity and mortality.76 There are no randomized trials comparing this operation with other therapies. However, immediate pain relief is seen in 80% of patients.110112 We have needed to perform this operation only on two occasions at the Royal Childrens Hospital and both patients have had long-term relief of pain. Pancreatic resection operations such as the Whipple and Frey operations76 are associated with high mortality and morbidity and are rarely needed.76

Prophylactic antibiotics
Several authors report that prophylactic antibiotics are indicated when there is pancreatic necrosis or when infection is either suspected or documented in severe acute pancreatitis.98,99 Buchler et al. suggest that an antibiotic treatment of necrotic pancreatitis may prevent surgery.100 In a recent Cochrane Review, Bassi et al. concluded that there was strong evidence that i.v. antibiotic prophylactic therapy for 1014 days decreases superinfection of necrotic tissue and mortality in patients with severe acute pancreatitis with proven pancreatic necrosis at CT.101 All these studies have been in adults.

Genetic testing
Genetic testing has both a diagnostic and a predictive role. Predictive testing is done when a patient does not have clinical evidence for the disease but where there is a positive family history. The strength of predictive testing lies in being able to modify outcome (e.g. development of adenocarcinoma) by early intervention (avoidance of smoking and alcohol consumption). A consensus for diagnostic of testing for PRSS1 mutations113 has been achieved but are not as well-dened for SPINK1 and CFTR mutations.1,113 These include testing patients for PRSS1 mutations who (i) have unexplained recurrent acute pancreatitis (two or more attacks); (ii) have unexplained chronic pancreatitis; and (iii) are children suffering from an unexplained episode of pancreatitis with a family history of pancreatitis. As to predictive testing, guidelines have been suggested for PRSS1.113 Such testing if widely applied would open a Pandoras box and hence we would strongly advocate predictive testing to be performed only in the research setting and after appropriate ethical approval has been obtained.

Surgery
Surgical management of acute pancreatitis is limited to debridement of infected pancreatic necrosis as well as cholecystectomy in patients with gallstone-induced pancreatitis. Pancreatic necrosis is necessary for the development of secondary pancreatic infection. This condition is associated with high mortality and is an indication for surgery.102 Sterile necrosis may be treated conservatively and this is supported by Buchler et al., who conducted a prospective study of adults and children.100 They found that in 204 patients, 42% had necrotizing disease, of which 66% had sterile and 34% infected necrosis on ne-needle aspiration. Patients with infected necrosis had more organ failure and a greater extent of necrosis. The death rate in the group with infected necrosis was 24% versus 1.8% in patients with sterile necrosis managed without surgery.100 Removal of infected necrotic tissue surgically is most unusual in children and has not been necessary in any patient with acute pancreatitis at the authors respective institutions. However, there are guidelines set down for this in the adult literature.103 As to gallstone-induced pancreatitis, early ERCP and papillotomy is required only if there is evidence of obstructive jaundice to prevent biliary sepsis.104 Otherwise, conservative therapy with cholecystectomy after recovery is recommended. In chronic pancreatitis the main indication for endoscopic therapy and surgery is chronic unremitting pain. The principal goal of these interventions is provision of adequate drainage of the pancreatic ducts. Again, pediatric data are sparse and limited to small
506

Conclusion
Childhood pancreatitis remains enigmatic with more questions than answers. There are several signicant gaps in our etiologic knowledge. Currently, our approach to childhood pancreatitis depends on adult physician experience and knowledge. However, as we all know, a child is not a small adult and these conditions (acute and chronic pancreatitis) behave differently in children. There is a substantial need for a coordinated national and international approach to research and clinical management of children with pancreatitis.

References
1 Witt H. Gene mutations in children with chronic pancreatitis. Pancreatology 2001; 1: 4328. 2 Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classication, and new genetic developments. Gastroenterology 2001; 120: 682707. 3 Sarles H. Denitions and classications of pancreatitis. Pancreas 1991; 6: 4704.

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A Nydegger et al.

