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Pancreatic Enzyme Replacement Therapy During Pancreatic Insufficiency Amy J. Berry Nutr Clin Pract 2014 29: 312 originally published online 31 March 2014 DOI: 10.1177/0884533614527773 The online version of this article can be found at: http://ncp.sagepub.com/content/29/3/312

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NCPXXX10.1177/0884533614527773Nutrition in Clinical PracticeBerry

Invited Review

Pancreatic Enzyme Replacement Therapy During Pancreatic Insufficiency

Nutrition in Clinical Practice Volume 29 Number 3 June 2014 312­–321 © 2014 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533614527773 ncp.sagepub.com hosted at online.sagepub.com

Amy J. Berry, MS, RD, CNSC1

Abstract Pancreatic stimulation and therefore digestion is a tightly controlled and hormonally mediated process. Any alterations affecting any of the systematic steps for successful digestion and absorption to occur will impair appropriate pancreatic enzymatic secretion, entry into the bowel lumen, functionality once inside the lumen, and thus appropriate mixing with foods and nutrients. Many causes of pancreatic insufficiency may require the initiation of pancreatic enzyme therapy, including but not limited to cystic fibrosis, pancreatic cancer, acute and chronic pancreatitis, and pancreatic surgery. This purpose of this article is to help clarify the conditions that cause pancreatic insufficiency, how to determine if the patient is malabsorbing, and the best use of pancreatic enzyme replacement therapy for treatment in these conditions. The first step in determining if pancreatic enzyme therapy is appropriate is to determine if the patient is malabsorbing specifically due to pancreatic exocrine insufficiency. An overview of the methods used to determine pancreatic insufficiency is provided, as well as appropriate treatment methods. Recent Food and Drug Administration regulations require a more thorough process, including randomized controlled trials to prove the safety and efficacy of pancreatic enzymes, to approve them for use. The studies used to verify efficacy also are examined. Last, dosing guidelines and some unconventional ways to administer pancreatic enzymes, such as during enteral feedings, are reviewed. (Nutr Clin Pract. 2014;29:312-321)

Keywords pancreatic diseases; pancreatitis; pancreatic cancer; cystic fibrosis; malabsorption syndromes; pancreatic enzymes; lipase; amylases; trypsin

Pancreatic stimulation and therefore digestion is a tightly controlled and hormonally mediated process. Food in the stomach entering into the small intestine is the most potent stimulator for these digestive reactions to occur.1 Most notably, the hormone secretin acts on the pancreas for bicarbonate release, and cholecystokinin (CCK) acts on the gallbladder and the pancreas to stimulate the release of bile and pancreatic secretions.2 Furthermore, the parasympathetic system is involved with acetylcholine, stimulating peristalsis and pancreatic secretion.3 Pancreatic juices flow out of the main pancreatic duct, which merges with the common bile duct, delivering bile from the liver and gallbladder. The contents of these 2 ducts are emptied into the duodenum through the ampulla of Vater. The sphincter of Oddi involves the muscle fibers around this area that control the flow of digestive juices into the duodenum. The pH of the duodenum has been noted to be 6–6.5 in healthy individuals and becomes higher the further down in the digestive tract toward the ileum.4 This is also an important factor in the ability of pancreatic enzymes to function appropriately.

pancreas and activated by trypsin and enterokinase at the brush border of the intestinal lumen.6 Normal pancreatic enzymatic release is thought to have continuous basal secretion, with a rapid and significant increase in the first 20 minutes after ingestion of a meal, which is sustained for about an hour and then decreases slightly but with a continued, sustained secretion continuing for 3–4 hours after meal ingestion.7,8 In healthy volunteers, a total release of 187–301 units × 103/h of total pancreatic enzymatic output has been noted.9 The greatest percentage of release included amylase, then lipase, followed by trysin. Another compilation of the data reports that at maximum levels, enzymatic release is 3000–6000 U/min/kg of lipase, 500–1000 U/min/kg of amylase, and 200–1000 U/min/kg of trypsin. In late-phase digestion, the steady state decreases to 2000–4000 U/min/kg of lipase, 500 U/min/kg of amylase, and 150–500 U/min/kg of trypsin.8 A classic study examined directly measuring pancreatic secretion in relation to separate components infused into the duodenum: From 1University of Virginia Health System, Charlottesville, Virginia.

