Pancreatitis in Childhood Mark E. Lowe, MD, PhD Division of Pediatric Gastroenterology Children’s Hospital of Pittsburgh and the University of Pittsburgh Medical Center 3705 Fifth Avenue Pittsburgh, PA 15213 Tel: 412-692-5180 FAX: 412-692-7355 firstname.lastname@example.org
AbstractInflammatory disease of the pancreas fall into two major classifications, acute andchronic. Acute pancreatitis is a reversible process whereas chronic pancreatitis producesirreversible changes in the architecture and function of the pancreas. The recent findingthat mutations in the gene encoding cationic trypsinogen associate with hereditarypancreatitis, the identification of genes that increase the risk for developing chronicpancreatitis and advances in cell biology have contributed greatly to our understanding ofthe molecular mechanisms leading to pancreatitis. Although pancreatitis is less commonin children than in adults, it still occurs with regularity and should be considered in anychild with acute or chronic abdominal pain. The major differences between pancreatitisin children and adults lie in the etiologies and outcome of acute pancreatitis and in theetiology of chronic pancreatitis. The treatment of acute and chronic pancreatitis is similarin all ages.
IntroductionKnowledge about the pathophysiology of pancreatitis and the development of effectivetherapy has lagged behind the progress made in many other important diseases. Over theyears, many factors have contributed to this disparity including the inaccessible locationof the pancreas, reluctance to employ invasive diagnostic methods, and a paucity ofhuman studies utilizing modern molecular methods. In recent years, the application ofadvances in cell biology and genetics and in imaging techniques in studies of pancreatitishas provided critical information about the pathophysiology, genetics and anatomy ofpancreatitis. Additionally, several new single and multicenter studies have improved ourunderstanding of the etiology and clinical course of pancreatitis in childhood. Takentogether within the context of pancreatic physiology, these advances provide the basis forfuture diagnostic methods, treatment and prevention of pancreatic inflammatory disease.Overview of PancreatitisInflammatory disorders of the pancreas fall into two classifications, acute pancreatitis andchronic pancreatitis. Acute pancreatitis is defined clinically as the sudden onset ofabdominal pain associated with a rise of pancreatic digestive enzymes in the serum orurine with or without radiographic changes in the pancreas. It is a reversible process withno lasting effects on pancreatic histology or function. In contrast, chronic pancreatitis isthe sequelae of long-standing destructive, inflammatory injury to the pancreas resulting infibrosis, loss of normal pancreatic cells, and chronic inflammatory infiltrates. Clinicaldiagnosis depends on identifying the typical histological and morphological changes inthe pancreas and, eventually, loss of pancreatic function. Thus, acute pancreatitis is anevent and chronic pancreatitis is a process.
Prevalence of Acute PancreatitisAcute pancreatitis is not common in children. Early published series reported 2 to 9cases per year. More recent studies show an increasing number of cases in large teachinghospitals where a 100 or more patients with acute pancreatitis may be seen in ayear[1-3●●]. The reason for this observation is not clear, but neither referral bias norimproved diagnosis appears to explain the change[1●●].Pathophysiology of Acute PancreatitisThree phases characterize the pathophysiology of acute pancreatitis[4●]. First, a numberof events can initiate the onset of acute pancreatitis. Next, a series of intra-acinar cellevents produce cellular injury and local tissue damage. Finally, acinar cell damageinduces a variety of local and systemic responses including the production of cytokines,the generation of reactive oxygen species and abnormalities in the local circulation. Theseverity of the clinical course is governed by the magnitude of these events and on theinduction of a systemic inflammatory response.Triggering Events or Etiology of Acute PancreatitisA number of factors can trigger an attack of acute pancreatitis (Table 1). Acutepancreatitis is often found in association with systemic illnesses and after organtransplant[1●●, 3●●]. The mechanism for pancreatitis in these illnesses is unknown andlikely multifactorial. Obstructive causes, which are common in adults, account for aportion of episodes in children. Gallstones may be more prevalent in children thanpreviously thought. In previous studies gallstones were frequently lumped with otherobstructive causes and the incidence is impossible to discern. One recent report fromKorea found gallstones in 29% of cases. Structural abnormalities, such as pancreas