Pancreatitis in children

4 Dodge JA. Paediatric and hereditary aspects of chronic pancreatitis. Digestion 1998; 59 (Suppl. 4): 4959. 5 Lopez MJ. The changing incidence of acute pancreatitis in children: a single-institution perspective. J. Pediatr. 2002; 140: 6224. 6 Werlin SL, Kugathasan S, Frautschy BC. Pancreatitis in children. J. Pediatr. Gastroenterol. Nutr. 2003; 37: 5915. 7 Oliver MR, Ranuh R, Heine RG, Gegati-Levy R, Crameri J. The changing incidence of acute pancreatitis in children: a 10-year experience in Melbourne. J. Pediatr. Gastroenterol. Nutr. 2004; 39 (Suppl. 1): S167. 8 Weizman Z. An update on diseases of the pancreas in children. Curr. Opin. Pediatr. 1997; 9: 4947. 9 Lerner A, Branski D, Lebenthal E. Pancreatic diseases in children. Pediatr. Clin. North Am. 1996; 43: 12556. 10 Whitcomb D. Hereditary and childhood disorders of the pancreas, including cystic brosis. In: Feldman M, Friedman LS, Sleisenger MH, eds. Gastrointestinal and Liver Disease, 7th edn. Philadelphia: Saunders, 2002; 881912. 11 Khokhar AS, Seidner DL. The pathophysiology of pancreatitis. Nutr. Clin. Pract. 2004; 19: 515. 12 DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme ouputs and malabsorption in severe pancreatic insufciency. N. Engl. J. Med. 1973; 288: 81315. 13 Comfort MW, Gambrill EE, Baggenstoss AH. Chronic relapsing pancreatitis. A study of twenty-nine cases without associated disease of the biliary or gastro-intestinal tract. Gastroenterology 1968; 54 (Suppl.): 7605. 14 Whitcomb DC. Hereditary pancreatitis: new insights into acute and chronic pancreatitis. Gut 1999; 45: 31722. 15 Whitcomb DC, Gorry MC, Preston RA et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat. Genet. 1996; 14: 1415. 16 Gorry MC, Gabbaizedeh D, Furey W et al. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology 1997; 113: 10638. 17 Chen JM, Montier T, Ferec C. Molecular pathology and evolutionary and physiological implications of pancreatitis-associated cationic trypsinogen mutations. Hum. Genet. 2001; 109: 24552. 18 Keim V, Bauer N, Teich N, Simon P, Lerch MM, Mossner J. Clinical characterization of patients with hereditary pancreatitis and mutations in the cationic trypsinogen gene. Am. J. Med. 2001; 111: 6226. 19 Le Bodic L, Bignon JD, Raguenes O et al. The hereditary pancreatitis gene maps to long arm of chromosome 7. Hum. Mol. Genet. 1996; 5: 54954. 20 Whitcomb DC, Preston RA, Aston CE et al. A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 1996; 110: 197580. 21 Whitcomb DC. Genetic predispositions to acute and chronic pancreatitis. Med. Clin. North Am. 2000; 84: 53147, vii. 22 Lowenfels AB, Maisonneuve P, DiMagno EP et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J. Natl Cancer Inst. 1997; 89: 4426. 23 Schneider A, Pftzer R, Whitcomb DC. Genetics and pancreatic disease. Curr. Opin. Gastroenterol. 2002; 18: 54551. 24 Mohan V, Premalatha G, Pitchumoni CS. Tropical chronic pancreatitis: an update. J. Clin. Gastroenterol. 2003; 36: 33746. 25 Rossi L, Pfutzer RH, Parvin S et al. SPINK1/PSTI mutations are associated with tropical pancreatitis in Bangladesh. A preliminary report. Pancreatology 2001; 1: 2425. 26 Pfutzer RH, Barmada MM, Brunskill AP et al. SPINK1/PSTI polymorphisms act as disease modiers in familial and idiopathic chronic pancreatitis. Gastroenterology 2000; 119: 61523. 27 Threadgold J, Greenhalf W, Ellis I et al. The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic

