Pancreatitis in Childhood

Mark E. Lowe, MD, PhDDivision of Pediatric GastroenterologyChildren’s Hospital of Pittsburgh and the University of Pittsburgh Medical Center3705 Fifth AvenuePittsburgh, PA 15213Tel: 412-692-5180FAX: 412-692-7355mark.lowe@chp.edu

Abstract

Inflammatory disease of the pancreas fall into two major classifications, acute and

chronic. Acute pancreatitis is a reversible process whereas chronic pancreatitis produces

irreversible changes in the architecture and function of the pancreas. The recent finding

that mutations in the gene encoding cationic trypsinogen associate with hereditary

pancreatitis, the identification of genes that increase the risk for developing chronic

pancreatitis and advances in cell biology have contributed greatly to our understanding of

the molecular mechanisms leading to pancreatitis. Although pancreatitis is less common

in children than in adults, it still occurs with regularity and should be considered in any

child with acute or chronic abdominal pain. The major differences between pancreatitis

in children and adults lie in the etiologies and outcome of acute pancreatitis and in the

etiology of chronic pancreatitis. The treatment of acute and chronic pancreatitis is similar

in all ages.

Introduction

Knowledge about the pathophysiology of pancreatitis and the development of effective

therapy has lagged behind the progress made in many other important diseases. Over the

years, many factors have contributed to this disparity including the inaccessible location

of the pancreas, reluctance to employ invasive diagnostic methods, and a paucity of

human studies utilizing modern molecular methods. In recent years, the application of

advances in cell biology and genetics and in imaging techniques in studies of pancreatitis

has provided critical information about the pathophysiology, genetics and anatomy of

pancreatitis. Additionally, several new single and multicenter studies have improved our

understanding of the etiology and clinical course of pancreatitis in childhood. Taken

together within the context of pancreatic physiology, these advances provide the basis for

future diagnostic methods, treatment and prevention of pancreatic inflammatory disease.

Overview of Pancreatitis

Inflammatory disorders of the pancreas fall into two classifications, acute pancreatitis and

chronic pancreatitis. Acute pancreatitis is defined clinically as the sudden onset of

abdominal pain associated with a rise of pancreatic digestive enzymes in the serum or

urine with or without radiographic changes in the pancreas. It is a reversible process with

no lasting effects on pancreatic histology or function. In contrast, chronic pancreatitis is

the sequelae of long-standing destructive, inflammatory injury to the pancreas resulting in

fibrosis, loss of normal pancreatic cells, and chronic inflammatory infiltrates. Clinical

diagnosis depends on identifying the typical histological and morphological changes in

the pancreas and, eventually, loss of pancreatic function. Thus, acute pancreatitis is an

event and chronic pancreatitis is a process.

Prevalence of Acute Pancreatitis

Acute pancreatitis is not common in children. Early published series reported 2 to 9

cases per year. More recent studies show an increasing number of cases in large teaching

hospitals where a 100 or more patients with acute pancreatitis may be seen in a year[1-

3●●]. The reason for this observation is not clear, but neither referral bias nor improved

diagnosis appears to explain the change[1●●].

Pathophysiology of Acute Pancreatitis

Three phases characterize the pathophysiology of acute pancreatitis[4●]. First, a number

of events can initiate the onset of acute pancreatitis. Next, a series of intra-acinar cell

events produce cellular injury and local tissue damage. Finally, acinar cell damage

induces a variety of local and systemic responses including the production of cytokines,

the generation of reactive oxygen species and abnormalities in the local circulation. The

severity of the clinical course is governed by the magnitude of these events and on the

induction of a systemic inflammatory response.

Triggering Events or Etiology of Acute Pancreatitis

A number of factors can trigger an attack of acute pancreatitis[5] (Table 1). Acute

pancreatitis is often found in association with systemic illnesses and after organ

transplant[1●●, 3●●]. The mechanism for pancreatitis in these illnesses is unknown and

likely multifactorial. Obstructive causes, which are common in adults, account for a

portion of episodes in children. Gallstones may be more prevalent in children than

previously thought. In previous studies gallstones were frequently lumped with other

obstructive causes and the incidence is impossible to discern. One recent report from

Korea found gallstones in 29% of cases[6]. Structural abnormalities, such as pancreas

divisum, choledochal cysts, and gastric or duodenal duplication cysts, and periampullary

lesions, such as Crohn disease or duodenal ulcer, can also obstruct pancreatic flow and

cause acute pancreatitis in children. Trauma remains an important etiology of acute

pancreatitis in childhood especially in younger children. A variety of medications have

been associated with acute pancreatitis[1●●, 3●●]. The anticonvulsant valproic acid is

the most common medication reported in most series, but other anticonvulsants and

chemotherapeutic agents have also been associated with acute pancreatitis. The

mechanism for drug-induced pancreatitis is speculative and most theories center on

disruption of cellular metabolism by the drugs or their metabolites.

