Pathophysiologic Basis of Exocrine Pancreatic Dysfunction in Childhood

INTRODUCTION The purpose of this review is to provide up-to-date insights into the process of prenatal and postnatal pancreatic development, and to explore the various mechanisms by which disorders of exocrine pancreatic function arise in childhood. It is not our intention to provide a comprehensive review of the clinical aspects of the various pancreatic disorders of childhood. Rather, specific medical conditions are highlighted to illustrate the various pathophysiological processes by which disease occurs. PRENATAL DEVELOPMENT Embryological development of the pancreas begins during the fifth week of intrauterine life, when dorsal, and later ventral evagination of the foregut produces epithelial buds. These buds proliferate and undergo rotation, eventually fusing together to form a differentiated organ by the seventh week of gestation (1,2). Although poorly understood, there appears to be only a few genes which influence the differential development of the pancreas from surrounding organs (gut, biliary or liver cells) at this stage of gestation (3). The pancreatic and duodenal homeobox 1 gene (PDX1, previously known as insulin promotor factor-1) is probably of vital importance to early pancreatic embryogenesis (4). PDX1 knockout mice exhibit early developmental arrest of the pancreatic epithelium and failure of differentiation from surrounding cells (5,6). A common pluripotent progenitor cell of endodermal origin is known to differentiate into exocrine and endocrine cells under the influence and control of several transcription factors (7). A recently described pancreatic exocrine transcription factor, DNA-binding factor p48, is a pancreas-specific basic helix-loop-helix protein. Homozygous mutant mice lacking p48 fail to develop any exocrine pancreatic tissue (8). Most current knowledge in this area concerns an evolving understanding of transcription factors involved in endocrine cell differentiation. One of these, transforming growth factor-beta 1 (TGF beta-1), appears to be an important regulator of pancreatic organogenesis. It induces pancreatic development by repressing the expression of Sonic hedgehog (Shh), a member of the hedgehog family of signaling molecules which antagonize pancreatic development (9). In mice, modest TGF-beta 1 expression early in gestation appears to favour differentiation of exocrine cell lineage, while further upregulation later in gestation is important for islet cell formation (10). The identification of other signaling pathways governing cellular interactions in the developing pancreas has allowed studies of the genetic and molecular basis of pancreatic development and function (11). Notch, TGF-β and Hedgehog pathways are thought to be crucial in regulating the appropriate balance of endocrine and exocrine development (12,13). Specific signaling genes have distinct roles at different developmental stages, which may explain the wide range of anatomic defects seen in abnormalities of these pathways. Mouse models have shown that inactivation of Sonic hedgehog causes overgrowth of ventral pancreatic tissue, and a phenotype that resembles annular pancreas seen in humans (9). Other defects identified in animal models include pancreatic hypoplasia (defects of Notch pathway genes Hes-1 and Jag-1), and pancreas divisum, which can result from either Hedgehog or TGF-β (Smad2 gene deficiency) defects (11). Later differentiation of endocrine and exocrine cells is thought to be influenced by insulin (14), which stimulates growth of exocrine cells and protein synthesis. Insulin is known to have general anabolic effects, resulting in hypertrophy and hyperplasia of individual organs (15). This is in contrast to a recent report (16), which demonstrated that in diabetic pregnancies only the fetal endocrine pancreas, as assessed by amniotic C peptide levels, is stimulated (by the increased fetal insulin due to the maternal hyperglycemia), while the exocrine function, as assessed by amniotic trypsin levels, was unaffected. Very little is known about the embryologic control of pancreatic duct formation in humans. Differentiation of ductal epithelium is important for subsequent exocrine and endocrine development, especially as endocrine stem cells are thought to arise from ductal epithelia (3,20). In a murine model of pancreatic embryogenesis, duct formation occurs following differentiation of the pancreatic epithelium under the influence of the surrounding milieu (17). Expression of the basement membrane glycoprotein, laminin-1, is of critical importance for the formation of pancreatic ducts (18) which occurs during a crucial “window of competence” in the first two weeks of gestation (19,20). POSTNATAL DEVELOPMENT The exocrine pancreas is functionally immature at birth, and there is considerable postnatal maturation of specific enzymes (21). In the first 3–6 months of postnatal life, infants have “physiological” steatorrhea (22), due to deficient bile acid secretion and lipase output which is 5%–10% of adult values (21,23). Pancreatic isoamylase secretion is negligible at birth and maturation to adult values is not achieved until around 2–3 years of age (21). While the molecular mechanisms controlling the asynchronous development of individual exocrine enzymes are not elucidated, the postnatal maturation of enzymes appear to reflect the changes in an infants diet over the first year of life. For example, delayed postnatal maturation of pancreatic amylase may occur because young infants have limited dependence on complex carbohydrates in their diet. In healthy infants, the relative immaturity of the exocrine pancreas has no clinical important consequences, but may well have an adverse effect on nutritional status in times of extreme metabolic and nutritional stress. The pancreas synthesizes and secretes large quantities of protein on a daily basis, primarily in the form of more than 25 exocrine