divisum, choledochal cysts, and gastric or duodenal duplication cysts, and periampullarylesions, such as Crohn disease or duodenal ulcer, can also obstruct pancreatic flow andcause acute pancreatitis in children. Trauma remains an important etiology of acutepancreatitis in childhood especially in younger children. A variety of medications havebeen associated with acute pancreatitis[1●●, 3●●]. The anticonvulsant valproic acid isthe most common medication reported in most series, but other anticonvulsants andchemotherapeutic agents have also been associated with acute pancreatitis. Themechanism for drug-induced pancreatitis is speculative and most theories center ondisruption of cellular metabolism by the drugs or their metabolites.Acinar Cell Events in Acute PancreatitisCurrent explanations for the early acinar cell events in acute pancreatitis center on theactivation of trypsinogen to trypsin. Initially, this speculation was based on the roletrypsin plays in activating other digestive enzymes, all of which could contribute toacinar cell damage in early pancreatitis. All of the major digestive enzymes, exceptamylase and lipase, are synthesized as pro-enzymes or zymogens that require activationthrough the cleavage of an activation peptide by trypsin. Normally, trypsinogen isactivated in the duodenum by the brush border enzyme, enterokinase, or by trypsin.Trypsinogen can also autoactivate and that ability has become an important mechanism intheories regarding the pathogenesis of acute pancreatitis. Because trypsinogen is storedin the same compartment as other zymogens and it can autoactivate, there is always thepotential for premature trypsinogen activation within the acinar cell, which can set off acascade of zymogen activation leading to autodigestion of the pancreas.
With time, experimental evidence to support the role of premature trypsinogenactivation in acute pancreatitis has accumulated from studies in animal models and fromobservations in humans. Production of trypsinogen activation peptide is one of theearliest detectable events in models of experimental pancreatitis. Pancreatitisassociated with endoscopic retrograde cholangiopancreatography (ERCP) can beattenuated by pretreatment with trypsin inhibitors. Perhaps, the most convincingevidence for the importance of trypsin in the pathophysiology of acute pancreatitis comesfrom genetic studies demonstrating an association of trypsin mutations with hereditarypancreatitis[9●●]. A number of experimental studies in animal models support the important role oftrypsin in the pathophysiology of acute pancreatitis. Activation of trypsinogen, asevidenced by the appearance of trypsin activation peptide, is first observed incytoplasmic vacuoles, whose formation is among the earliest detectable changes in theacinar cell during experimental pancreatitis[4●, 10]. Both digestive enzymes andlysosomal hydrolases co-localize in these vacuoles. Normally, digestive enzymes andlysosomal hydrolases are packaged separately, but disruption of normal secretion as mayoccur early in acute pancreatitis leads to a defect in intracellular transport and sorting ofenzymes. Once the digestive and lysosomal enzymes co-localize, lysosomal hydrolasescan activate trypsinogen. Cathepsin B may activate trypsinogen in the vacuoles asevidenced by the observations that cathepsin B activates trypsinogen in vitro, thatspecific cathepsin B inhibitors prevent the activation of trypsin in isolated acinar cellsafter hyperstimulation with cerulein, a secretogogue, and that cathepsin B deficient micehave decreased trypsinogen activation after the induction of pancreatitis. Shortly
after forming, the vacuoles disintegrate and release their contents into the cytoplasmwhere the activated digestive enzymes can now damage the acinar cell. Important support for the central role of trypsinogen activation in acutepancreatitis and a major advance in our understanding of the pathophysiology ofpancreatitis comes from genetic studies of families with recurrent pancreatitis in multiplemembers[12●]. First described in 1952, hereditary pancreatitis causes repeated episodesof acute pancreatitis and, in about 75% of patients, results in chronic pancreatitis. In1996, a single point mutation in the third exon of the gene encoding cationic trypsinogenwas shown to segregate with the disease[13●]. The point mutation causes an arginine tohistidine substitution at position 122, R122H trypsinogen. Subsequently, additionalmutations in the trypsinogen gene were found in other pedigrees with hereditarypancreatitis, including N29I, A16V, D22G, K23R and R122C. Three of these mutations,R122H, R122C, and N29I, account for the majority of the patients[12●]. Increased resistance of the R122H mutant trypsin to the normal protectivemechanisms of the acinar cell has been proposed as a model for the defect in hereditarypancreatitis. Most protective mechanisms center on the control of trypsin levels inthe acinar cell by preventing trypsinogen activation, inhibiting or destroying activetrypsin, and flushing trypsin out of the pancreas. As mentioned above, the first lines ofdefense against active trypsin accumulating in the cells are the synthesis trypsinogen andthe packaging of trypsinogen and other zymogens in granules, which isolates them fromother cellular enzymes like lysosomal hydrolases. If trypsinogen is activated inside thecell, the product, trypsin, is inhibited by pancreatic secretory trypsin inhibitor (PSTI),which is also known as serine protease inhibitor, Kazal type 1 (SPINK 1). Normally, the