Acinar Cell Events in Acute Pancreatitis

Current explanations for the early acinar cell events in acute pancreatitis center on the

activation of trypsinogen to trypsin. Initially, this speculation was based on the role

trypsin plays in activating other digestive enzymes, all of which could contribute to

acinar cell damage in early pancreatitis. All of the major digestive enzymes, except

amylase and lipase, are synthesized as pro-enzymes or zymogens that require activation

through the cleavage of an activation peptide by trypsin. Normally, trypsinogen is

activated in the duodenum by the brush border enzyme, enterokinase, or by trypsin.

Trypsinogen can also autoactivate and that ability has become an important mechanism in

theories regarding the pathogenesis of acute pancreatitis. Because trypsinogen is stored

in the same compartment as other zymogens and it can autoactivate, there is always the

potential for premature trypsinogen activation within the acinar cell, which can set off a

cascade of zymogen activation leading to autodigestion of the pancreas.

With time, experimental evidence to support the role of premature trypsinogen

activation in acute pancreatitis has accumulated from studies in animal models and from

observations in humans. Production of trypsinogen activation peptide is one of the

earliest detectable events in models of experimental pancreatitis[7]. Pancreatitis

associated with endoscopic retrograde cholangiopancreatography (ERCP) can be

attenuated by pretreatment with trypsin inhibitors[8]. Perhaps, the most convincing

evidence for the importance of trypsin in the pathophysiology of acute pancreatitis comes

from genetic studies demonstrating an association of trypsin mutations with hereditary

pancreatitis[9●●].

A number of experimental studies in animal models support the important role of

trypsin in the pathophysiology of acute pancreatitis. Activation of trypsinogen, as

evidenced by the appearance of trypsin activation peptide, is first observed in

cytoplasmic vacuoles, whose formation is among the earliest detectable changes in the

acinar cell during experimental pancreatitis[4●, 10]. Both digestive enzymes and

lysosomal hydrolases co-localize in these vacuoles. Normally, digestive enzymes and

lysosomal hydrolases are packaged separately, but disruption of normal secretion as may

occur early in acute pancreatitis leads to a defect in intracellular transport and sorting of

enzymes. Once the digestive and lysosomal enzymes co-localize, lysosomal hydrolases

can activate trypsinogen. Cathepsin B may activate trypsinogen in the vacuoles as

evidenced by the observations that cathepsin B activates trypsinogen in vitro, that

specific cathepsin B inhibitors prevent the activation of trypsin in isolated acinar cells

after hyperstimulation with cerulein, a secretogogue, and that cathepsin B deficient mice

have decreased trypsinogen activation after the induction of pancreatitis[11]. Shortly

after forming, the vacuoles disintegrate and release their contents into the cytoplasm

where the activated digestive enzymes can now damage the acinar cell.

Important support for the central role of trypsinogen activation in acute

pancreatitis and a major advance in our understanding of the pathophysiology of

pancreatitis comes from genetic studies of families with recurrent pancreatitis in multiple

members[12●]. First described in 1952, hereditary pancreatitis causes repeated episodes

of acute pancreatitis and, in about 75% of patients, results in chronic pancreatitis. In

1996, a single point mutation in the third exon of the gene encoding cationic trypsinogen

was shown to segregate with the disease[13●]. The point mutation causes an arginine to

histidine substitution at position 122, R122H trypsinogen. Subsequently, additional

mutations in the trypsinogen gene were found in other pedigrees with hereditary

pancreatitis, 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 protective

mechanisms of the acinar cell has been proposed as a model for the defect in hereditary

pancreatitis[14]. Most protective mechanisms center on the control of trypsin levels in

the acinar cell by preventing trypsinogen activation, inhibiting or destroying active

trypsin, and flushing trypsin out of the pancreas. As mentioned above, the first lines of

defense against active trypsin accumulating in the cells are the synthesis trypsinogen and

the packaging of trypsinogen and other zymogens in granules, which isolates them from

other cellular enzymes like lysosomal hydrolases. If trypsinogen is activated inside the

cell, 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 trypsinogen

activation is brisk, the capacity of SPINK1 to inhibit trypsin becomes overwhelmed and

the next tiers of defense mechanisms come into play. Among these is the degradation of

trypsin by autolysis and, perhaps, by other proteases. The first step in degradation is

proteolytic cleavage after Arg122. In vitro studies demonstrate that R122H trypsin is

resistant to autolysis and also reveal that the mutation increases autoactivation of R122H

trypsinogen[15]. Similar studies on N29I cationic trypsinogen show that the mutation

results in faster autoactivation and increase trypsin stability[16]. Thus, both N29I and

R122H trypsin mutants are more likely to accumulate in acinar cells and cause increased

activation of other zymogens. Consequently, patients with these mutations develop

pancreatitis more readily than people who have normal trypsinogen.