28

29

30

31

32 33 34 35

36 37 38

39

40 41

42

43

44 45

46 47

48 49 50

51

chronic pancreatitis but does not cause the disease. Gut 2002; 50: 67581. 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: 679. 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: 21316. Sharer N, Schwarz M, Malone G et al. Mutations of the cystic brosis gene in patients with chronic pancreatitis. N. Engl. J. Med. 1998; 339: 64552. Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS. Relation between mutations of the cystic brosis gene and idiopathic pancreatitis. N. Engl. J. Med. 1998; 339: 6538. Wilson C, McArdle CS, Carter DC, Imrie CW. Surgical treatment of acute necrotizing pancreatitis. Br. J. Surg. 1988; 75: 111923. Grace SG, State D. Septic complications of pancreatitis. Br. J. Surg. 1976; 63: 22932. Erwin PJ, Lewis H, Dolan S et al. Lipopolysaccharide binding protein in acute pancreatitis. Crit. Care Med. 2000; 28: 1049. Weber CK, Adler G. From acinar cell damage to systemic inammatory response: current concepts in pancreatitis. Pancreatology 2001; 1: 35662. Nagar AB, Gorelick FS. Acute pancreatitis. Curr. Opin. Gastroenterol. 2002; 18: 5527. Norman J. The role of cytokines in the pathogenesis of acute pancreatitis. Am. J. Surg. 1998; 175: 7683. Saluja AK, Steer MLP. Pathophysiology of pancreatitis. Role of cytokines and other mediators of inammation. Digestion 1999; 60 (Suppl. 1): 2733. Haddock G, Coupar G, Youngson GG, MacKinlay GA, Raine PA. Acute pancreatitis in children: a 15-year review. J. Pediatr. Surg. 1994; 29: 71922. Weizman Z, Durie PR. Acute pancreatitis in childhood. J. Pediatr. 1988; 113 (1 Part 1): 249. Cox KL, Ament ME, Sample WF, Sarti DA, ODonnell M, Byrne WJ. The ultrasonic and biochemical diagnosis of pancreatitis in children. J. Pediatr. 1980; 96 (3 Part 1): 40711. Steinberg WM, Goldstein SS, Davis ND, Shammaa J, Anderson K. Diagnostic assays in acute pancreatitis. A study of sensitivity and specicity. Ann. Intern. Med. 1985; 102: 57680. DiMagno EP, Chari S. Acute pancreatitis. In: Feldman M, Friedman LS, Sleisenger MH, eds. Gastrointestinal and Liver Disease, 7th edn. Philadelphia: Saunders, 2002; 91341. Gumaste V, Dave P, Sereny G. Serum lipase: a better test to diagnose acute alcoholic pancreatitis. Am. J. Med. 1992; 92: 23942. Gwozdz GP, Steinberg WM, Werner M, Henry JP, Pauley C. Comparative evaluation of the diagnosis of acute pancreatitis based on serum and urine enzyme assays. Clin. Chim. Acta 1990; 187: 24354. Russell MK. Acute pancreatitis: a review of pathophysiology and nutrition management. Nutr. Clin. Pract. 2004; 19: 1624. Frank B, Gottlieb K. Amylase normal, lipase elevated: is it pancreatitis? A case series and review of the literature. Am. J. Gastroenterol. 1999; 94: 4639. Elmas N. The role of diagnostic radiology in pancreatitis. Eur. J. Radiol. 2001; 38: 12032. Fleischer AC, Parker P, Kirchner SG, James AE Jr. Sonographic ndings of pancreatitis in children. Radiology 1983; 146: 1515. Neoptolemos JP, Hall AW, Finlay DF, Berry JM, Carr-Locke DL, Fossard DP. The urgent diagnosis of gallstones in acute pancreatitis: a prospective study of three methods. Br. J. Surg. 1984; 71: 2303. Steinberg W, Tenner S. Acute pancreatitis. N. Engl. J. Med. 1994; 330: 1198210.