pancreas synthesizes trypsinogen and SPINK1 at a molar ratio of 5 to 1. If trypsinogenactivation is brisk, the capacity of SPINK1 to inhibit trypsin becomes overwhelmed andthe next tiers of defense mechanisms come into play. Among these is the degradation oftrypsin by autolysis and, perhaps, by other proteases. The first step in degradation isproteolytic cleavage after Arg122. In vitro studies demonstrate that R122H trypsin isresistant to autolysis and also reveal that the mutation increases autoactivation of R122Htrypsinogen. Similar studies on N29I cationic trypsinogen show that the mutationresults in faster autoactivation and increase trypsin stability. Thus, both N29I andR122H trypsin mutants are more likely to accumulate in acinar cells and cause increasedactivation of other zymogens. Consequently, patients with these mutations developpancreatitis more readily than people who have normal trypsinogen. Although autodigestion of the acinar cells by digestive enzymes plays a centralrole in most theories of acute pancreatitis, other processes may also contribute to acinarcell damage in early pancreatitis. Several authors have proposed an important role forreactive oxygen species in acute pancreatitis[17, 18]. They point to studies showingincreases of lipid peroxides during experimental pancreatitis, alterations in cytoskeletonfunction because of lipid peroxidation and increases in cell permeability that correlatewith the production of free oxygen radicals as evidence. Additionally, abnormalities ofthe blood supply probably contribute to early injury. In experimental pancreatitis,regions of the organ with good perfusion are less injured than regions withhypoperfusion. Finally, activation of resident macrophages in the pancreas and themigration of activated leukocytes into the pancreas contribute to the severity of glandinflammation in acute pancreatitis[20-22]. Nude mice lacking lymphocytes have
decreased severity of pancreatitis and the return of T-lymphocytes to these mice increasesthe severity of acute pancreatitis.Late Events in Acute PancreatitisThe early events produce pancreatic edema and stimulate a local inflammatory responseassociated with the release of inflammatory mediators into the systemic circulation[23,24]. These cytokines and chemokines mediate a systemic inflammatory response, acommon pathway in many forms of injury. The clinical severity of pancreatitis dependsin part on the magnitude of the systemic response and the balance between pro-inflammatory and anti-inflammatory mediators determines the clinical course. Inreaction to a brisk systemic inflammatory response, activated leukocytes migrate intoother organs, particularly the lungs, kidneys and liver, to cause tissue edema and damage.According to current data, the activated immune response plays the major role in thesystemic complications of acute pancreatitis. Most likely, the damage of distant organsby circulating pancreatic digestive enzymes is minimal.Diagnosis of Acute PancreatitisThe diagnosis of acute pancreatitis still depends on clinical suspicion and confirmatorylaboratory and radiographic studies[1-3●●]. Amylase and lipase remain the mostcommonly employed laboratory tests. Other pancreatic products like phospholipase A2,trypsin, trypsinogen activation peptide and elastase are elevated in acute pancreatitis, butnone have gained widespread use in the clinical laboratory. Although levels of lipase andamylase that are three times the upper reference limit suggest pancreatitis, the level ofelevation is not diagnostic. Both enzymes can be elevated in conditions unrelated to
pancreatitis and both can be normal when there is radiographic evidence of acutepancreatitis (Table 2). Computed tomography (CT) and ultrasound images of the pancreas serve toconfirm the presence of pancreatitis, to identify complications and to investigate othercauses for the symptoms. Ultrasound findings included enlargement of the pancreas,altered echogenicity of the pancreas, a dilated main pancreatic duct, gallstones, biliarysludge, dilated common and intrahepatic ducts, pancreatic calcification, choledochalcysts, and fluid collections. A CT scan will show similar findings, except that abnormalattenuation is seen rather than altered echogenicity. Studies in animals indicate the CTcontrast given early in the course of acute pancreatitis may further diminish blood flow toischemic areas