Although autodigestion of the acinar cells by digestive enzymes plays a central

role in most theories of acute pancreatitis, other processes may also contribute to acinar

cell damage in early pancreatitis. Several authors have proposed an important role for

reactive oxygen species in acute pancreatitis[17, 18]. They point to studies showing

increases of lipid peroxides during experimental pancreatitis, alterations in cytoskeleton

function because of lipid peroxidation and increases in cell permeability that correlate

with the production of free oxygen radicals as evidence. Additionally, abnormalities of

the blood supply probably contribute to early injury. In experimental pancreatitis,

regions of the organ with good perfusion are less injured than regions with

hypoperfusion[19]. Finally, activation of resident macrophages in the pancreas and the

migration of activated leukocytes into the pancreas contribute to the severity of gland

inflammation in acute pancreatitis[20-22]. Nude mice lacking lymphocytes have

decreased severity of pancreatitis and the return of T-lymphocytes to these mice increases

the severity of acute pancreatitis.

Late Events in Acute Pancreatitis

The early events produce pancreatic edema and stimulate a local inflammatory response

associated with the release of inflammatory mediators into the systemic circulation[23,

24]. These cytokines and chemokines mediate a systemic inflammatory response, a

common pathway in many forms of injury. The clinical severity of pancreatitis depends

in part on the magnitude of the systemic response and the balance between pro-

inflammatory and anti-inflammatory mediators determines the clinical course. In

reaction to a brisk systemic inflammatory response, activated leukocytes migrate into

other 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 the

systemic complications of acute pancreatitis. Most likely, the damage of distant organs

by circulating pancreatic digestive enzymes is minimal.

Diagnosis of Acute Pancreatitis

The diagnosis of acute pancreatitis still depends on clinical suspicion and confirmatory

laboratory and radiographic studies[1-3●●]. Amylase and lipase remain the most

commonly employed laboratory tests. Other pancreatic products like phospholipase A2,

trypsin, trypsinogen activation peptide and elastase are elevated in acute pancreatitis, but

none have gained widespread use in the clinical laboratory. Although levels of lipase and

amylase that are three times the upper reference limit suggest pancreatitis, the level of

elevation is not diagnostic. Both enzymes can be elevated in conditions unrelated to

pancreatitis and both can be normal when there is radiographic evidence of acute

pancreatitis (Table 2).

Computed tomography (CT) and ultrasound images of the pancreas serve to

confirm the presence of pancreatitis, to identify complications and to investigate other

causes for the symptoms. Ultrasound findings included enlargement of the pancreas,

altered echogenicity of the pancreas, a dilated main pancreatic duct, gallstones, biliary

sludge, dilated common and intrahepatic ducts, pancreatic calcification, choledochal

cysts, and fluid collections. A CT scan will show similar findings, except that abnormal

attenuation is seen rather than altered echogenicity. Studies in animals indicate the CT

contrast given early in the course of acute pancreatitis may further diminish blood flow to

ischemic areas of the pancreas and increase the likelihood of necrosis. Although similar

studies have not been done in humans, it is reasonable to avoid CT scans early in the

course of pancreatitis and save this study for patients that do not show

improvement[1●●]. ERCP is reserved for patients with unexplained recurrent episodes

of pancreatitis, prolonged episodes of pancreatitis where a structural defect or duct

disruption is suspected, and in some cases of gallstone pancreatitis. Magnetic resonance

cholangiopancreatography (MRCP) can be helpful in defining abnormalities of the ductal

system and with the development of improved software MRCP may supplant ERCP as

the method of choice for evaluating the anatomy of the ductal system.

Treatment of Acute Pancreatitis

Treatment of pancreatitis has not changed significantly over the years. The mainstay of

treatment in children remains analgesia, intravenous fluids, pancreatic rest and

monitoring for complications[1●●]. Volume expansion early in the course of acute

pancreatitis is important to maintain cardiovascular stability and to prevent the

development of pancreatic necrosis. Nutrition should be implemented early if a severe or

prolonged course is anticipated. Until recently, parenteral nutrition was considered the

only option, but several studies show that adult patients with acute pancreatitis tolerate

jejunal feedings with fewer complications than those given parenteral nutrition[25].

