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Journal of Pediatric Gastroenterology & Nutrition:
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Research Agenda for Pediatric Gastroenterology, Hepatology and Nutrition: Cystic Fibrosis and Pancreatic Diseases: Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation

Lowe, Mark E.; Ameen, Nadia; Freedman, Stephen; Mulberg, Andrew E.; Werlin, Steven L.

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St Louis

Miami

Boston

Titusville

Milwaukee

Address requests for reprints to: Executive Director, Children's Digestive Health and Nutrition Foundation, PO Box 6, Flourtown, PA, 19031, U.S.A. (e-mail: NASPGHAN@naspghan.org).

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RATIONALE

Although pancreatic disease has traditionally been viewed as a problem in adults, exocrine pancreatic insufficiency and pancreatitis can occur in children as well (1–3). Pancreatitis is a clinical diagnosis. In many suspected cases, no single test or series of tests reliably confirms the diagnosis. The lack of a definitive diagnostic test for pancreatitis hampers epidemiologic and clinical studies.

Just as there is no definitive diagnostic test, there is no specific therapy for pancreatitis. Current therapy consists of supportive care (1). No intervention effectively alters the course of pancreatitis or prevents recurrent episodes. Efforts to develop new therapies will be advanced by the development of suitable animal models for pancreatitis.

Recent studies provide a potential direction for developing models of pancreatitis. Two genes and another locus have been linked to recurrent pancreatitis (2). Mutations in the gene encoding cationic trypsinogen are associated with hereditary pancreatitis. Linkage studies suggest that another gene predisposing to hereditary pancreatitis resides on chromosome 12. A large proportion of patients with idiopathic chronic pancreatitis have mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) (2,4). Even though several gene mutations have been identified, the role of gene products in the pathophysiology of chronic pancreatitis remains to be elucidated and the genes have not been exploited to create animal models of pancreatitis.

Exocrine pancreatic dysfunction is present in a number of diseases in children (5). Another organ may be primarily affected, such as the liver in Alagille syndrome, but the pancreatic dysfunction contributes to clinical symptoms. In Shwachman-Diamond syndrome, pancreatic insufficiency presents in infancy and is a major clinical problem (6). For unexplained reasons, the pancreatic insufficiency improves with age. The improvement may be related to the developmental program of the pancreas. An understanding of the mechanisms contributing to the improvement in pancreatic function in Shwachman-Diamond syndrome may lead to the development of novel therapies for patients with pancreatic insufficiency.

The most common cause of pancreatic insufficiency in children is cystic fibrosis (CF) (5,7). Up to 90% of patients with CF develop pancreatic insufficiency and do not digest food adequately. The resultant malabsorption of nutrients affects growth and health. Most patients require replacement therapy with fat-soluble vitamins and pancreatic enzymes, which often do not restore fat absorption completely. Since most patients with CF do not have exocrine pancreatic insufficiency at birth, therapies potentially could be developed to arrest the process if the pathophysiology is better understood.

Although pancreatic insufficiency and pulmonary disease predominate in CF, intestinal and liver disease also can cause significant morbidity and mortality (8). Intestinal obstruction with thickened secretions can present 1) as meconium ileus or peritonitis in 10% to 15% of newborns with CF or 2) as distal-bowel obstruction at any age in about 10% of patients. Approximately 5% of patients with CF have hepatic cirrhosis, which can progress to liver failure and require a liver transplant.

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AREAS OF EMPHASIS

Define the Molecular Basis of Pancreatic Disease in Cystic Fibrosis
Research Goals

Although the CFTR gene has been identified, the molecular events leading to pancreatic complications in CF have yet to be elucidated. Studies should be encouraged that analyze the effect of CFTR mutations on pancreatic function. Also to be encouraged are studies in healthy individuals that detail CFTR function at the molecular level.

The recent demonstration of increased phospholipid-bound arachidonic acid and decreased docosahexaenoic acid in the pancreas of patients with CF raises questions about the role of CFTR in fatty acid biosynthesis (9). The consequences of an imbalance of fatty acids on the function of other membrane proteins in the pancreas also should be evaluated.

CFTR dysfunction results in increased levels of some cytokines and decreased levels of others, leading to excessive inflammation in the pancreas and lungs. Investigations are recommended to determine the precise mechanisms by which CFTR affects the inflammatory process.

