Nutrition in Pancreatic Diseases1
Amit Raina
Stephen J. D. O’Keefe
1Abbreviations: AP, acute pancreatitis; ARDS, acute respiratory distress syndrome; CCK, cholecystokinin; CP, chronic pancreatitis; CRP, C-reactive protein; EN, enteral nutrition; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; ICU, intensive care unit; IL, interleukin; MAP, mitogen- activated protein; MCP-1, monocyte chemotactic protein-1; MOFS, multiorgan failure syndrome; NG, nasogastric; NGJ, nasogastrojejunal; PEG, percutaneous endoscopic gastrostomy; PN, parenteral nutrition; PYY, peptide YY; RCT, randomized controlled trial; SAP, severe acute pancreatitis; SIRS, systemic i nflammatory response; TNF-α, tumor necrosis factor-α; TPN, total parenteral nutrition.
The pancreas, a retroperitoneal glandular organ, serves both endocrine and exocrine functions. The exocrine pancreas secretes at least 10 digestive enzymes, which are essential for the digestion and absorption of nutrients. The endocrine pancreas also secretes several hormones that play a key role in maintaining the metabolic homeostasis of the body. Three major pancreatic disorders discussed in this chapter are acute pancreatitis (AP), chronic pancreatitis (CP), and pancreatic cancer. These diseases, by altering the functioning of the pancreas, can all lead to major derangements in nutritional and metabolic homeostasis, although the underlying pathophysiologic mechanisms are different. This chapter at the outset briefly outlines the role pancreatic enzymes play in the absorption of nutrients and then focuses on pathophysiology, clinical presentation, assessment of nutritional status, and the principles of nutritional therapy in these three major pancreatic diseases.
PHYSIOLOGY OF PANCREATIC SECRETION
Knowledge of the mechanisms of pancreatic secretion is fundamental to the management of patients with pancreatic disease, especially AP. Pancreatic secretion is precisely orchestrated by the release of peptide hormones and neurotransmitters from the gastrointestinal (GI) tract after contact with ingested food. Traditionally, pancreatic stimulation is divided into three phases: the cephalic, gastric, and intestinal phases. The thought of food primes the pancreas to commence the process of zymogen aggregation and secretion. Next, the ingestion and swallowing of food, followed by expansion of the stomach wall, induce vagally mediated pancreatic secretion. Finally, the entry of food into the duodenum induces the most powerful stimulation, associated with acetylcholine and cholecystokinin (CCK) release by the mucosa and propelled by migrating motor complexes. In physiologic studies in healthy volunteers, a liquid formula diet was delivered to different regions of the upper GI tract, and the secretory response was greatest if a polymeric diet was infused into the duodenum (1) (Fig. 81.1). Further, the secretory response could be reduced significantly if the composition was changed to low-fat elemental. Additional studies showed that total parenteral nutrition (TPN) had no stimulatory effect, and that pancreatic rest could be maintained if the enteral feeding was delivered more than 40 cm past the ligament of Treitz (2). Finally, ileal delivery stimulated the ileal brake peptides peptide YY (PYY) and glucagonlike peptide-1 (GLP-1), resulting in inhibition of secretion.
DIGESTION OF NUTRIENTS
Without the pancreas, humans cannot survive because the gland is essential for the digestion of food. The normal pancreas secretes digestive enzymes, together
with water and electrolytes, predominantly bicarbonate, which enhances luminal enzyme function by neutralizing gastric acid. The most active enzymes are lipase, amylase, and trypsin. Amylase (α-amylase) hydrolyzes dietary starch into disaccharides and trisaccharides, which are then broken down by enzymes on the brush border to absorbable forms as glucose and maltose. Pancreatic lipase hydrolyzes fat molecules. Bile salts secreted by the liver aid the digestive action of lipase by coating and emulsifying large fat droplets into smaller droplets, thus increasing the overall surface area for lipase to work. Fat hydrolysis results in formation of monomers (two free fatty acids and one 2-monoacylglycerol), which are then absorbed downstream into the lymphatic system by the lacteals. The main proteolytic enzyme, trypsin, is synthesized in the pancreas in an inactive form, as trypsinogen. Following a meal, when the pancreas is stimulated by CCK and cholinergic reflexes, trypsinogen is released from zymogen stores in the acinar cells and is secreted into the duodenum. Once in the small intestine, the intestinal enzyme enteropeptidase activates it into trypsin by proteolytic cleavage. Trypsins then, by the process of autocatalysis, activate more trypsinogen molecules. Once activated, the trypsin breaks down food proteins and peptides (proteins broken down to peptides in the stomach by pepsin) to amino acids, which are then absorbed by active transport systems.