Antibiotics are usually unnecessary except for the most severe cases.

Outcome of Acute Pancreatitis

Acute pancreatitis is usually divided into mild and severe forms. Because the clinical

course and outcome differ significantly between mild and severe cases, the physician

must make a rapid assessment of the patient’s condition and predict the risk of a mild or

severe clinical course. Several scoring systems have been developed to assist the

physician in this decision[26-28]. Until recently, none of these systems had been

validated in children. One group analyzed the criteria of the Ranson and Glasgow scores

plus additional criteria and developed a scoring system for children that was validated in

three centers[3●●]. Of note, young age and low weight are major risk factors.

Although acute pancreatitis can be life threatening, death does not occur in

pediatric patients as frequently as in adults[1●●]. Early causes of death are shock and

respiratory failure. Late life-threatening complications of pancreatitis are generally

associated 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 acute

pancreatitis and the incidence may be increasing, but there are no reliable estimates of the

true prevalence.

Pathophysiology of Chronic Pancreatitis

Early in the course, chronic pancreatitis may be difficult to distinguish from acute

pancreatitis on clinical grounds[14]. In chronic pancreatitis continued inflammation

produces irreversible morphological changes in the gland such as fibrosis, acinar cell

loss, islet cell loss and infiltration by inflammatory cells. Because the diagnosis depends

on identifying decreased function and chronic changes, both of which occur late in the

course, studies of natural history and of potential therapies have been hindered.

Consequently, many theories to explain the pathophysiology of chronic pancreatitis have

been proposed.

In the last half of the twentieth century, the dominant view held that recurrent

acute pancreatitis progressed to chronic pancreatitis although some authors developed

theories that did not include acute pancreatitis as part of the pathway to chronic

pancreatitis. Current research suggests that chronic pancreatitis is a progression that

begins with acute pancreatitis and continues with chronic and recurrent inflammation to

produce end stage fibrosis[29]. In the last decade, it has become clear that susceptibility

to chronic pancreatitis is influenced by both genetic and environmental factors. In

children, chronic pancreatitis generally associates with abnormal genetic alleles or is

idiopathic.

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 R122H

and N29I mutations. Hereditary pancreatitis caused by these mutations usually presents

as 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 10

years after the first bout of acute pancreatitis although some patients will present with

chronic pancreatitis without a clear history of acute pancreatitis[30]. The most important

clinical clue is the presence of pancreatitis in other family members. The diagnosis is

confirmed by testing of the gene encoding cationic trypsinogen.

The association of cationic trypsinogen with hereditary pancreatitis led to the

search for families with mutations in SPINK1. By 2000, mutations in the gene encoding

SPINK1, N34S and P55S, were correlated with idiopathic chronic pancreatitis[31].

Almost 90% of patients with SPINK1 mutations develop pancreatitis before the age of

twenty. 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 risk

of a SPINK1 mutation carrier developing chronic pancreatitis is about 1%. SPINK1

mutations probably increase susceptibility to recurrent acute and chronic pancreatitis

when homozygous mutations are present or in association with mutations in other genes

as part of a polygenic condition with multiple genetic risk factors.

In pediatrics, cystic fibrosis is the most common cause of chronic pancreatitis[32].

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause

cystic fibrosis. CFTR is a membrane protein located on the apical membrane of

pancreatic 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 mutation

on CFTR protein expression and function. Some mutations completely abrogate CFTR

function and are classified as severe. Other mutations permit some function and are

classified 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 residual

CFTR function and generally have atypical symptoms. In particular, compound

heterozygote mutations have been associated with chronic pancreatitis. Initial reports

found 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 with

having 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 pancreatitis

over the general population.

Recently, it was suggested that CFTR mutation-associated pancreatitis can be

divided into 4 subtypes based on potential mechanisms[36]. Type 1 is classic CF with

two severe alleles. Type 2 is atypical CF with a severe and mild-variable genotype. Of

specific interest are CFTR mutations that block bicarbonate conductance but not chloride

conductance. These mutations can potentially target the pancreas over other organs since

bicarbonate 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. For

instance, the risk for developing chronic pancreatitis was increased 900-fold in patients

with heterozygous mutations in both the CFTR and SPINK1 genes[33]. Type 4 is a

heterozygote with a severe or mild-variable allele and a strong environmental risk factor

like alcohol.