digestive enzymes. The mature exocrine pancreas has a large functional reserve. This observation was first made in patients who underwent massive pancreatectomy (for either chronic pancreatitis or pancreatic carcinoma), who demonstrated an average coefficient of fat absorption of 80% following a 95% subtotal pancreatectomy (24). In their classic pancreatic stimulation studies of patients with fat maldigestion due to chronic pancreatitis Di Magno et al (25) showed that signs of maldigestion occurs after 90% of pancreatic reserve is lost. Gaskin et al (26,27) who identified the central role of pancreatic colipase as the main determinant of fat absorption, showed that steatorrhea (fecal fat losses >7% of fat intake) correlated with lipase or colipase secretion less than 1% of normal. In other words, approximately 99% of enzyme secretory capacity must be lost before manifestations of maldigestion become evident. Thus, patients can have severe exocrine pancreatic dysfunction without symptoms and signs of maldigestion. In practical terms, patients with exocrine pancreatic disease are classified as having either pancreatic insufficiency (PI) if they have incurred significant loss of exocrine function to result in clinical evidence of maldigestion. The term pancreatic sufficiency (PS) describes patients with exocrine pancreatic dysfunction who have retained sufficient exocrine pancreatic reserve to digest nutrients normally. The distinction is important, as PI patients require pancreatic enzyme therapy with meals and fat soluble vitamin supplementation. CAUSES OF PANCREATIC EXOCRINE DYSFUNCTION Table 1 classifies the various childhood causes of exocrine pancreatic dysfunction on the basis of our current understanding of the underlying pathophysiologic process. While advances in genetics have helped us to understand the mechanisms of certain diseases such as cystic fibrosis (CF) or hereditary pancreatitis, very little is known about pathophysiologic mechanisms in the majority of the pancreatic disorders of childhood. For example, early intrauterine events, probably in the first trimester, will affect embryologic development of the pancreas and result in generalized disorders such as aplasia or agenesis of the pancreas. Syndromes of acinar cell failure, such as Shwachman Diamond or Johansson Blizzard, are likely to be associated with a molecular defect affecting acinar cell differentiation. Isolated deficiencies of specific pancreatic enzymes, such as lipase or trypsinogen, are predicted to be due to mutations in a specific gene. While mitochondrial abnormalities have been identified in patients with Pearsons Bone Marrow Pancreas syndrome, the precise mode by which pancreatic disease occurs remains to be defined.TABLE 1: Classification of causes of exocrine pancreatic dysfunction in childhoodDEVELOPMENTAL While the molecular mechanisms controlling prenatal development of the pancreas are poorly understood genetic defects in development are thought to give rise to many of the conditions which present in early postnatal life. These conditions can be classified into those occurring at an early stage of development (affecting both the exocrine and endocrine elements of the pancreas), and disorders arising during later stages of gestation. For example, inherited disorders such as Shwachman Diamond or Johansson Blizzard syndromes appear to affect acinar cells while the ductal and endocrine elements seem to be intact. Early Developmental Disorders Aplasia (or agenesis) of the pancreas, which probably occurs early in development, is rare and not with of pancreatic aplasia in the while associated with of the and A fetal of identified two of or aplasia and of pancreatic agenesis of the pancreas from a defect occurring early in development, and be by mutations in transcription factors or signaling pathways. This has been demonstrated in a in the PDX1 gene was the likely of pancreatic agenesis have been several of insulin together with exocrine pancreatic in the in or years later It is these aplasia or hypoplasia of the pancreas, or are Later in development of acinar cells in deficient of pancreatic exocrine enzymes. The of endocrine and ductal elements that the defect occurs later in development, after differentiation of exocrine ductal and endocrine cells from progenitor Shwachman Diamond described in as a of pancreatic insufficiency and hypoplasia Shwachman Diamond has a wide of abnormalities affecting organ The of the are exocrine pancreatic and dysfunction Other abnormalities and and are Disorders of and function have been cystic is the common inherited of exocrine pancreatic dysfunction is with an of of an an mode of studies have the gene to the of that there a of gene mutations which in be for the manifestations of the present no common defect has been identified to explain the wide of a growth factor or transcription factor affecting cell differentiation and development explain the disease manifestations in the exocrine pancreas and in other from the pancreas acinar cell and The appears to be of the pancreas. studies of exocrine and secretion in further the observation that the pancreatic defect is to acinar there is of enzyme secretion but and and secretion is with contrast of the of a with Shwachman Diamond of the pancreas is with which to the of the liver and patients with present in with fat maldigestion due to pancreatic insufficiency pancreatic function with age in a of by years of age of patients have fat balance In the exocrine pancreatic function remains who become pancreatic sufficient of pancreatic enzyme secretion on pancreatic stimulation that patients with have defects in pancreatic acinar cell It is pancreatic function with age in have of pancreatic function status with which that genetic factors are of failure are the causes of and in may result in and there is a of and The of or has been to be as as This rare causes exocrine pancreatic abnormalities of the cystic and