Effects of Parenteral Nutrition on the Exocrine Pancreas in Response to Cholecystokinin

By Fan, Bo-Guang

ABSTRACT. Background: Clinical and experimental data have revealed that parenteral nutrition (PN) can lead to hypotrophy and dysfunction in the morphology and physiology of the pancreas. These adverse alterations appear to be related to many different factors. One important factor is the absence of a gastrointestinal hormone, such as cholecystokinin, which is the most important stimulator for the integrity of the pancreas. The level of cholecystokinin is decreased during absent enteral feeding, and the stimulatory effect of cholecystokinin is significantly reduced during PN. Methods: Original and review articles, editorials, and case reports published primarily in English and listed in MEDLINE/ISI up to September 2006 or identified by a manual search have been reviewed in an attempt to provide a comprehensive overview of the effects of PN on the exocrine pancreas in response to cholecystokinin. Results: When hypercholecystokininemia, produced by endogenous and exogenous procedures, is present during PN, the morphology and functions of the pancreas are still unable to be fully reversed. Conclusions: Other growth factors besides cholecystokinin are probably involved in the pancreatic regulation, and enteral feeding seems to be important for the full expression of the trophic effects of cholecystokinin on the pancreas. (Journal of Parenteral and Enteral Nutrition 32:57-62, 2008) The development of effective clinical techniques for parenteral nutrition (PN) has greatly improved the management of patients with many different diseases since the first description by Dudrick et al.1 The most important benefit of PN is that fistulas of the alimentary tract close spontaneously in the vast majority of patients and possibly faster and with a lower mortality rate than that which occurs after operative attempts to manage such fistulas. More specifically, attacks of acute or chronic pancreatitis with and without pancreatic fistulas have been successfully managed by the conservative regimen of total bowel rest and PN.2,3 The mechanism responsible for the increased healing rate seems to be a decrease in the fluid output from fistulas, related to a decrease in digestive secretion.

On the other hand, the decreased secretion caused by PN is probably its adverse effect. It has been well established that PN induces atrophy of the gastrointestinal (GI) mucosa and increases intestinal permeability and bacterial translocation. Since the first study of the pancreatic alterations in physiology and morphology during PN treatment reported in the 1970s,4 more solid evidence that PN negatively affects the pancreas has been reported. It is demonstrated that the absence of food in the GI tract leads to severe functional and structural changes in the pancreas, featured by a decrease in pancreatic protein, weight, and enzyme level. These changes have been shown to be due to a lack of GI hormonal stimuli.

Many GI hormones are involved in the regulation of the pancreas, and the influence of those GI hormones on the pancreas during PN was studied, with various conclusions. This article reviews the literature and summarizes the current understanding of the exocrine pancreas in response to cholecystokinin (CCK) during PN.

Effects of PN on the GI System

The GI system may be the first system affected by the adverse effects of PN, which results in subsequent different atrophic alterations in many other systems and organs, including the pancreas.5,6 It has been shown that PN or the absence of food in the GI tract can result in atrophy of GI mucosa, gut barrier dysfunction, and increases of GI mucosal permeability and bacterial translocation.3,7-9 The atrophic and functional changes resulting from PN seem to be due to the absence of hormonal stimuli because the administration of CCK prevents intestinal hypoplasia.10,11 This could be a direct effect of the peptides, but it is most likely mediated by stimulation of the secretion of bile, pancreatic enzymes, and bicarbonate.11 Along with atrophy, PN induces hypomotility of the intestine12 and gallbladder, and cholestasis is a problem often seen during long-term PN.13,14 The cholestasis may be secondary to inadequate stimulation of the gallbladder and flow of bile by CCK, which normally induces gallbladder contraction and increases intrahepatic bile flow.15-18 Furthermore, the presence of bile in the duodenum is important for the regulation of plasma CCK levels.19 During PN, stimulation of bile in the GI tract is absent.