Journal of Gastroenterology and Hepatology 21 (2006) 499509 2006 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd

507

Pancreatitis in children

A Nydegger et al.

52 Uhl W, Roggo A, Kirschstein T et al. Inuence of contrast-enhanced computed tomography on course and outcome in patients with acute pancreatitis. Pancreas 2002; 24: 1917. 53 Stark DD, Moss AA, Goldberg HI, Davis PL, Federle MP. Magnetic resonance and CT of the normal and diseased pancreas: a comparative study. Radiology 1984; 150: 15362. 54 Ranson JH, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC. Prognostic signs and the role of operative management in acute pancreatitis. Surg. Gynecol. Obstet. 1974; 139: 6981. 55 Ranson JH. Etiological and prognostic factors in human acute pancreatitis: a review. Am. J. Gastroenterol. 1982; 77: 6338. 56 Blamey SL, Imrie CW, ONeill J, Gilmour WH, Carter DC. Prognostic factors in acute pancreatitis. Gut 1984; 25: 13406. 57 DeBanto JR, Goday PS, Pedroso MR et al. Acute pancreatitis in children. Am. J. Gastroenterol. 2002; 97: 172631. 58 Sarles H. Pancreatitis. Symposium of Marseille, 1963. Basel: Karger, 1965. 59 Sarles H. Proposal adopted unanimously by the participants of the Symposium, Marseille 1963. Bibl. Gastroenterol. 1965; 7: 78. 60 Singer MV, Gyr K, Sarles H. Revised classication of pancreatitis. Report of the Second International Symposium on the Classication of Pancreatitis in Marseille, France, March 2830, 1984. Gastroenterology 1985; 89: 6835. 61 Sarles H, Adler G, Dani R et al. The pancreatitis classication of MarseillesRome 1988. Scand. J. Gastroenterol. 1989; 24: 6412. 62 Sarner M, Cotton PB. Denitions of acute and chronic pancreatitis. Clin. Gastroenterol. 1984; 13: 86570. 63 Sarner M, Cotton PB. Classication of pancreatitis. Gut 1984; 25: 7569. 64 Whitcomb DC, Lowe ME. Acute and chronic pancreatitis. In: Walker WA, Goulet OG, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR, eds. Pediatric Gastrointestinal Disease. Hamilton, Ontario: BC Decker, 2004; 158497. 65 Ammann RW, Akovbiantz A, Largiader F, Schueler G. Course and outcome of chronic pancreatitis. Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 1984; 86 (5 Part 1): 8208. 66 Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP. The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994; 107: 14817. 67 Lankisch PG, Lohr-Happe A, Otto J, Creutzfeldt W. Natural course in chronic pancreatitis. Pain, exocrine and endocrine pancreatic insufciency and prognosis of the disease. Digestion 1993; 54: 14855. 68 Gaskin KJ, Durie PR, Lee L, Hill R, Forstner GG. Colipase and lipase secretion in childhood-onset pancreatic insufciency. Delineation of patients with steatorrhea secondary to relative colipase deciency. Gastroenterology 1984; 86: 17. 69 Lowenfels AB, Maisonneuve P, Cavallini G et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N. Engl. J. Med. 1993; 328: 14337. 70 Belkind-Gerson J, Fernandez-Peters A, Furnes R et al. Pancreatic disorders and cystic brosis: Working Group report of the second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J. Pediatr. Gastroenterol. Nutr. 2004; 39 (Suppl. 2): S68894. 71 Oliver MR, Couper RT. Pancreatic function tests. In: Walker WA, Goulet OG, Kleinman RE, Sherman PM, Shneider BL, Sanderson IR, eds. Pediatric Gastrointestinal Disease. Hamilton, Ontario: BC Decker, 2004; 181629. 72 Niederau C, Grendell JH. Diagnosis of chronic pancreatitis. Gastroenterology 1985; 88: 197395. 73 Forsmark CE. The diagnosis of chronic pancreatitis. Gastrointest. Endosc. 2000; 52: 2938.