with water and electrolytes, predominantly bicarbonate, which enhances luminal enzyme function by neutralizing gastric acid. The most active enzymes are lipase, amylase, and trypsin. Amylase (α-amylase) hydrolyzes dietary starch into disaccharides and trisaccharides, which are then broken down by enzymes on the brush border to absorbable forms as glucose and maltose. Pancreatic lipase hydrolyzes fat molecules. Bile salts secreted by the liver aid the digestive action of lipase by coating and emulsifying large fat droplets into smaller droplets, thus increasing the overall surface area for lipase to work. Fat hydrolysis results in formation of monomers (two free fatty acids and one 2-monoacylglycerol), which are then absorbed downstream into the lymphatic system by the lacteals. The main proteolytic enzyme, trypsin, is synthesized in the pancreas in an inactive form, as trypsinogen. Following a meal, when the pancreas is stimulated by CCK and cholinergic reflexes, trypsinogen is released from zymogen stores in the acinar cells and is secreted into the duodenum. Once in the small intestine, the intestinal enzyme enteropeptidase activates it into trypsin by proteolytic cleavage. Trypsins then, by the process of autocatalysis, activate more trypsinogen molecules. Once activated, the trypsin breaks down food proteins and peptides (proteins broken down to peptides in the stomach by pepsin) to amino acids, which are then absorbed by active transport systems.
 Fig. 81.1. Amylase secretion in response to enteral and parenteral nutrition. Relative amylase secretory responses to enteral and parenteral feeding, illustrating no difference between oral and duodenal feeding of a complex diet, an intermediate response to duodena elemental diet feeding, and no stimulatory effect of intravenous feeding compared with placebo saline. |
ACUTE PANCREATITIS
Demographic and Clinical Presentation
AP is an acute inflammatory process of the pancreas that may involve the peripancreatic tissue and even remote organs. In the United States, about 75% to 80% cases of AP are attributed to alcohol abuse or gallstones (3, 4, 5). Other factors associated with AP include medications, trauma, infections, and metabolic causes (6). Biliary pancreatitis AP is more common in female patients, and alcoholic AP is more common in male patients (7). Clinical presentation typically consists of severe upper abdominal pain, nausea, and vomiting. Laboratory testing reveals elevated lipase and amylase in the bloodstream.
About 75% of cases of AP in patients admitted to hospitals are mild (edematous and interstitial pancreatitis) and follow a benign, self-limited course, with discharge home by day 4 (8). The remaining 25% cases, called severe AP (SAP), progress with the development of a profound systemic inflammatory response (SIRS), commonly associated with pancreatic gland necrosis, acute peripancreatic fluid collections, and multiorgan failure syndrome (MOFS). All the mortality (≤50%) from the condition is associated with these complications. The inflamed and swollen pancreatic gland may itself or by development of acute fluid collections compress the stomach and duodenum. The result is obstruction to the outflow from the stomach, and patients present clinically with nausea and vomiting. The SIRS is usually associated with ileus and increased mucosal permeability. These critically ill patients often spend weeks in intensive care units (ICUs) and frequently need surgery for pancreatic necrosis and infections. However, early surgery is associated with elevated mortality rates because it is extremely difficult, and every effort should be made to manage patients conservatively for more than 4 weeks with enteral nutrition (EN) until the area of pancreatic necrosis or fluid collection becomes walled off, thus allowing a more definitive approach.
Pathophysiology
Basic understanding of the pathophysiology of AP is essential to comprehend the principles of nutritional therapy in these patients. Figure 81.2 helps illustrate some of what is known to happen in the evolution of the severe disease. AP is initiated by premature activation of trypsinogen within the acinar cells. Once trypsinogen, which normally is stored in zymogens within the acinar cells in an inactive form, is stimulated within the acinar cells, it autoactivates
other trypsinogen molecules and autodigestion of the cell (9, 10). Intracellular injury results in generation of a cascade of proinflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-8, IL-15, monocyte chemotactic protein-1 (MCP-1), and IL-18 (11, 12, 13, 14, 15, 16, 17) via activation of periacinar myofibrocytic nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein (MAP) kinase (18). The intense inflammatory response results in arterial constriction with resultant apoptosis, which, in an extreme situation, may lead to pancreatic necrosis. If the inflammation were contained within the pancreatic bed, the disease process would be far less serious. Unfortunately, the cytokines are released into the circulation, and a secondary response commencing approximately 48 hours later leads to the generation of prostaglandin-2, thromboxane, leukotriene B4, and oxygen-derived free radicals within the bronchial and intestinal mucosa that produce cytotoxic lung injury (19, 20).