of the pancreas and increase the likelihood of necrosis. Although similarstudies have not been done in humans, it is reasonable to avoid CT scans early in thecourse of pancreatitis and save this study for patients that do not showimprovement[1●●]. ERCP is reserved for patients with unexplained recurrent episodesof pancreatitis, prolonged episodes of pancreatitis where a structural defect or ductdisruption is suspected, and in some cases of gallstone pancreatitis. Magnetic resonancecholangiopancreatography (MRCP) can be helpful in defining abnormalities of the ductalsystem and with the development of improved software MRCP may supplant ERCP asthe method of choice for evaluating the anatomy of the ductal system.Treatment of Acute PancreatitisTreatment of pancreatitis has not changed significantly over the years. The mainstay oftreatment in children remains analgesia, intravenous fluids, pancreatic rest andmonitoring for complications[1●●]. Volume expansion early in the course of acute
pancreatitis is important to maintain cardiovascular stability and to prevent thedevelopment of pancreatic necrosis. Nutrition should be implemented early if a severe orprolonged course is anticipated. Until recently, parenteral nutrition was considered theonly option, but several studies show that adult patients with acute pancreatitis toleratejejunal feedings with fewer complications than those given parenteral nutrition.Antibiotics are usually unnecessary except for the most severe cases.Outcome of Acute PancreatitisAcute pancreatitis is usually divided into mild and severe forms. Because the clinicalcourse and outcome differ significantly between mild and severe cases, the physicianmust make a rapid assessment of the patient’s condition and predict the risk of a mild orsevere clinical course. Several scoring systems have been developed to assist thephysician in this decision[26-28]. Until recently, none of these systems had beenvalidated in children. One group analyzed the criteria of the Ranson and Glasgow scoresplus additional criteria and developed a scoring system for children that was validated inthree centers[3●●]. Of note, young age and low weight are major risk factors. Although acute pancreatitis can be life threatening, death does not occur inpediatric patients as frequently as in adults[1●●]. Early causes of death are shock andrespiratory failure. Late life-threatening complications of pancreatitis are generallyassociated with infected pancreatic necrosis and multi-system organ failure. Fortunately,pancreatic necrosis appears to be uncommon in children and only 1 case in 380 (0.3%)was found in patients from 7 centers[1●●, 3●●].Prevalence of Chronic Pancreatitis
The prevalence of chronic pancreatitis in childhood is certainly less than that of acutepancreatitis and the incidence may be increasing, but there are no reliable estimates of thetrue prevalence.Pathophysiology of Chronic PancreatitisEarly in the course, chronic pancreatitis may be difficult to distinguish from acutepancreatitis on clinical grounds. In chronic pancreatitis continued inflammationproduces irreversible morphological changes in the gland such as fibrosis, acinar cellloss, islet cell loss and infiltration by inflammatory cells. Because the diagnosis dependson identifying decreased function and chronic changes, both of which occur late in thecourse, studies of natural history and of potential therapies have been hindered.Consequently, many theories to explain the pathophysiology of chronic pancreatitis havebeen proposed. In the last half of the twentieth century, the dominant view held that recurrentacute pancreatitis progressed to chronic pancreatitis although some authors developedtheories that did not include acute pancreatitis as part of the pathway to chronicpancreatitis. Current research suggests that chronic pancreatitis is a progression thatbegins with acute pancreatitis and continues with chronic and recurrent inflammation toproduce end stage fibrosis. In the last decade, it has become clear that susceptibilityto chronic pancreatitis is influenced by both genetic and environmental factors. Inchildren, chronic pancreatitis generally associates with abnormal genetic alleles or isidiopathic.Genetics of Chronic Pancreatitis