Normal Pancreatic Function

Financial disclosure: None declared.

On average, the pancreas produces approximately 500–1000 mL of digestive juices per day.3,5 Components of these secretions include amylase and lipase, which are stored in the active form in the pancreas, as well as bicarbonate. Proteolytic enzymes include trypsinogens, chymotrypsinogen A and B, and procarboxy peptidase A and B, which are inactive until secreted by the

This article originally appeared online on March 31, 2014. Corresponding Author: Amy J. Berry, MS, RD, CNSC, Surgical Nutrition Support Team, University of Virginia Health System, 1215 Lee Street, PO Box 800673, Charlottesville, VA 22903, USA. Email: [email protected]

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normal saline, dextrose, fatty acid, or essential amino acids. With each component infused, a release of all pancreatic enzymes occurred, including trypsin, lipase, and amylase. This study showed amino acids most effectively stimulated pancreatic secretion, followed closely by fat infusion.7 The second hour of secretory output from the pancreas was significantly higher with the amino acid infusion than any other component. The dextrose infusion did not elicit a pancreatic secretion response any different from normal saline infusion, both of which were significantly lower than fat and amino acid infusions.7 This study shows that protein is the most potent stimulator of pancreatic enzyme secretion, with carbohydrate by far the least potent. Secretion of enzymes after a meal far exceeds what is necessary for normal digestion to occur; in fact, malabsorption is not found to occur until enzymatic output falls below 10% of normal levels.10,11 Enzymes themselves are highly degradable and do not survive the entire intraluminal transit. In healthy people with normal pancreatic secretion, 74% amylase, 22% trypsin, and only 1% lipase survive intestinal transit from the duodenum through the ileum.4,12 Complete absorption of fat is also dependent on the presence of bile acids and colipase, as well as pancreatic lipase.6 Therefore, maximal absorption of fat occurs in the proximal gut. Furthermore, lipase degrades very quickly in the absence of triglycerides in the gut lumen.12 For all of these reasons, fat absorption is most affected by the altered release of pancreatic lipase. Protein and carbohydrate have additional pathways for digestion, even with decreased enzymatic release by the pancreas. It has been postulated that protein may have a greater digestion potential in the absence of pancreatic proteolytic activity, due to the digestive process being initiated by gastric acid and pepsin in the stomach, then aided by intestinal brush-border proteases.1,13 Salivary amylase has a more significant role in digestion, accounting for approximately 50% of carbohydrate digestion, whereas salivary lipase is not this effective.1,6 Carbohydrate digestion is further aided by brush-border oligosaccharides, as well as digestion of malabsorbed carbohydrate by colonic flora.1,14 Therefore, the digestion of fat is most dependent on pancreatic enzymatic activity, while carbohydrate digestion is the least dependent.

Pancreatic Insufficiency and Malabsorption Due to the well-regulated process of digestion and absorption, it becomes clear that any alterations impairing pancreatic secretion and entry into the bowel lumen, functionality once inside the lumen, and appropriate mixing with foods and nutrients could vastly affect absorption capacity. Several conditions cause pancreatic exocrine insufficiency or inadequate mixing of enzymes with nutrients in the bowel lumen, including cystic fibrosis, acute and chronic pancreatitis, pancreatic cancer, pancreatic and gastric surgery, bowel obstruction, and small bowel intestinal overgrowth syndrome. Cystic fibrosis (CF) is a genetic disorder that causes a thick, sticky mucus to form in secretory channels, most notably

