Pancreatic Disorders and Cystic Fibrosis: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition (2002)

I. SUMMARY OF THE PROBLEM Definition The exocrine pancreas is pivotal to the digestion and absorption of nutrients. Pancreatic disorders manifest either with pain secondary to inflammation or with malabsorption secondary to acinar malfunction, paucity, or dropout. Children suffer from the full range of pancreatic disease seen in adults, and some pancreatic disorders first become apparent in childhood. The spectrum of pancreatic disease is listed below. Congenital anatomic abnormalities Formation anomalies: annular pancreas, pancreas divisum, pancreatic hypoplasia and agenesis. Situation anomalies: heterotopic pancreas Inborn errors Cystic fibrosis Congenital secretory deficiencies: Shwachman-Diamond syndrome, Johanson-Blizzard syndrome, Pearson bone marrow pancreas syndrome, isolated enzyme deficiencies (lipase, colipase) Hereditary pancreatitis Pancreatitis; idiopathic, viral, drugs, traumatic, metabolic, collagen vascular diseases; autoimmune; fibrosing, nutritional (tropical) Neoplastic disease (rare in childhood) Pancreatic insufficiency secondary to other disorders (Alagille syndrome, Celiac disease) Most of these disorders are either uncommon or rare. The exceptions are cystic fibrosis (CF), which is the commonest severe autosomal recessive disease of humans, and nutritional pancreatitis. The gene frequency for cystic fibrosis in western communities is 1:25 to 1:35, with a live birth incidence of 1:2,500 to 1:5,000. Between 30,000 and 40,000 CF patients live in the United States. Nutritional pancreatitis is endemic in some parts of the tropics, including Kerala in Southern India, and parts of Indonesia and Africa. MAJOR ADVANCES IN PANCREATIC DISEASE Pancreatic Physiology Before the mid 19th century, knowledge of the pancreas was descriptive. The concept of the pancreas as digestive organ began with the description by Claude Bernard of lipolytic activity in pancreatic juice in 1856. The mechanisms governing pancreatic secretions were advanced by the discovery in intestinal extracts of secretin that drives water and anion secretion by Bayliss and Starling in 1902 and pancreozymin (cholecystokinin) by Harper and Raper in 1943. These hormones were synthesized by Mutt and Jorpes in the 1960s. Many other neuroenteric hormones that act on the pancreas have since been discovered. The 1980s saw the advent of the concept of ion channels and the realization that the CF gene was most likely an apical chloride channel. Pancreatic Function Tests An understanding of pancreatic physiology allowed pancreatic function tests to be developed. This was particularly important because of the inaccessible nature of the exocrine pancreas. These tests were either direct, which required sampling of pancreatic secretions obtained from a stimulated exocrine pancreas, or indirect, which relied on measuring malassimilated nutrients either in blood, urine, or feces. More recently, pancreatic-specific proteins such as cationic trypsinogen or pancreatic polypeptide have been measured in blood. The first use of secretion/cholecystokinin to stimulate the pancreas and obtain secretions in children was undertaken by Shwachman in 1943. This test was further refined by using marker perfusion and bilumen tubes. The modern method for measuring fecal fat was developed by Van der Kamer in 1949. Crossley and Elliott first measured immunoreactive cationic trypsinogen in blood spots in 1979, and this test forms the basis for newborn screening for CF. Pancreatic Function and Relationship to Malabsorption The development of pancreatic function tests allowed the concept of pancreatic reserve to be developed. Di Magno and Go in 1973 estimated on the basis of secretin/cholecystokinin stimulation that 90% of exocrine pancreatic lipolytic activity had to be lost before fat malabsorption became manifest. This was subsequently revised to a loss of 98% to 99% of lipase/colipase activity by Gaskin in 1984. This allowed patients to be classified as either pancreatic insufficient (PI), less than 2% of normal activity, or pancreatic sufficient (PS), 2% to 100% of normal activity. This was particularly important in CF, in which it was shown by Gaskin that PS patients had a markedly improved prognosis. Molecular Biology Advances in molecular biology have allowed the genes for specific pancreatic disorders to be pinpointed and the molecular structure of gene products determined. Intracellular localisation of gene specific proteins