Effects of CCK on the Exocrine Pancreas

CCK is secreted from cells in the duodenum and upper small intestine.20,21 It stimulates pancreatic secretion22,23 and induces growth of the pancreas.24-26 CCK also stimulates the release of several pancreatic hormones such as insulin,27 glucagons, somatostatin,28 and polypeptide.29

CCK is released into the circulation upon luminal stimulation of the intestine by factors such as protein, fatty acids, or fat.30 After its release, CCK stimulates pancreatic secretion and gallbladder contraction.31 The release of CCK is controlled by a negative-feedback mechanism.19,32 CCK-A receptors occur predominantly at the peripheral level, where they are responsible for the effects of CCK on digestion: biliary smooth muscle contraction, pancreatic enzyme secretion, and trophic effects on the pancreas.

The effects of CCK on the exocrine pancreas have been studied both with endogenously and exogenously induced hypercholecystokininemia (hyperCCKemia), which resulted in greatly trophic changes in the pancreas.25,33 This trophic effect was mediated via CCK-A receptors that existed in the pancreas34,35 and was further conformed by using blockade of endogenous CCK which was followed by the pancreatic atrophy.24,26

Effects of PN on the Exocrine Pancreas

The regulation of the exocrine pancreas is involved in a number of hormonal and neural factors. The nutrition components in the intestinal lumen play a major role in this regulation. Therefore, it would be expected that PN and the concomitant absence of food passage through the GI system induce changes in the pancreatic morphology and function.

During prolonged fasting, the decrease in pancreatic weight and secretion is probably due to lack of nutrients, whereas during PN, there is no lack of nutrients but the nutrients do not pass through the GI tract. Gut hormonal release is dependent on the chemical and physical stimulus exerted by food in the GI tract,36 and PN induces changes in the serum levels of GI hormones.37 This has been explained by the fact that the negative influences of PN on the pancreas can be reversed by endogenous hyperCCKemia induced by pancreaticobiliary diversion, ,38 or exogenous hyperCCKemia induced by infusion of CCK.7 Thus, atrophy and dysfunction of the exocrine pancreas during PN are not due to the lack of nutrients in the circulation but rather to lack of stimulation by hormones.

It has been suggested that different nutrients in the PN solution have their own effects on the pancreas. Amino acids reduce the amylase level via a stimulation of glucagon secretion produced by pancreatic endocrine alpha-cells, glucose stimulates the amylase synthesis,39,40 and fat suppresses insulin release.41,42

DISCUSSION

The effect of PN on pancreatic function was first described in 19774 and demonstrated that pancreatic juice secretion was decreased after using PN. The adverse effects on the pancreatic morphology and physiology have been increasingly reported since then; all studies have shown that PN results in an atrophy of the pancreatic histology and a dysfunction of the pancreatic physiology,37,43,44 featured by a decrease in the pancreatic weight and enzyme secretion or synthesis.

The exploration of the mechanisms behind those atrophic alterations caused by PN has demonstrated that the adverse effects are mainly due to the absence of stimuli resulting from the ingestion and presence of food within the GI tract,7,37,43,44 although other mechanisms, such as neural, physical, and chemical stimulations, are also involved. It has been shown that morphologic alterations of the pancreas during PN are correlated with a significant decrease in serum levels of CCK,37,45,46 which are known positively to influence the exocrine pancreas.

The chemical and physical stimuli exerted on the pancreas during the course of digestion are the most important for pancreatic integrity.44,47 Their stimulatory effects are mediated mainly by neural and hormonal pathways produced by passage within the GI tract.36,44,48-50 Several peptide hormones regulate the pancreatic enzyme secretion and pancreatic growth. The hormone that stimulates the growth of a normal pancreas is mainly CCK.49,51 The role of cholinergic mechanisms in regulating exocrine secretion has been well described,52 and several hormones, including CCK, act through a cholinergic vagal pathway.53,54 However, during PN there is no stimulus within the GI tract, and hormonal and neuronal influences induced by stimulation from the GI tract are greatly impaired.