Up to 15% of patients with CF do not have exocrine pancreatic insufficiency, even though they may have CFTR mutations (5,7). Studies comparing patients with and without pancreatic insufficiency will provide insight into the mechanism of pancreatic insufficiency. The objectives of such studies include the identification of a) CFTR alleles associated with pancreatic insufficiency, b) differences in CFTR function between the two patient subgroups, and c) other genes that may modify the effects of mutant CFTR.

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Research Strategies

To achieve these goals, clinical and epidemiologic studies are needed, as well as molecular, biochemical, and genetic studies of CFTR function. Clinical research studies will require multicenter participation.

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Projected Timetable and Funding Requirements

These research goals will require two to four separate research groups and may take 5 to 10 years to make significant progress. Potential funding sources would include government agencies.

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Develop New Therapies and Diagnostic Tests for Pancreatic Insufficiency
Research Goals

Current therapies for pancreatic insufficiency generally do not restore fat absorption to the normal range, resulting in significant loss of calories and fat-soluble vitamins (10). Tests for pancreatic insufficiency are imprecise or invasive and specialized. The widely available fecal fat analysis requires adequate dietary fat during the test, may not be suitable in young infants, and is unwieldy as a routine screening test.

Studies are recommended to:

Develop and validate a noninvasive test of pancreatic function. A simple, accurate measure of pancreatic sufficiency would improve both diagnosis and the monitoring of treatment

Evaluate alternatives to standard enzyme replacement therapy, such as gastric lipase and bacterial or fungal lipases

Identify parameters that affect the efficacy of current enzyme preparations

Develop potential therapeutics that may halt or reverse the progression to pancreatic insufficiency

Develop new vectors that have potential applications in gene therapy for pancreatic disorders and

Develop screening programs to identify newborns with CF

A promising new therapy is docosahexaenoic acid, which has been shown in CFTR-deficient mice to reverse pathologic changes (9). Future evaluation of this therapy would hasten clinical trials in humans.

The ability to reliably identify newborns with CF will be critical if potential therapies are developed that prevent progression to pancreatic insufficiency.

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Research Strategies

Both laboratory and clinical studies are needed to develop and validate noninvasive tests of pancreatic function. Clinical trials of alternatives to standard enzyme replacement therapy are important. Several of the proposed research goals require multicenter clinical studies. Further studies in CFTR-deficient mice are warranted to confirm the safety and efficacy of docosahexaenoic acid in reversing pathology. In addition, studies are needed to develop a formulation that is well absorbed in humans.

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Projected Timetable and Funding Requirements

The development of diagnostic tests and therapies for pancreatic insufficiency will require two to four separate research groups and may take 5 to 10 years to make significant progress. In addition to government funding agencies, industry sources could contribute to implementation of several research strategies, including studies aimed at improving therapy for pancreatic insufficiency.

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Characterize the Pathophysiology of Liver and Intestinal Disease in Cystic Fibrosis
Research Goals

Liver and intestinal disorders cause significant morbidity and mortality in patients with CF (8). However, little is known about the mechanisms underlying these complications. The prevention and treatment of hepatic and intestinal disorders in patients with CF can be accomplished only through a better understanding of the underlying pathophysiology.

An important research goal is to understand the contribution of hepatic and intestinal function to the malabsorption seen in patients with CF. Studies may reveal important insights into the mechanism of malabsorption and advance the development of new therapies.

Risk factors, including genetic factors, for the development of hepatic or intestinal complications need to be identified. Patients in whom risk factors are present can be given appropriate anticipatory guidance. Therapies to prevent or ameliorate these complications can be evaluated only if high-risk patient populations are identified.

Another research goal is to understanding the function of CFTR in the intestinal and biliary epithelium and its relationship to liver and intestinal disease. Studies should include, but not be limited to, defining the transport properties of CFTR, the relationship of CFTR to intestinal mucins, and the regulation of CFTR function.

As the lifespan of patients with CF increases, additional complications may develop. There is evidence to suggest that patients with CF have an increased cancer risk, but the actual risk is unclear. Studies are needed to determine the risk of liver cancer associated with cystic fibrosis.

