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Title: Fat digestion in exocrine pancreatic insufficiency

Olle Hernell
Contemporary Pediatrics, Gastroenterology, Hepatology and Child Feeding
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Fat digestion in exocrine pancreatic insufficiency

A seemingly ever-increasing demand for energy is one of the major characteristics of the dynamie and vulne-rable perinatal period. Birth represents a radical transition from a carbohydrate to a fat dominated energy supply. Fat provides about half of the energy content in human milkand modern infant formulas. Energy-rich long-chain triglycerides (TG, triacylglycerols) account for at least 98% of the lipids in human milk. The balance is madę up by phospholipids (PL), cholesterol (Ch), fat soluble vita-mins (A, D, E and K), and other minor constituents. Hence, infants depend on efficient mechanisms for assi-milation of dietary lipids. However, newborn infants, par-ticularly preterm infants, have, for physiologic reasons, relative insufficient exocrine pancreatic and hepatic func-tions, resulting in Iow postprandial intraluminal concentra-tions of colipase-dependent pancreatic lipase, pancreatic bile salt-stimulated lipase (BSSL, cholesterol esterase) and bile salt concentrations, limiting not only digestion of TG, cholesteryl esters (ChE) and fat soluble vitamin esters to absorbable products, but also solubilisation of the products into mixed micelles from which absorption oceurs. Nonetheless, breast-fed infants do have surpri-singly efficient fat digestion and absorption. The energy-rich milk TG are digested by concerted action of gastric lipase, the activity of which is relatively high also in newborns, colipase-dependent lipase and BSSL. In some species the latter enzyme is secreted not only from the panereas but also from the lactating mam-mary gland and is thus a constituent of milk. In fact, in the breast-fed newborn milk isthe major source of BSSL. In contrast to gastric lipase and colipase-dependent lipase BSSL is a non-specific lipase with capacity to hy-drolyze not only TG and diglyceride (DG), but also mono-glyceride (MG), which means that it can by itself mediate complete digestion of each TG to three free fatty acids (FA) and one molecule of free glycerol. Whether that is important or not in the in vivo situation is an unsolved que-stion. Moreover, milk BSSL contributes to efficient use of lysophospholipids (lyso-PL), Ch- and fat soluble vi-tamin esters. For effective hydrolysis, dietary fat must be dispersed to form stable emulsion particles. It is at the surface of such emulsion particles where lipasesact. Emulsification is achieved with membranę lipids, denatured proteins and polysaccharides acting as emulsifiers and forming a mo-nomolecular layer enveloping the hydrofobie core of the emulsion particle. PL and Ch, in typical dietary propor-tions, are excellent emulsifiers with Iow monomeric so-lubilities in oil or in water, but excellent oil/water (O/W) interfacial solubilities. TG and DG will form the core of the emulsion particle together with ChE and other non-polar lipids. Emulsification will oceur during preparation of the food and by mechanical mixing in słomach con-tents. In milk the fat is present as an emulsion, the milk fat globules, already when secreted from the mammary gland. When the dietary fat enters the duodenum a minor fraction of TG has been digested to DG and FA by gastric lipase operating in gastric contents. During fat digestion polar products of lipolysis first locate at the O/W inter-face, i.e. at the surface of the milk fat globule or any other emulsion particle composed of the dietary lipids. Also bile lipids adsorb to the interface and eventually the surface pressure inereases and surplus of surface materiał "bud--off" as multilamellar liquid crystals that are then transfor-med by bile salts to form unilamellar vesicles with a hy-drated radii (Rh) of 20 to 60 nm. Subsequent dissolution of unilamellar vesicles by bile salt micelles saturate the latter with mixed digestive lipid products (mixed micelles) which are smaller particles with Rh less than 4.0 nm. In intestinal contents unilamellar vesicles and micelles co-exist. Lipid absorption from micelles is fast while it is be-lieved that absorption from vesicles would be slow. However, under conditions of Iow intraluminal bile salt concentration absorption from vesicles may become important. In complete absence of bile salts lipid absorption takes place all along the smali intestine with an efficiency of up to 75%, supporting that vesicles and liquid-crystal-line phases may indeed be important in facilitating fat absorption. This may be particularly important in neonates because of a high lipid intake at the same time as the intraluminal bile salt concentrations may be Iow. Under such circumstances hydrolysis of MG by BSSL to yield FA and glycerol as end products of TG digestion rather than MG and FA could be an advantage. In absence of bile salts, FA, as vesicles, but not MG seem to be com-pletely absorbed. In Western societies cystic fibrosis (CF), an autosomal recessive disorder, is the most common cause of exo-crine pancreatic insufficiency in infants and children. Cloning of the CF gene, coding for the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, the function of which is to regulate transmembrane chlo-ride ion transport, has increased the understanding of the pathophysiology of the disease. Defect chloride and wa-tertransepithelial transport results in mucus with increased viscosity in various organs. Among the organs com-monly affected, the lungs and exocrine pancreas are the two most frequently involved in serious symptoms at young age. The exocrine pancreatic insufficiency results in fat malabsorption due to impaired intestinal TG digestion resulting from reduced pancreatic output of coli-pase-dependent lipase and BSSL. Impaired TG digestion is partly compensated for by gastric lipase, the activity of which is favored by the morę acidic environment of pro-ximal duodenum and milk BSSL if the infant is breast-fed. With respect to digestion of ChE and fat soluble vitamin esters impaired function of pancreatic BSSL is not compensated for after the infant is weaned from the breast. CF patients also have impaired absorption of long--chain fatty acids. The reason for this is not entirely under-stood. However, at advanced disease impaired hepatic function may contribute to reduced bile salt secretion and bile acid pool size. Low intraluminal pH may result in pre-cipitation of bile salts, reducing the intraluminal micellar capacity for solubilisation of lipolysis products. Also impaired intestinal mucosal function may contribute to impaired absorption. It is possible that also CF patients to some extent benefit from product absorption from unila-mellarvesicles. Standard treatment of CF patients aim at achieving a good nutritional status because this is important for their well-being and long-term survival. Typical recommen-dations include a daily energy intake exceeding RDA by 20 to 50%, fat accounting for 40% of the energy, and increased intake of other nutrients, e.g. fat soluble vita-mins; a situation not too different from that of the newborn infants. The most effective treatment of pancreatic insufficiency is to restore lipase activity, which is accom-plished by orał administration of pancreatic enzymes, i.e. crude extracts of porcine pancreas. In spite of high dosage of the most modern formulations many patients never achieve normal fat absorption. This suggests that either the digestive capacity (lipolytic activity) is not fully restored despite dosing causing serious side effects, or that the remaining fat malabsorption does not result from impaired digestion but from impaired absorption. Interestingly, a common characteristic of all pancreatic enzyme formulations on the market is that even when the colipase-dependent lipase activity is high, the BSSL activity is low. Hence, part of the problem could be insufficient BSSLsubstitution. In fact, BSSL could be an ideał enzyme for supplementation therapy under con-ditions of impaired fat digestion due to pancreatic insufficiency, be it for physiological or pathological reasons. Being a constituent of human milk, BSSL is designed to be administered by the orał route, to be stable during passage through the słomach and to be activated and operate first when mixed with bile in duodenal contents. Furthermore, the enzyme is non-specific with the potential to hydrolyze by itself most dietary lipids. Successful production in mammalian celi lines and transgenic animals of recombinant human BSSL with indistinguishable functional properties from native BSSL has now made it possible to test this hypothesis.