Long-term PN reduces the pancreatic weight, along with a decrease in the content of pancreatic protein, DNA, and amylase.47,55 Atrophic effects shown during PN can also be induced by starvation, which is followed by pancreatic hypotrophy and changes in the synthesis of pancreatic enzymes.56 One of the mechanisms of the atrophic alterations seen during PN is the absence of CCK because the atrophy induced by starvation can be reduced and even reversed by hyperCCKemia.38,57 Effects of HyperCCKemia on the Pancreas During PN

As stated above, CCK is the most important hormone for the maintenance of normal pancreatic growth and function,58 and CCK reverses PN-induced pancreatic atrophy. In the meantime, it has also been shown that the concentration of CCK and the number of cells secreting CCK are reduced during PN.36,38

Theoretically, according to these findings, the atrophic changes resulted from PN could easily be prevented by a complementary infusion of CCK. However, many of the results obtained from these studies differ from these expectations. The findings from the observation of pancreatic alterations in response to hyperCCKemia during PN have shown that severalfold CCK concentrations are elevated and that the hyperCCKemia causes an obvious hyperplasic response in the pancreas of both orally and parenterally fed rats.25,57,59 However, in a comparison to the PN-treated and the freely fed rats, significant responses were obtained in the rats freely fed with CCK but not seen in the PN-treated rats. In other words, the stimulatory effects of hyperCCKemia are impaired after PN, and CCK administration cannot totally reverse the pancreatic atrophy resulting from PN. It is therefore inferred that some stimulatory response to CCK remains, whereas its effects on the pancreatic cell proliferation vanish when enteral feeding is missing. In addition, in the absence of other cofactors released during eating and passage of food through the GI tract, the CCK receptors may be down-regulated.16,55

Therefore, although CCK is important in maintaining pancreatic integrity, the trophic effect of CCK is reduced during PN. This indicates the importance of other factors that may be compromised during the absence of food in the GI tract. However, how CCK interacts with “other factors” and their further mechanisms is worth exploration.

Effects of IV Nutrients on the Exocrine Pancreas

Even though PN causes pancreatic hypotrophy and dysfunction, IV fat, glucose, and amino acids as main nutrients in the PN solution may play different stimulatory or inhibitory effects on the pancreas. This indicates it may be of clinical importance for clinicians to choose special nutrients as therapeutic agents.

It has been demonstrated that fat has inhibitory effects on the exocrine pancreas, characterized by a decrease in amylase level.60 These changes may be explained by 2 different mechanisms: (a) IV fat does not stimulate the release of CCK or other gut hormones that increase the synthesis and release of amylase61; and (b) the fat emulsion elevates the levels of free fatty acid that indirectly suppress insulin release via an inhibitory effect on beta-cell function.41,42 Subsequently, the low concentration of insulin suppresses the synthesis of the pancreatic enzymes.62,63

Data on the role of glucose in the exocrine pancreas are controversial. Recent studies,39,40 however, have shown that a higher amylase level is obtained with a higher concentration of glucose in circulation, suggesting that hypertonic glucose has a stimulatory effect on the exocrine pancreas. The mechanism behind the stimulatory effect is most likely due to the effect of indirect stimulation of the exocrine pancreas by insulin64 or gut hormone (such as CCK) stimulating the synthesis of amylase.18,65 The present understanding is that the endocrine pancreas can affect the exocrine pancreas,66 and there is a close association between the endocrine pancreas and the duct system.67 Glucose is an important stimulant of the endocrine pancreas, and insulin has been shown to have a fundamental role in the synthesis of pancreatic amylase.67 Moreover, CCK releases and stimulates insulin secretion when a high concentration of glucose is present.

Intestinal perfusion with amino acids results in a release of CCK and subsequent stimulation of the secretion from the exocrine pancreas. In the state of PN, however, the possible stimulatory effect of IV amino acids on the exocrine pancreas is less apparent. It has been proven that pancreatic size and pancreatic protein are dependent on IV amino acids.39 This further suggests that amino acids as a source of protein are needed to maintain pancreatic protein during PN.39,63 In addition, IV amino acids are a potent stimulant of pancreatic alpha-cells producing glucagon67; glucagon inhibits the exocrine pancreas.68,69 Therefore, the reduced amylase level obtained by an infusion of amino acids may be affected by a stimulation of the secretion of glucagon. On the other hand, amino acids stimulate significant signaling in beta-cells and stimulate beta-cell growth and proliferation. Specifically, a prominent role for glutamine was identified in mediating amino acid stimulation of insulin secretion.70-73 Glutamine was demonstrated to play a signaling role in insulin secretion from the beta-cell, which involves 2-ketoglutarate73 and other 2-keto acids,70,73 but the precise mechanism remains to be determined.