74 Catalano MF, Lahoti S, Geenen JE, Hogan WJ. Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis. Gastrointest. Endosc. 1998; 48: 1117. 75 Wiersema MJ, Hawes RH, Lehman GA, Kochman ML, Sherman S, Kopecky KK. Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin. Endoscopy 1993; 25: 55564. 76 Forsmark CE. Chronic pancreatitis. In: Feldman M, Friedman LS, Sleisenger MH, eds. Gastrointestinal and Liver Disease. Philadelphia: Saunders, 2002; 94369. 77 Sica GT, Braver J, Cooney MJ, Miller FH, Chai JL, Adams DF. Comparison of endoscopic retrograde cholangiopancreatography with MR cholangiopancreatography in patients with pancreatitis. Radiology 1999; 210: 60510. 78 Marik PE, Zaloga GP. Meta-analysis of parenteral nutrition versus enteral nutrition in patients with acute pancreatitis. BMJ 2004; 328: 140710. 79 McClave SA, Greene LM, Snider HL et al. Comparison of the safety of early enteral vs parenteral nutrition in mild acute pancreatitis. JPEN J. Parenter. Enteral Nutr. 1997; 21: 1420. 80 Mathew P, Wyllie R, Van Lente F, Steffen RM, Kay MH. Antioxidants in hereditary pancreatitis. Am. J. Gastroenterol. 1996; 91: 155862. 81 Uden S, Bilton D, Nathan L, Hunt LP, Main C, Braganza JM. Antioxidant therapy for recurrent pancreatitis: placebo-controlled trial. Aliment. Pharmacol. Ther. 1990; 4: 35771. 82 Niederau C, Schonberg M. New developments in the pathophysiology of inammatory pancreatic disease. Hepatogastroenterology 1999; 46: 272235. 83 McMahon MJ. Acute pancreatitis: when is enzyme treatment indicated? Digestion 1993; 54 (Suppl. 2): 402. 84 Isaksson G, Ihse I. Pain reduction by an oral pancreatic enzyme preparation in chronic pancreatitis. Dig. Dis. Sci. 1983; 28: 97102. 85 Slaff J, Jacobson D, Tillman CR, Curington C, Toskes P. Proteasespecic suppression of pancreatic exocrine secretion. Gastroenterology 1984; 87: 4452. 86 Mossner J, Secknus R, Meyer J, Niederau C, Adler G. Treatment of pain with pancreatic extracts in chronic pancreatitis: results of a prospective placebo-controlled multicenter trial. Digestion 1992; 53: 5466. 87 Halgreen H, Pedersen NT, Worning H. Symptomatic effect of pancreatic enzyme therapy in patients with chronic pancreatitis. Scand. J. Gastroenterol. 1986; 21: 1048. 88 Giger U, Stanga Z, DeLegge MH. Management of chronic pancreatitis. Nutr. Clin. Pract. 2004; 19: 379. 89 Li Y, Hao Y, Owyang C. Diazepam-binding inhibitor mediates feedback regulation of pancreatic secretion and postprandial release of cholecystokinin. J. Clin. Invest. 2000; 105: 3519. 90 Malesci. A, Gaia E, Fioretta A et al. No effect of long-term treatment with pancreatic extract on recurrent abdominal pain in patients with chronic pancreatitis. Scand. J. Gastroenterol. 1995; 30: 3928. 91 Larvin M, McMahon MJ, Thomas WEG. Creon (enteric coated pancreatin microspheres) for the treatment of pain in chronic pancreatitis: a double-blind randomised placebo-controlled crossover trial. Gastroenterology 1991; 100: A283. 92 Kutz K, Nuesch E, Rosenthaler J. Pharmacokinetics of SMS 201995 in healthy subjects. Scand. J. Gastroenterol. 1986; 119 (Suppl): 65 72. 93 Mosdell KW, Visconti JA. Emerging indications for octreotide therapy, Part 1. Am. J. Hosp. Pharm. 1994; 51: 118492. 94 Andriulli A, Leandro G, Clemente R et al. Meta-analysis of somatostatin, octreotide and gabexate mesilate in the therapy of acute pancreatitis. Aliment. Pharmacol. Ther. 1998; 12: 23745.