affecting the lungs and the pancreas. It is reported that more than 90% of patients with CF have pancreatic exocrine insufficiency (PEI).15 Even if their pancreatic gland is able to function adequately enough for absorption early on, with advancing age, pancreatic function often will decline.16 Chronic pancreatitis is a progressive disorder, causing fibrosis and destruction of the pancreatic tissue. Further complications include duct blockages and pseudocysts, either blocking pancreatic secretions or causing them to leak out into an encapsulated area. Often, PEI causing malabsorption does not present until late in the disease and is correlated with the severity of gland dysfunction.17 If medical management fails in these patients, they will eventually require pancreatic surgery. Studies have reported that 32%–41% of patients with chronic pancreatitis present with PEI significant enough to cause malabsorptive symptoms prior to surgical intervention.15,16 Long-term postoperative follow-up has reported that 50%–75% of these patients will continue to have PEI.18-20 It can be expected that if the patient was requiring pancreatic enzyme supplementation before the operation, after additional loss of the pancreatic tissue, these patients will continue to have PEI. This also is true in patients with severe acute pancreatitis, who may or may not need pancreatic enzyme therapy, depending on the severity of destruction to the gland and its ability to adequately secrete pancreatic enzymes. If surgical intervention is required in these patients, such as pancreatic necrosectomy, varying amounts of pancreatic tissue are removed, so it is variable if these patients will require pancreatic enzyme replacement therapy (PERT) or not. Patients with pancreatic cancer commonly have signs and symptoms of PEI. Studies have reported that 22%–45% of patients with pancreatic cancer have malabsorptive symptoms, which likely depends on how far the disease has progressed.21,22 Another study reported a much lower incidence of only 4% of patients with pancreatic cancer presenting with PEI, as defined by the presence of steatorrhea.23 Unfortunately, only about 15%–20% of patients with pancreatic cancer are able to undergo surgical resection for excision of their carcinoma due to progression of disease at diagnosis. Park et al23 found that in patients with pancreatic cancer following resection, steatorrhea was reported to have worsened right after surgical pancreatic resection but returned to baseline by 12 months. In contrast, 2 other studies found that 48%–74%21,22 of these patients continued to experience malabsorption in the months following the operation, with Matsumoto et al22 reporting 50% of patients continuing to have these symptoms at 1 year. Both patients with pancreatic cancer and chronic pancreatitis may undergo partial or full removal of the pancreatic gland. In patients who undergo total pancreatectomy, the entire gland is removed, and thus patients will require pancreatic enzyme therapy for life. It would make sense that these patients may require higher doses of enzyme therapy, as there will be no residual function remaining. Pancreatic, and even gastric, surgery patients can have asynchrony of pancreatic stimulation and secretion in response to nutrient entry into the lumen,

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therefore causing insufficient mixing with food.24 This can occur more commonly if a patient has a Roux limb from surgery. In an altered gastrointestinal (GI) anatomy, the enzymatic release will first move through the Roux limb before it reaches the efferent limb where nutrients are entering the digestive tract. Therefore, simultaneous mixing between bile/pancreatic enzymes and nutrient intake does not occur efficiently, resulting in malabsorption. Inadequate mixing of enzymes with nutrients in the bowel lumen can also occur with external duodenal fluid loss. This is common in patients who have a duodenal obstruction, which can occur in both the acute and chronic pancreatitis patient population. These patients may require a nasogastric or percutaneous gastric tube in place for drainage of built-up digestive and gastric secretions, causing ongoing losses of bile and pancreatic enzymes needed for appropriate absorption. These patients may be able to be fed enterally past the obstruction, but infusion of intact nutrients will likely be malabsorbed due to significant digestive fluid losses. In these patients, reinfusion of the duodenal contents through a jejunal tube may be a valid option, which is described in depth elsewhere.5 Patients after pancreatic resection with resulting pancreatic or biliary leak may have drain placements that can incur significant pancreatobiliary fluid loss. If this occurs, comparing the volume of drain output with normal daily pancreatic or biliary secretory production may be helpful in identifying if these fluid losses are significant enough to require PERT to enable appropriate absorption, in the case the patient has ongoing unexplained malabsorptive symptoms. Of note, when monitoring drain output, typically pancreatic juice can look clear or cloudy, whereas bile is easily identified with its green color. However, be aware that a multitude of variables can change drain colors, such as infection, mixing of various enteric fluids captured by the drain, and medications. Another complication that can cause malabsorption in the pancreatic-insufficient patient population is small intestine bacterial overgrowth (SIBO). This condition occurs when an excess number of bacteria arise, usually in the proximal small bowel, causing gas, bloating, flatulence, abdominal discomfort, diarrhea, steatorrhea, weight loss, and potentially micronutrient deficiency.25 Alterations predisposing patients to SIBO include intestinal stasis/stagnation (which may occur in surgically created blind loops) and low acid states due to gastric resection or use of proton pump inhibitors (PPIs), which are common in GI surgical patients and those with chronic pancreatitis.26,27 However, the use of PPIs in contributing to the prevalence of SIBO has been challenged recently due to 1 observational study that showed no difference between PPI users vs nonusers in developing SIBO.28 Reports show that as high as 40% of patients with pancreatic insufficiency have SIBO.26,29 In addition, up to 77% of gastrectomy patients 6 months postoperatively may have this condition.30 Vitamin B12 deficiency can be seen due to bacterial conversion of this vitamin into a biologically unavailable form; folate levels are