The Clinical Importance of Atrophic Alterations and Complications Caused by PN

As discussed above in the present review, PN induces atrophy of the pancreas and GI mucosa, damages gut barrier function, increases mucosal permeability and bacterial translocation,7-9 and even impairs glucose tolerance.47 On the other hand, those atrophic alterations caused by PN may be beneficial and are of importance in clinical practice. Potential benefits include the reduction of secretion through enterocutaneous and pancreatic fistulas and the decrease of synthesis and secretion of enzymes in the pancreas, which subsequently accelerate fistula closure and pancreatitis management. The mechanism responsible for this benefit actually is the combined decrease in gastric, biliary, intestinal, and pancreatic secretions. Therefore, those atrophic alterations in the pancreas and GI mucosa are not only the adverse effects resulted from PN but are of clinical importance.

Refeeding syndromes are likely to arise with PN.74 Long-term starvation is accompanied by adaptive changes and micronutrient deficiencies. Organ function may be impaired and starved individuals may have poor cardiac reserve and an inability to excrete an excess salt and water load. Overrapid or unbalanced nutrition support can precipitate micronutrient deficiencies and dangerous changes in fluid and electrolyte balance.74 All patients, therefore, require close monitoring, and those at particular risk should have restricted energy provision during the early phase of nutrition support.75

Bacterial translocation associated with PN may be the cause of sepsis resulting in multisystem organ failure in critically ill patients. It was hypothesized that PN caused intestinal atrophy or barrier dysfunction and increased bacterial translocation and promoted sepsis.7-9 A growing number of studies have suggested that feeding nutrients through the GI tract prevents this sepsis and results in less morbidity and mortality than does PN, and that enteral nutrition (EN) is superior to PN in almost all circumstances.76 Therefore, by promoting gut function and preventing the translocation of intestinal bacteria, EN has obtained much more favor than PN in recent years.

However, a number of studies have demonstrated that glutamine improves small intestine mucosal thickness,77-80 limits intestinal permeability,81 and reduces gut atrophy.81,82 A recent clinical study has shown that PN supplemented with glutamine in intensive care unit patients is associated with a reduced rate of infectious complications and better metabolic tolerance.83 Although further studies and more trials are needed to create a clearer picture of the role of glutamine with PN in the supportive care of patients, this result provides a great potential for positive clinical outcomes in complex PN.

SUMMARY

Enteral delivery of food arouses a concert of different growth factors, gut peptides, and neural mechanisms, which work together in the absorption and use of nutrients. The lack of food passage in the GI tract during PN puts the digestive organs at rest and results in the atrophy and dysfunction of the pancreas. During such a period, the effects of peptides may be examined independently of other substances whose release is stimulated by food passage.

During PN, hypotrophy of the exocrine pancreas is seen, along with a decrease in the amylase level. The mechanisms behind the atrophic changes are due to the low level of CCK because CCK reverses the hypotrophy and atrophy of the pancreas. However, hyperCCKemia is unable to completely prevent the hypoplastic changes. The trophic effect of CCK is greatly reduced, and CCK cannot reach its full potential of trophic effect during PN. Therefore, other growth factors than CCK, induced during food passage in the GI tract, are involved in the pancreatic regulation, and enteral feeding is important for the maintenance of normal pancreatic integrity.

The nutrients in a PN solution have different stimulatory and inhibitory effects on the pancreas. These effects may act indirectly or through the interaction of the endocrine and exocrine pancreas.

The atrophic pancreas or lack of pancreatic exocrine secretion during PN is of clinical importance; these alterations accelerate the pancreatic fistula closure and management of pancreatitis. Glutamine was shown to improve small intestine mucosal thickness and insulin secretion, reduce infectious complications, and improve metabolic tolerance in clinical management with PN. More evidence is needed in exploring whether glutamine prevents those adverse alterations in exocrine pancreas resulting from PN.

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Bo-Guang Fan, MD, PhD

From the Centre for Gastrointestinal Disease, Taizhou Hospital, Zhejiang, China

Received for publication May 30, 2006.

Accepted for publication July 5, 2007.

Correspondence: Bo-Guang Fan, MD, PhD, Centre for Gastrointestinal Disease, Taizhou Hospital, Taizhou 317000, Zhejiang, China. Electronic mail may be sent to fanboguang@gmail.com.

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