Trypsinogen mutations associate with the majority of hereditary pancreatitis kindreds.As discussed above, the most common mutations include the cationic trypsinogen R122Hand N29I mutations. Hereditary pancreatitis caused by these mutations usually presentsas recurrent acute pancreatitis in childhood with a median age of 10 years with a range of>1year to 60 years of age[9●]. In 50% of patients, chronic pancreatitis develops about 10years after the first bout of acute pancreatitis although some patients will present withchronic pancreatitis without a clear history of acute pancreatitis. The most importantclinical clue is the presence of pancreatitis in other family members. The diagnosis isconfirmed by testing of the gene encoding cationic trypsinogen. The association of cationic trypsinogen with hereditary pancreatitis led to thesearch for families with mutations in SPINK1. By 2000, mutations in the gene encodingSPINK1, N34S and P55S, were correlated with idiopathic chronic pancreatitis.Almost 90% of patients with SPINK1 mutations develop pancreatitis before the age oftwenty. Interestingly, the mutations implicated in chronic pancreatitis are found in 1-4%of the population, yet most of these carriers do not develop pancreatitis. In fact, the riskof a SPINK1 mutation carrier developing chronic pancreatitis is about 1%. SPINK1mutations probably increase susceptibility to recurrent acute and chronic pancreatitiswhen homozygous mutations are present or in association with mutations in other genesas part of a polygenic condition with multiple genetic risk factors. In pediatrics, cystic fibrosis is the most common cause of chronic pancreatitis.Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) causecystic fibrosis. CFTR is a membrane protein located on the apical membrane ofpancreatic duct cells where it regulates water flow and chloride conductance. Over 1000
identified mutations organize into 5 major classes depending on the effect of the mutationon CFTR protein expression and function. Some mutations completely abrogate CFTRfunction and are classified as severe. Other mutations permit some function and areclassified as mild or variable. Patients with two severe alleles have classic cystic fibrosis.Those who are compound heterozygotes for a severe and a mild allele have some residualCFTR function and generally have atypical symptoms. In particular, compoundheterozygote mutations have been associated with chronic pancreatitis. Initial reportsfound a correlation between mutations in a single CFTR allele and chronic pancreatitis,but a later study with a more detailed analysis of the CFTR alleles correlated risk withhaving two CFTR mutations[33-35]. These patients with one severe and one mild-variable mutation have a 40-fold increase in the risk of developing chronic pancreatitisover the general population. Recently, it was suggested that CFTR mutation-associated pancreatitis can bedivided into 4 subtypes based on potential mechanisms. Type 1 is classic CF withtwo severe alleles. Type 2 is atypical CF with a severe and mild-variable genotype. Ofspecific interest are CFTR mutations that block bicarbonate conductance but not chlorideconductance. These mutations can potentially target the pancreas over other organs sincebicarbonate secretion by duct cells is central to pancreatic fluid secretion and function.Type 3 is a severe or a mild-variable CFTR allele plus a second susceptibility gene. Forinstance, the risk for developing chronic pancreatitis was increased 900-fold in patientswith heterozygous mutations in both the CFTR and SPINK1 genes. Type 4 is aheterozygote with a severe or mild-variable allele and a strong environmental risk factorlike alcohol.
Genetic Testing in Recurrent or Chronic PancreatitisGenetic testing for pancreatic diseases has become an important part of medicalpractice[37●-39]. The purpose of genetic testing can be divided into two generalcategories, diagnostic and predictive. Diagnostic testing is done when a patient hassymptoms of a disease and a genetic test can determine the underlying cause. Predictivetesting is genetic testing in subjects who do not have evidence of pancreatic disease, butmay have relatives with pancreatic disease or a known mutation in the genes encodingCFTR or cationic trypsinogen. In general the indications for diagnostic testing validateits use, but the role of predictive testing is less clear and controversial. The primary indications for R122H and N29I cationic trypsinogen mutationtesting are diagnostic and include recurrent idiopathic acute pancreatitis, idiopathicchronic pancreatitis, and patients with a family history of acute pancreatitis (Table 3).Early identification of a cationic trypsinogen gene mutation can prevent an expensive andprolonged evaluation of recurrent pancreatitis in children. Knowledge of the diagnosisalso allows the physician to counsel the family and patient about the natural history of thedisease, particularly the greatly increased risk for pancreatic cancer. Some have advocated predictive genetic testing in family members with firstdegree relatives that have a mutation in the gene encoding cationic trypsinogen. Anegative test result in a family with a known mutation essentially eliminates the risk ofthis genetic form of pancreatitis. A positive test result in a clinically unaffected personconfers a significantly increased risk of pancreatitis, which may diminish with age.Those who argue for testing point out that alcohol, tobacco, emotional stress and fattyfoods may precipitate attacks of pancreatitis in patients with hereditary pancreatitis.