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Research Strategies

Laboratory, epidemiologic, and clinical studies are encouraged to understand the contribution of hepatic and intestinal dysfunction to the malabsorption seen in CF. These studies could provide important insights into the mechanism of malabsorption, which may translate into new therapies. Several clinical studies will require multicenter participation. Epidemiologic studies are needed to determine whether patients with CF are at risk of liver cancer.

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Projected Timetable and Funding Requirements

As with the other areas of pancreatic disease research, it is estimated that the research goals described above will require two to four separate research groups and take 5 to 10 years to make significant progress. Funding sources potentially include the pharmaceutical industry and government agencies.

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Characterize the Clinical Features of Childhood Pancreatitis
Research Goals

The identification and treatment of children with pancreatitis will be greatly aided if the clinical features of the disorder are well documented. Our current knowledge is based on retrospective studies and there are critical problems with case definitions. Studies are needed that:

Characterize the epidemiology and clinical presentation of childhood pancreatitis, with investigations addressing incidence, natural history, risk factors (environmental and genetic), optimal diagnostic criteria (biochemical and/or radiographic measures), and prognosis

Identify genes that act alone or interact with known trypsinogen or CFTR mutations to predispose patients to acute or recurrent pancreatitis

Determine the role of endoscopic retrograde cholangiopancreatography and magnetic resonance imaging in the diagnosis of pancreatitis

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Research Strategies

Multicenter epidemiologic studies are encouraged to characterize childhood pancreatitis. Genetic studies can identify genes or CFTR mutations that predispose an individual to acute or recurrent pancreatitis (2,4).

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Projected Timetable and Funding Requirements

As with the other areas of pancreatic disease research, it is estimated that the research goals described above will require two to four separate research groups and take 5 to 10 years to make significant progress. Funding sources potentially include the pharmaceutical industry and government agencies.

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Determine the Pathogenesis of Acute and Chronic Pancreatitis
Research Goals

The lack of a suitable animal model for pancreatitis has greatly hampered investigations into its pathophysiology, particularly in defining the early events of pancreatitis. Current animal models do not faithfully recapitulate the characteristics of human pancreatitis and often produce fulminate pancreatitis, which makes studies of early events impossible (11). A greater understanding of the genetics of pancreatitis should guide the creation of new animal models that mimic the events of the disease in humans and provide an opportunity to delineate the pathophysiology.

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Research Strategies

Basic science studies are needed to define the molecular basis of gene regulation and to describe the biologic mechanisms for known gene mutations that predispose to pancreatitis. Animal models are required in which pancreatitis is induced using transgenic or gene ablation technology.

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Projected Timetable and Funding Requirements

As with the other areas of pancreatic disease research, these research goals will require two to four separate research groups and may take 5 to 10 years to make significant progress. Funding sources include government agencies.

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Further Clarify the Molecular Events Governing Development of the Pancreas
Research Goals

A detailed examination of the molecular events governing pancreatic development should lead to novel therapies to improve nutrition in premature infants and to restore pancreatic acinar tissue in patients with chronic pancreatitis. Studies are recommended to:

Identify genes that govern the differentiation of pancreatic stem cells into the various cell types in the pancreas

Identify genes that determine the development of the ventral and dorsal pancreas and that regulate the fusion of the two glands and their ducts

Define the molecular regulation of pancreas-specific genes. In particular, studies are needed to determine the factors regulating the temporal expression of these genes and means of altering that expression.

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Research Strategies

Genetic studies are needed to achieve these research goals.

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Projected Timetable and Funding Requirements

Each research goal may require two to four separate research groups and take 5 to 10 years to make significant progress. Funding sources potentially include the pharmaceutical industry and government agencies.

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Determine the Mechanism of Pancreatic Dysfunction in Disorders Other than Cystic Fibrosis
Research Goals

Characterization of pancreatic dysfunction in disorders other than CF will provide insight into the onset of pancreatic insufficiency in more prevalent diseases and could provide clues to the development of novel therapies that may retard or even reverse the progression to pancreatic insufficiency. Studies are recommended to:

Identify the gene(s) responsible for Shwachman-Diamond syndrome

Define the clinical features of Shwachman-Diamond syndrome

Determine the mechanisms of pancreatic dysfunction in Alagille syndrome, celiac disease and other illnesses in which pancreatic complications are not the primary manifestation

Determine if CFTR contributes to pancreatic dysfunction in these disorders

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Research Strategies

Genetic as well as multicenter epidemiologic studies are needed to characterize these disorders.