other trypsinogen molecules and autodigestion of the cell (9, 10). Intracellular injury results in generation of a cascade of proinflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-8, IL-15, monocyte chemotactic protein-1 (MCP-1), and IL-18 (11, 12, 13, 14, 15, 16, 17) via activation of periacinar myofibrocytic nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein (MAP) kinase (18). The intense inflammatory response results in arterial constriction with resultant apoptosis, which, in an extreme situation, may lead to pancreatic necrosis. If the inflammation were contained within the pancreatic bed, the disease process would be far less serious. Unfortunately, the cytokines are released into the circulation, and a secondary response commencing approximately 48 hours later leads to the generation of prostaglandin-2, thromboxane, leukotriene B4, and oxygen-derived free radicals within the bronchial and intestinal mucosa that produce cytotoxic lung injury (19, 20).
 Fig. 81.2. Generation of the systemic inflammatory response (SIRS) and acute respiratory distress syndrome (ARDS) by acute pancreatitis and sites where enteral feeding may favorably influence these responses. ICAM-1, intercellular adhesion molecule 1; Ig, immunoglobulin; IL, interleukin; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; TNF-α, tumor necrosis factor-α. |
Substantial evidence indicates that the gut plays a pivotal role in the systemic response. Increased mucosal permeability is characteristic of AP, and the combination of mucosal injury secondary to ischemia and antegrade colonization of the stagnant bowel (ileus) both amplifies the proinflammatory cytokine response and liberates toxic bacterial products into the bloodstream (21, 22). Later in the disease, the leaky mucosa predisposes to bacterial translocation, thus accounting for the observation that most infective complications are caused by gut-derived organisms (21). The situation is compounded further by the release of proteolytic enzymes such as trypsin, elastase, phospholipase, and caspase-l into the circulation, which leads to amplification of cell injury within the lung (second hit) that induces severe lung injury and acute respiratory distress syndrome (ARDS). The systemic injury is accompanied by massive outpouring of vascular fluids, which exacerbate the pulmonary dysfunction and lead to edema and prerenal failure. These complications of ARDS, acute renal failure and intestinal failure, account for nearly all the mortality associated with the disease, which can approach 30% to 50%, in patients with severe necrotizing pancreatitis.
Understanding the pathologic response to AP makes it clear that in the early stages of AP, pancreatic stimulation should be avoided because it can lead to production and activation of more proteolytic enzymes and can thereby exacerbate the pancreatic inflammation. Once established, AP complicated by MOFS represents one of the most catabolic diseases seen in ICUs, and protein deficiency can occur within the first week unless nutritional support is commenced. A study showed that early EN (i.e., ≤5 days of the onset of symptoms) can prevent some of the progression of these events and thus improve outcome (23). Patients with SAP often spend weeks in the ICU on ventilators and can suffer severe protein calorie malnutrition in absence of timely nutritional therapy.
Predicting Severity of Pancreatitis and Nutritional Implications
Some patients with SAP present with MOFS and profound SIRS at the outset. Others present with mild AP and then go on to exhibit features of SAP over the next few days. Predicting which of these patients will develop a severe course should help determine the urgency for intervention with specialized nutritional support. Although clinical judgment remains the easiest and most commonly used tool, it often underpredicts the severity of pancreatitis (24). Among the laboratory studies, lipase and amylase are most widely used. Although elevated amylase and lipase are used to diagnose AP, there is no correlation between the severity of disease and elevation of these enzymes. Daily monitoring of amylase and lipase does not help in determining the prognosis or the course of the disease (25).
Various scoring systems (e.g., Balthazar Score, Acute Physiology and Chronic Health Evaluation [APACHE II] score, Ranson score [Tables 81.1 and Table 81.2]) have been employed over the years to predict severity of pancreatitis (26, 27, 28, 29, 30, 31). Some scoring tests can be performed on the day of admission, and some need 48 to 72 hours to complete. None of these scoring systems is accurate consistently, but these systems are somewhat better than clinical judgment (32). This situation has led to the search for a simpler measurement.