Others respond that counseling to avoid fatty foods, alcohol, and tobacco representsexcellent general medical advice and therefore does not provide a compelling reason forgenetic testing. In either case, the patient and their family should be offered adequategenetic counseling and the personal desires of older children should be considered. Bothphysicians and patients need to understand the implications of genetic testing for thepatient’s future health, family, employment and insurability. Older children maypostpone testing or may proceed with testing to relieve their own anxieties and to learnmore about their personal health. Although testing for SPINK1 mutations in children with chronic pancreatitis mayprovide information about predisposing factors, most experts do not advocate genetictesting for SPINK1 mutations at this time[41, 42]. Heterozygous SPINK1 mutationsalone are probably not disease causing. Homozygous mutations are stronglyassociated with chronic pancreatitis, but may still be part of a polygenic disorder. Thus,identifying a SPINK1 mutation does not preclude the search for other causes of chronicpancreatitis. Genetic testing in pre-symptomatic individuals is futile since less than 1%of patients who are heterozygotes for a SPINK1 mutation will develop pancreatitis. There has been much interest in testing patients with idiopathic chronicpancreatitis for CFTR mutations. The major problem with this approach is that currentlyavailable panels only test for the most common CF-causing gene mutations, notpancreatitis associated mutations. Less common or unique mutant alleles will not beidentified unless broader screening procedures become available. New techniques, suchas denaturing ion-pair reverse-phase high-performance liquid chromatography, showpromise for rapidly analyzing the complete coding sequence of the CFTR gene. These
new tools will allow investigators to fully interpret the CFTR genotype-pancreatitisrelationship which will provide the basis for recommendations on the utility of geneticscreening for CFTR mutations in patients with chronic pancreatitis. On the other hand,acute pancreatitis may be the first sign of CF or atypical CF and these children shouldundergo an evaluation for CF. The evaluation should begin with a sweat test and genetictesting should be considered only when family history or other symptoms suggestatypical CF.ConclusionsInflammatory disorders of the pancreas are seen with regularity in regional children’shospitals. Both acute and chronic pancreatitis occur in childhood and the incidence maybe increasing. Important differences in the etiologies between children and adults existfor both acute and chronic pancreatitis, but the treatment is the same. The greatestprogress in understanding the pathophysiology of pancreatitis has come from studieslinking genetic mutations to increased risk for pancreatitis. Mutations in the geneencoding cationic trypsinogen cause hereditary pancreatitis. Mutations in genes encodingCFTR and SPINK1 act as modifiers that along with other factors, such as other genes,drugs or toxins, increase the risk of developing pancreatitis. A greater understanding ofthe genes involved in pancreatitis and in the biological events associated with pancreatitiswill eventually lead to better diagnostic methods, new treatments and improvedprevention of pancreatic inflammatory disease.