508

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A Nydegger et al.

Pancreatitis in children

95 Uhl W, Buchler MW, Malfertheiner P, Beger HG, Adler G, Gaus W. A randomised, double blind, multicentre trial of octreotide in moderate to severe acute pancreatitis. Gut 1999; 45: 97104. 96 Chen YK, Foliente RL, Santoro MJ, Walter MH, Collen MJ. Endoscopic sphincterotomy-induced pancreatitis: increased risk associated with nondilated bile ducts and sphincter of Oddi dysfunction. Am. J. Gastroenterol. 1994; 89: 32733. 97 Andriulli A, Leandro G, Niro G et al. Pharmacologic treatment can prevent pancreatic injury after ERCP: a meta-analysis. Gastrointest. Endosc. 2000; 51: 17. 98 Golub R, Siddiqi F, Pohl D. Role of antibiotics in acute pancreatitis: a meta-analysis. J. Gastrointest. Surg. 1998; 2: 496503. 99 Slavin J, Neoptolemos JP. Antibiotic prophylaxis in severe acute pancreatitis: what are the facts? Langenbecks Arch. Surg. 2001; 386: 1559. 100 Buchler MW, Gloor B, Muller CA, Friess H, Seiler CA, Uhl W. Acute necrotizing pancreatitis: treatment strategy according to the status of infection. Ann. Surg. 2000; 232: 61926. 101 Bassi C, Larvin M, Villatoro E. Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis. Cochrane Database Syst. Rev. 2003; 4: CD002941. 102 Jackson WD. Pancreatitis: etiology, diagnosis, and management. Curr. Opin. Pediatr. 2001; 13: 44751. 103 Uhl W, Warshaw A, Imrie C et al. IAP guidelines for the surgical management of acute pancreatitis. Pancreatology 2002; 2: 56573. 104 Folsch UR, Nitsche R, Ludtke R, Hilgers RA, Creutzfeldt W. Early ERCP and papillotomy compared with conservative treatment for

105 106

107

108

109

110 111

112

113

acute biliary pancreatitis. The German Study Group on Acute Biliary Pancreatitis. N. Engl. J. Med. 1997; 336: 23742. Weber TR, Keller MS. Operative management of chronic pancreatitis in children. Arch. Surg. 2001; 136: 5504. Cremer M, Deviere J, Delhaye M, Baize M, Vandermeeren A. Stenting in severe chronic pancreatitis: results of medium-term follow-up in seventy-six patients. Endoscopy 1991; 23: 1716. Smits ME, Badiga SM, Rauws EA, Tytgat GN, Huibregtse K. Longterm results of pancreatic stents in chronic pancreatitis. Gastrointest. Endosc. 1995; 42: 4617. Ashby K, Lo SK. The role of pancreatic stenting in obstructive ductal disorders other than pancreas divisum. Gastrointest. Endosc. 1995; 42: 30611. Ponchon T, Bory RM, Hedelius F et al. Endoscopic stenting for pain relief in chronic pancreatitis: results of a standardized protocol. Gastrointest. Endosc. 1995; 42: 4526. Prinz RA, Greenlee HB. Pancreatic duct drainage in 100 patients with chronic pancreatitis. Ann. Surg. 1981; 194: 31320. Adams DB, Ford MC, Anderson MC. Outcome after lateral pancreaticojejunostomy for chronic pancreatitis. Ann. Surg. 1994; 219: 481 7;discussion 4879. Nealon WH, Thompson JC. Progressive loss of pancreatic function in chronic pancreatitis is delayed by main pancreatic duct decompression. A longitudinal prospective analysis of the modied puestow procedure. Ann. Surg. 1993; 217: 45866;discussion 4668. Ellis I, Lerch MM, Whitcomb DC. Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent and privacy issues. Pancreatology 2001; 1: 40515.

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