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Projected Timetable and Funding Requirements

As with the other areas of research emphasis, these research goals will require two to four separate research groups and may take 5 to 10 years to make significant progress. The potential for development of targeted therapies suggests that the pharmaceutical industry as well as government agencies may be interested in providing funding.

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HEALTH AND ECONOMIC OUTCOMES

Cystic fibrosis affects approximately 30,000 children and adults in the US (12). One in 31 Americans, or about 10 million people, carry the gene for CF (13,14). If two carriers of this recessive gene marry, 1 in 4 of their children will have CF. In 1995 the cost of medical care for a patient with CF was about $40,000 a year. Total medical costs related to cystic fibrosis approached $900 million annually. The burden to the family extends beyond the medical costs. For example, frequent visits to the physician and frequent hospitalizations cause parents to miss work. For any family with a chronically ill child, the emotional and social effects can be overwhelming and potentially lead to a breakup of the family.

The economic and social impact of other pancreatic diseases in childhood is less well documented. From the 1960s to the mid-1980s, the incidence of pancreatitis in adults increased about tenfold (1). The precise incidence in children is not known. Among pediatric gastroenterologists, there is an impression that the incidence is increasing, but this has not been documented. As with families of children with CF, the families of children with recurrent pancreatitis face significant burdens socially and emotionally. Acute pancreatitis accounts for 3% to 5% of hospital admissions, and mortality from pancreatitis can reach about 10% in adults (1). Acute pancreatitis is a significant cause of hospitalization in children, and as a frequent complication of systemic illnesses, pancreatitis can result in prolonged hospitalization and associated morbidity.

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REFERENCES

1. Steinberg W, Tenner S. Acute pancreatitis. N Engl J Med 1994; 330:1198–210.

2. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001; 120:682–707.

3. Weizman Z. Acute pancreatitis in childhood: research of pathogenesis and clinical implications. Can J Gastroenterol 1997; 11:249–53.

4. Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998; 339:653–8.

5. Durie PR. Pancreatic aspects of cystic fibrosis and other inherited causes of pancreatic dysfunction. Med Clin North Am 2000; 84:609–20, ix.

6. Mack DR, Forstner GG, Wilschanski M, Freedman MH, Durie PR. Shwachman syndrome: exocrine pancreatic dysfunction and variable phenotypic expression. Gastroenterology 1996; 111:1593–602.

7. Bronstein MN, Sokol RJ, Abman SH, Chatfield BA, Hammond KB, Hambidge KM, Stall CD, Accurso FJ. Pancreatic insufficiency, growth, and nutrition in infants identified by newborn screening as having cystic fibrosis. J Pediatr 1992; 120(4 pt 1):533–40.

8. Rothbaum RJ. Cystic fibrosis: pancreatic, hepatic, and intestinal manifestations. In: Balistreri WF, Ohi R, Todani T, Tsuchida Y, eds. Hepatobiliary, Pancreatic and Splenic Disease in Children: Medical and Surgical Management. Amsterdam, The Netherlands: Elsevier Science BV; 1997: 459–78.

9. Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG. A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr(−/−) mice Proc Natl Acad Sci U S A 1999; 96:13995–4000.

10. Guarner L, Rodriguez R, Guarner F, Malagelada JR. Fate of oral enzymes in pancreatic insufficiency. Gut 1993; 34:708–12.

11. Go V, Dimagno E, Gardner J, Lebenthal E, Reber H, Scheele GA, eds. The Pancreas: Biology, Pathobiology, and Disease, 2nd ed. New York, NY: Raven Press; 1993.

12. Genetic testing for cystic fibrosis. National Institutes of Health Consensus Development Conference Statement on genetic testing for cystic fibrosis. Arch Intern Med 1999; 159:1529–39.

13. Danks DM, Allen J, Anderson CM. A genetic study of fibrocystic disease of the pancreas. Ann Hum Genet 1965; 28:323–56.

14. Steinberg AG, Brown DC. On incidence of cystic fibrosis of pancreas. Am J Hum Genet 1960; 12:416–24.

© 2002 Lippincott Williams & Wilkins, Inc.

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