References and Recommended ReadingPapers of particular interest, published recently, have been highlighted as● Of importance●● Of major importance1.●● Werlin SL, Kugathasan S, Frautschy BC: Pancreatitis in children. J Pediatr Gastroenterol Nutr 2003, 37:591-595.The paper describes the incidence, etiology and outcome of pancreatitis at a regionalchildrens hospital. Two hundred fourteen episodes in 180 patients were analyzed.2.●● Lopez MJ: The changing incidence of acute pancreatitis in children: a single- institution perspective. J Pediatr 2002, 140:622-624.Two hundred seventy four cases of pancreatitis were analyzed for etiology. The studyprovides the first evidence of rising incidence of acute pancreatitis in childhood.3.●● DeBanto JR, Goday PS, Pedroso MR, et al.: Acute pancreatitis in children. Am J Gastroenterol 2002, 97:1726-1731.This multi-center study describes the incidence etiology and outcome in 301 cases ofpancreatitis. It also develops and validates a pediatric scoring system for acutepancreatitis in childhood.4.● Steer ML: Frank Brooks memorial Lecture: The early intraacinar cell events which occur during acute pancreatitis. Pancreas 1998, 17:31-37.The text of an address by Dr. Steer provides an excellent overview of current theories ofthe pathogenesis of acute pancreatitis.5. Sakorafas GH, Tsiotou AG: Etiology and pathogenesis of acute pancreatitis: current concepts. J Clin Gastroenterol 2000, 30:343-356.
6. Choi BH, Lim YJ, Yoon CH, et al.: Acute pancreatitis associated with biliary disease in children. J Gastroenterol Hepatol 2003, 18:915-921.7. Otani T, Chepilko SM, Grendell JH, et al.: Codistribution of TAP and the granule membrane protein GRAMP-92 in rat caerulein-induced pancreatitis. Am J Physiol 1998, 275:G999-G1009.8. Cavallini G, Frulloni L: Antiproteasic agents in the prevention of post-ERCP pancreatitis: rationale for use and clinical results. Jop 2003, 4:75-82.9.●● Whitcomb DC: Genetic predispositions to acute and chronic pancreatitis. Med Clin North Am 2000, 84:531-547.This review covers the evidence for the role of genetic mutations and polymorphisms inacute and chronic pancreatitis.10. Frossard JL, Past CM: Experimental acute pancreatitis: new insights into the pathophysiology. Front Biosci 2002, 7:d275-287.11. Halangk W, Lerch MM, Brandt-Nedelev B, et al.: Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis. J Clin Invest 2000, 106:773-781.12.● Schneider A, Whitcomb DC: Hereditary pancreatitis: a model for inflammatory diseases of the pancreas. Best Pract Res Clin Gastroenterol 2002, 16:347-363.The review highlights the genetic studies on kindreds with hereditary pancreatitis,reviews a risk classification scheme and reviews the major independent theories on thedevelopment of chronic pancreatitis.13.● Whitcomb DC, Gorry MC, Preston RA, et al.: Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996, 14:141-145.
This paper is the original description of the association of a mutation in cationictrypsinogen with hereditary pancreatitis.14. Etemad B, Whitcomb DC: Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001, 120:682-707.15. Kukor Z, Toth M, Pal G, et al.: Human cationic trypsinogen. Arg(117) is the reactive site of an inhibitory surface loop that controls spontaneous zymogen activation. J Biol Chem 2002, 277:6111-6117.16. Sahin-Toth M: Human cationic trypsinogen. Role of Asn-21 in zymogen activation and implications in hereditary pancreatitis. J Biol Chem 2000, 275:22750-22755.17. Sanfey H, Sarr MG, Bulkley GB, et al.: Oxygen-derived free radicals and acute pancreatitis: a review. Acta Physiol Scand Suppl 1986, 548:109-118.18. Guice KS, Miller DE, Oldham KT, et al.: Superoxide dismutase and catalase: a possible role in established pancreatitis. Am J Surg 1986, 151:163-169.19. Anderson MC, Schoenfeld FB, Iams WB, et al.: Circulatory changes in acute pancreatitis. Surg Clin North Am 1967, 47:127-140.20. Demols A, Le Moine O, Desalle F, et al.: CD4(+ )T cells play an important role in acute experimental pancreatitis in mice. Gastroenterology 2000, 118:582-590.21. Gloor B, Todd KE, Lane JS, et al.: Hepatic Kupffer cell blockade reduces mortality of acute hemorrhagic pancreatitis in mice. J Gastrointest Surg 1998, 2:430-435.22. Pezzilli R, Billi P, Beltrandi E, et al.: Impaired lymphocyte proliferation in human acute pancreatitis. Digestion 1997, 58:431-436.