has followed. The cellular and biochemical consequences of gene disruption have begun to be determined. The first gene responsible for a pancreatic disorder the CF gene on chromosome 7q was characterized by Rommens, Tsui and Collins in 1989 (1) and the product CFTR (cystic fibrosis transmembrane regulator) structurally determined to be an apical chloride channel by Riordan. Since then, more than 850 separate mutations have been described in this gene, although the pathology is attributed in over 99% of individuals to approximately six common defects, of which a defect resulting in a deletion of phenylalanine in the first nucleotide binding fold ΔF508 is by far the most common (approximately 70% to 80% of homozygotes and 90% of heterozygotes). The determination of genotype has also allowed a functional classification of gene defects depending on the intracellular location of CFTR and its degree of residual function. The hereditary pancreatitis gene on chromosome 7q was discovered by Whitcomb in 1996 (2) and shown to cause unusual stability in intracellular cationic trypsin preventing autocatalysis of trypsin. Two defects, R117H and N21I, are by far the predominant mutations (3). A defect in mitochondrial DNA has been shown to be responsible for Pearson bone marrow pancreas syndrome, and a single patient with pancreatic aplasia has been shown to have a defect in the pancreatic duodenal homeobox gene. The gene locations for lipase and colipase are known to be situated on chromosomes 10q and 6p, respectively. The genes responsible for Shwachman syndrome and Johanson Blizzard syndrome remain to be determined. Pancreatic Imaging Until the 1950s, pancreatic pathology was unable to be detected by imaging techniques unless pancreatitis had resulted in calcification. Two-dimensional gray scale ultrasound developed in 1958 allowed pancreatic swelling and pseudocysts to be detected. Direct visualization of pancreatic ductular structures became possible in 1968 with the use of the side-viewing endoscope and the direct cannulation and injection of dye into the pancreatic ducts (endoscopic retrograde cholangiopancreatography). Computerized tomographic and imaging of the pancreas became available in 1973 and allowed visualization of structures adjacent to the pancreas. Magnetic resonance cholangiopancreatography became available in 1994 and allowed noninvasive imaging of the pancreatic ducts. The last technique has not been widely used in children because of concerns regarding the safety of contrast agents and movement artefact. MAJOR DISEASE STATES Cystic Fibrosis Until 1938, when Andersen described the autopsy manifestations, CF was regarded as a subset of celiac disease. CF is the commonest severe autosomal recessive disease in humans. It results in a generalized exinocrinopathy in which ductular structures in organs with exocrine glands secreting protein, water, and anions become clogged with inspissated proteinaceous secretions. The secretory defect that results from a mutation in an apical chloride channel in the epithelial cells of exocrine glands resulting in reduction of C1−, HCO−3 and water secretion. Of CF patients, 85% are PI, 65% are PI at birth, and 20% become rapidly insufficient during the first few months and years of life (3). The 15% of CF patients who are PS have a markedly improved prognosis (4) and disease in other organ 15% of CF at birth with either or at some of disease of patients intestinal of CF patients disease secondary to This in either or secondary to CF disease is an as prognosis and most patients into The common to of ductular structures with inspissated proteinaceous secretions. it is not some patients with common severe mutations are PI at birth and some are not and PI and some PI patients on to or intestinal syndrome or disease and some The pathology of pancreatitis is and were as important a and in direct cellular Most of pancreatitis not have an Two are responsible for a more understanding of pancreatitis. The first was the of the genes for autosomal hereditary pancreatitis and cystic the and more is the that some are in including epithelial and The of pancreatitis is by the of specific tests and is on the basis of pancreatic such as and lipase in the of of pancreatic pain and a pancreas on either ultrasound or of as to the of pancreatitis into or severe disease. Nutritional (tropical) pancreatitis was first described in and the cause is This disorder in pain and also from nutritional pancreatitis. 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