often elevated due to bacterial synthesis.25 Although not diagnostic, these are suggestive of SIBO and require further investigation. In symptomatic patients, oral antimicrobial therapy that targets both aerobic and anaerobic organisms should be considered along with any intervention that might help decrease bacterial colonization.25 It is important to identify and treat SIBO if indicated before assuming enzyme therapy is needed or current therapy is ineffective. Another cause of inadequate absorption is a lower luminal pH. In the natural state, the pancreas secretes both bicarbonate and pancreatic enzymes. Thus, if the pancreas is secreting a lower amount of enzymes due to dysfunction, it is likely secreting a lower amount of bicarbonate, although this mechanism seems to be more delayed than the former.8 Another mechanism for lower duodenal pH is dumping of gastric contents too quickly into the duodenum, which causes a decreased duodenal pH. If available bicarbonate is not adequate to lower the pH of the duodenum, denaturation of the remaining functional enzymes will result. This is less of an issue for pancreatic surgery patients who have had the Whipple procedure or a total pancreatectomy, since they remain on PPIs or H2 blockers for life. Another complication resulting from lowered intraluminal duodenal pH is bile acid precipitation and micelle formation disruption, causing altered fat digestion.2,24 See Table 1 for possible indications for exogenous PERT and other conditions that may mimic the symptoms of pancreatic insufficiency.

Determination of Malabsorption The functional reserve of the pancreas is quite impressive, with the classic study by DiMagno et al,11 which was replicated by Lankisch et al,10 showing that malabsorption did not occur in patients until pancreatic lipase and trypsin output fell below 10% of normal secretion in most patients. This is an interesting anomaly, since in pancreatic resection procedures, only about ~30% of the pancreatic tissue is removed, yet patients commonly report symptoms of malabsorption. This ascribes to the importance of the health of the remaining tissue. It should be noted that both studies had outliers to this result; a small percentage of patients experienced malabsorption with >10% enzymatic output, and a few were able to maintain normal absorptive capacity with 7% of the total amount of fat consumed is obtained from the stool collection, this indicates fat malabsorption. Often, ≥15 g/d is considered indicative of severe steatorrhea.34 In the clinical setting, often these patients will not tolerate such a high-fat diet, and it may be impractical to enforce this regimen simply for the diagnosis of pancreatic insufficiency. It seems that valid information could still be obtained if the test were done with a lower fat diet; if a high

Conditions That Can Mimic Symptoms of Pancreatic Insufficiency Clostridium difficile diarrhea, other infectious diarrhea, or colitis Small bowel bacterial overgrowth Dumping syndrome Celiac disease

percentage of fat is found in the stool compared with what the patient has been fed, it holds clinical significance. Furthermore, this test was not designed for patients currently receiving PERT. However, it holds clinical significance if the patient is receiving PERT and malabsorption continues, therefore signifying current PERT therapy is not adequately working. Other alternative ways to use the fecal fat test include a shorter duration of fecal fat collection (eg, a 2-day collection without administration of a highfat diet). One study examined the implementation of PERT only if the fecal fat showed >15 g of loss on a 100-g diet or if the participants continued to have weight loss despite fecal output of

Pancreatic enzyme replacement therapy during pancreatic insufficiency.

Pancreatic stimulation and therefore digestion is a tightly controlled and hormonally mediated process. Any alterations affecting any of the systemati...
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