23. Bhatia M, Brady M, Shokuhi S, et al.: Inflammatory mediators in acute pancreatitis. J Pathol 2000, 190:117-125.24. Bhatia M, Neoptolemos JPSlavin J: Inflammatory mediators as therapeutic targets in acute pancreatitis. Curr Opin Investig Drugs 2001, 2:496-501.25. Abou-Assi S, Craig K, OKeefe SJ: Hypocaloric jejunal feeding is better than total parenteral nutrition in acute pancreatitis: results of a randomized comparative study. Am J Gastroenterol 2002, 97:2255-2262.26. Ranson JH: Etiological and prognostic factors in human acute pancreatitis: a review. Am J Gastroenterol 1982, 77:633-638.27. Blamey SL, Imrie CW, ONeill J, et al.: Prognostic factors in acute pancreatitis. Gut 1984, 25:1340-1346.28. Knaus WA, Draper EA, Wagner DP, et al.: APACHE II: a severity of disease classification system. Crit Care Med 1985, 13:818-829.29. Whitcomb DC: Hereditary pancreatitis: new insights into acute and chronic pancreatitis. Gut 1999, 45:317-322.30. Applebaum-Shapiro SE, Finch R, Pfutzer RH, et al.: Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-Center Pancreatic Study Group Study. Pancreatology 2001, 1:439-443.31. 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, 25:213-216.32. Naruse S, Kitagawa M, Ishiguro H, et al.: Cystic fibrosis and related diseases of the pancreas. Best Pract Res Clin Gastroenterol 2002, 16:511-526.
33. Noone PG, Zhou Z, Silverman LM, et al.: Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations. Gastroenterology 2001, 121:1310-1319.34. Sharer N, Schwarz M, Malone G, et al.: Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998, 339:645-652.35. Cohn JA, Bornstein JD, Jowell PS: Cystic fibrosis mutations and genetic predisposition to idiopathic chronic pancreatitis. Med Clin North Am 2000, 84:621-631, ix.36. Whitcomb DC: Value of genetic testing in management of pancreatitis. Gut 2004, in press.37.● Ellis I, Lerch MM, Whitcomb DC: Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent and privacy issues. Pancreatology 2001, 1:405-415.The paper provides a good synopsis of the many issues related to genetic testing.38. Applebaum-Shapiro SE, Peters JA, OConnell JA, et al.: Motivations and concerns of patients with access to genetic testing for hereditary pancreatitis. Am J Gastroenterol 2001, 96:1610-1617.39. Applebaum SE, Kant JA, Whitcomb DC, et al.: Genetic testing. Counseling, laboratory, and regulatory issues and the EUROPAC protocol for ethical research in multicenter studies of inherited pancreatic diseases. Med Clin North Am 2000, 84:575-588, viii.
40. Lowenfels AB, Maisonneuve P, Whitcomb DC, et al.: Cigarette smoking as a risk factor for pancreatic cancer in patients with hereditary pancreatitis. Jama 2001, 286:169-170.41. Whitcomb DC: Motion--genetic testing is useful in the diagnosis of nonhereditary pancreatic conditions: arguments for the motion. Can J Gastroenterol 2003, 17:47-52.42. Cohn JA: Motion--genetic testing is useful in the diagnosis of nonhereditary pancreatic conditions: arguments against the motion. Can J Gastroenterol 2003, 17:53-55.43. Pfutzer RH, Barmada MM, Brunskill AP, et al.: SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology 2000, 119:615-623.
Table 1. Etiologies of acute pancreatitis in three recent studies of children Werlin et al.  Lopez  Debanto et al.  Number of cases 180 274 301 Systemic 18 48 10 Gallstone 12 4 Structural 8 10 2 Infectious 8 3 3 Medications 12 5 11 Trauma 14 19 13 Post ERCP 6 3 Familial 3 5 Cystic Fibrosis 0.6 2 Idiopathic 8 17 34 Other 21 8 13
Table 3. Indications for genetic testing for cationic trypsinogen mutations a. Recurrent attacks of acute pancreatitis with no apparent etiology. b. Idiopathic chronic pancreatitis. c. History of pancreatitis is a first, second or third degree relative. d. An unexplained episode of documented pancreatitis occurring in a child that has required hospitalization. e. As part of an Institutional Review Board approved research protocol.