Genetic Testing in Recurrent or Chronic Pancreatitis

Genetic testing for pancreatic diseases has become an important part of medical

practice[37●-39]. The purpose of genetic testing can be divided into two general

categories, diagnostic and predictive. Diagnostic testing is done when a patient has

symptoms of a disease and a genetic test can determine the underlying cause. Predictive

testing is genetic testing in subjects who do not have evidence of pancreatic disease, but

may have relatives with pancreatic disease or a known mutation in the genes encoding

CFTR or cationic trypsinogen. In general the indications for diagnostic testing validate

its use, but the role of predictive testing is less clear and controversial.

The primary indications for R122H and N29I cationic trypsinogen mutation

testing are diagnostic and include recurrent idiopathic acute pancreatitis, idiopathic

chronic pancreatitis, and patients with a family history of acute pancreatitis (Table 3).

Early identification of a cationic trypsinogen gene mutation can prevent an expensive and

prolonged evaluation of recurrent pancreatitis in children. Knowledge of the diagnosis

also allows the physician to counsel the family and patient about the natural history of the

disease, particularly the greatly increased risk for pancreatic cancer[40].

Some have advocated predictive genetic testing in family members with first

degree relatives that have a mutation in the gene encoding cationic trypsinogen. A

negative test result in a family with a known mutation essentially eliminates the risk of

this genetic form of pancreatitis. A positive test result in a clinically unaffected person

confers a significantly increased risk of pancreatitis, which may diminish with age.

Those who argue for testing point out that alcohol, tobacco, emotional stress and fatty

foods may precipitate attacks of pancreatitis in patients with hereditary pancreatitis.

Others respond that counseling to avoid fatty foods, alcohol, and tobacco represents

excellent general medical advice and therefore does not provide a compelling reason for

genetic testing[39]. In either case, the patient and their family should be offered adequate

genetic counseling and the personal desires of older children should be considered. Both

physicians and patients need to understand the implications of genetic testing for the

patient’s future health, family, employment and insurability. Older children may

postpone testing or may proceed with testing to relieve their own anxieties and to learn

more about their personal health.

Although testing for SPINK1 mutations in children with chronic pancreatitis may

provide information about predisposing factors, most experts do not advocate genetic

testing for SPINK1 mutations at this time[41, 42]. Heterozygous SPINK1 mutations

alone are probably not disease causing[43]. Homozygous mutations are strongly

associated 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 chronic

pancreatitis. 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 chronic

pancreatitis for CFTR mutations. The major problem with this approach is that currently

available panels only test for the most common CF-causing gene mutations, not

pancreatitis associated mutations. Less common or unique mutant alleles will not be

identified unless broader screening procedures become available. New techniques, such

as denaturing ion-pair reverse-phase high-performance liquid chromatography, show

promise for rapidly analyzing the complete coding sequence of the CFTR gene. These

new tools will allow investigators to fully interpret the CFTR genotype-pancreatitis

relationship which will provide the basis for recommendations on the utility of genetic

screening 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 should

undergo an evaluation for CF. The evaluation should begin with a sweat test and genetic

testing should be considered only when family history or other symptoms suggest

atypical CF.

Conclusions

Inflammatory disorders of the pancreas are seen with regularity in regional children’s

hospitals. Both acute and chronic pancreatitis occur in childhood and the incidence may

be increasing. Important differences in the etiologies between children and adults exist

for both acute and chronic pancreatitis, but the treatment is the same. The greatest

progress in understanding the pathophysiology of pancreatitis has come from studies

linking genetic mutations to increased risk for pancreatitis. Mutations in the gene

encoding cationic trypsinogen cause hereditary pancreatitis. Mutations in genes encoding

CFTR 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 of

the genes involved in pancreatitis and in the biological events associated with pancreatitis

will eventually lead to better diagnostic methods, new treatments and improved

prevention of pancreatic inflammatory disease.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as

● Of importance

●● Of major importance

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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 study

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The text of an address by Dr. Steer provides an excellent overview of current theories of

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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, O'Connell 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.

Werlin et al. [1] Lopez [2] Debanto et al. [3]

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 1. Etiologies of acute pancreatitis in three recent studies of children

Table 2. Causes of elevated amylase or lipase

Pancreatic Disease Nonpancreatic Causes

Acute pancreatitisChronic pancreatitisPancreatic ascitesPancreatic cancerPseudocyst

SalpingitisSalivary adenitisEnd-stage renal diseaseBurnsAcute cholecystitisUpper endoscopyMacroamylasemiaMacrolipasemia

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.