to be considerable with other syndromes of syndrome, and a of disease is to the various syndromes with may present with due to which is to the manifestations of patients with the few a pancreatic distinct from Pancreatic fibrosis and formation appear to be of the Johansson Blizzard This rare was first described by Johansson and Blizzard in from exocrine pancreatic other of the include aplasia or hypoplasia of the and Developmental as well as and are common abnormalities include growth and has been by and abnormalities are in Johansson Blizzard with Johansson Blizzard have evidence of pancreatic with pancreatic ducts and islet cells by tissue et the pathophysiologic basis of the after pancreatic stimulation in two was secretion of enzymes which in the pancreatic while the secretion of and and was Thus, the exocrine pancreatic that in appears to be due to failure of acinar It is not known patients with Johansson Blizzard an of pancreatic function with In our with two there has been no in exocrine pancreatic function status over a of Isolated of Specific Later in have been several of deficiencies of individual exocrine pancreatic enzymes. These are and the of disease has not been In the are to and in there may be of an which be for by the maturation of the pancreas. the specific of the enzyme the of disease is likely due to specific mutations in our knowledge of the enzyme deficiencies have been at the genetic of lipase was first described by in pancreatic stimulation studies in a year with to any lipase colipase was While the pancreatic lipase gene has been and to no mutations in the lipase gene have been patients with lipase as a lipase to on in the of bile et described who lipase and colipase in the colipase gene have not been described in a with colipase In two patients with have been described In these secretion of both lipase and colipase was less than two of while secretion of other pancreatic enzymes was normal. are several of an of pancreatic isoamylase which is thought to be in origin of these may be due to postnatal maturation of amylase than a failure of maturation pancreatic isoamylase has been in patients with who have fat this be in patients with isoamylase The is in several different but as and of was in a week with and failure to who enzyme in duodenal trypsin was to the duodenal of and but trypsin was not the later of which produces an clinical and pathophysiological the in the gene for trypsinogen, which is on patients to hereditary pancreatitis and in of the known mutations result in of is because of the different form of trypsin are under control of different mutations in mitochondrial first described in our understanding of the role of mitochondrial in certain diseases has While exocrine pancreatic is not a common disorders of mitochondrial function a wide of disorders which can affect organ The by which mutations of mitochondrial exocrine pancreatic dysfunction is not et described with failure and exocrine pancreatic they with a of and Bone showed of and with and In those who in early and pancreatic exocrine insufficiency was by pancreatic stimulation These studies showed defects of acinar and and acinar fibrosis and but without any or of the pancreas is not a of the of mitochondrial of mitochondrial which has been demonstrated in a wide range of involved is a in The of the phenotype in to be due to the of to mitochondrial In the organs pancreas and there is a of mitochondrial while less or cells have of mitochondrial the expression of disease appears to require a of mitochondrial The of the exocrine pancreatic disease in is or Johansson Blizzard the pancreas appears to have in but during postnatal there is exocrine pancreatic The exocrine pancreas has primarily due to role in large quantities of protein. of due to may the pancreas more to by the of and the of mitochondrial or factor into These mechanisms may loss of pancreatic a process which appears to be the of mitochondrial Pearsons Marrow Pancreas may present with Other involved organs may include the liver liver and and the endocrine pancreas A few who develop manifestations of syndrome, with and with have the mitochondrial as seen in cells in the several which exocrine pancreatic secretion in to the of nutrients in the and are the secretory which pancreatic and acinar cell as well as and bile process which the of pancreatic will pancreatic or exocrine Thus, any severe to the or or medical which or the pancreatic This process is probably but to be pancreatic dysfunction is in the if the is of pancreatic stimulation may pancreatic and pancreatic severe affecting the is likely to result in pancreatic The common is with and is more in In pancreatic dysfunction is and after a diet is of the pancreatic and from the to failure to exocrine pancreatic This has been demonstrated by evidence of enzyme output in to stimulation with a duodenal of while in pancreatic enzyme output has demonstrated hyperplasia of the and cells in the of patients with disease This that the pancreas can to but that due to the there is of pancreatic with pancreatic and fibrosis is to occur in It may become when symptoms of steatorrhea appropriate It is more common in with disease but there have been several in childhood It is that of the pancreas induces acinar cell and In as will be severe may to acinar cell and fibrosis are of any of a of a recent report that an of explain the well and severe et described an adult with by and This severe and was to have and cells in duodenal It was that of endocrine of in was by a rise in and the of cells in the duodenal The of the was to reflect the of OF an the of to in induces a of of other pancreatic such as and The gene has been to of and have pathophysiologic present with severe from after birth, with symptoms of and failure to described in is Although there have been a few subsequent in the there are no a molecular defect in the gene. 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