Elevated serum creatinine concentration (>1.8 g/dL) was suggested by Muddana et al (33) to be highly predictive of development of pancreatic necrosis, but a subsequent study by Lankish et al (34) did not find similar association. Wu et al (35) found the admission hematocrit (e.g., hematocrit >44 during the first 48 hours) and blood urea nitrogen (BUN) levels to be predictive of progression to severe complicated disease. Other laboratory blood tests, such as C-reactive protein (CRP), polymorphonuclear elastase, human pancreas-specific protein/procarboxypeptidase B, α2-macroglobulin, and serum macrophage migration inhibitory factor, have been researched as markers for development of necrosis, but only CRP is clinically available at present.
TABLE 81.1 RANSON SCORE (INCLUDES EQUALLY [1 POINT] WEIGHTED VARIABLES)a | ||||||||||||||||||||||||||||||
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TABLE 81.2 COMPUTED TOMOGRAPHY SEVERITY SCORE (BALTHAZAR SCORE)a | |||||||||||||||||||||||||||||||||||||||
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Among the imaging studies, bolus-contrasted (pancreatitis protocol) computed tomography (CT) of the pancreas can accurately differentiate interstitial from necrotizing pancreatitis. This imaging test, however, is not possible to obtain in patients who develop renal insufficiency as a complication of pancreatitis. Studies have shown that the persistence of the SIRS (with two or more of the following features: temperature >38°C or <36°C; heart rate >90 beats/minute; respiratory rate >20 breaths/minute; (4) white blood cell count <4000 cells/mm3 or > 12,000/mm3; or partial pressure of carbon dioxide <32 mm Hg) or organ failure after initial resuscitation is the strongest predictor of mortality (29, 30).
Nutritional Therapy
Pancreatic rest, as mentioned earlier, is a critical step in the initial management of all patients with AP. The need for nutritional therapy in these patients is determined by the severity of their disease.
Mild Acute Pancreatitis
In the mild form of AP, management is mainly supportive. Management strategy includes pain control, aggressive hydration with intravenous fluids, and nothing by mouth
for pancreatic rest for 48 hours. In most cases, the pain improves, nausea and vomiting resolve, serum lipase and amylase levels drop, the patient feels better, and oral intake can be retested. Traditionally, patients have been started on a clear liquid diet and then advanced to a low-fat soft diet. More recent randomized controlled trials (RCTs) have, however, reported that starting these patients on a low-fat soft diet is as safe as a clear liquid diet, with varying effect on length of hospital stay (36, 37, 38). These findings suggest that after 2 to 3 days of pancreatic rest, patients can be tried on a low-fat soft diet with close monitoring for abdominal pain, nausea, vomiting, or any other complication. Once patients exhibit tolerance to this diet, they can be advanced to a regular diet over next 3 to 4 days.
for pancreatic rest for 48 hours. In most cases, the pain improves, nausea and vomiting resolve, serum lipase and amylase levels drop, the patient feels better, and oral intake can be retested. Traditionally, patients have been started on a clear liquid diet and then advanced to a low-fat soft diet. More recent randomized controlled trials (RCTs) have, however, reported that starting these patients on a low-fat soft diet is as safe as a clear liquid diet, with varying effect on length of hospital stay (36, 37, 38). These findings suggest that after 2 to 3 days of pancreatic rest, patients can be tried on a low-fat soft diet with close monitoring for abdominal pain, nausea, vomiting, or any other complication. Once patients exhibit tolerance to this diet, they can be advanced to a regular diet over next 3 to 4 days.
Severe Acute Pancreatitis
As discussed earlier, patients with SAP represent a very sick group of patients who often go on to develop complications such as acute fluid collections, pseudocyst collections, pancreatic necrosis, and infection of fluid collection or MOSF. Mortality rates vary between 5% and 50%, depending on access to modern ICU management. Aggressive management in the ICU, especially aggressive hydration with several liters intravenous fluids to correct hypotension and maintain urine output, is crucial in initial management to prevent progression to organ failure. Patients commonly have nausea and vomiting, and eating exacerbates the pain. Consequently, they can be effective fed only by the intravenous route or by jejunal feeding combined with gastric decompression.
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