10Pancreatic enzyme replacement therapy in chronic pancreatitis
Section snippets
Exocrine pancreatic insufficiency and chronic pancreatitis
In EPI the pancreas is unable to deliver sufficient amounts of pancreatic enzymes to the small intestine to digest intraluminal nutrients. EPI may occur due to loss of functional parenchyma (atrophy), blockage of the pancreatic duct, or postprandial asynchrony. Besides CP, other conditions that can result in loss of parenchyma are severe acute pancreatitis (which can cause transient EPI), pancreatic resection, and cystic fibrosis (CF). Chronic obstruction of the main pancreatic duct can be
Pancreatic secretion
The pancreas plays a crucial role in the digestive system. The gland produces pancreatic juice that consists of a mixture of more than two dozen digestive enzymes in the pre-activated form, called zymogens. Zymogens are produced by acinar cells and mixed with a bicarbonate rich fluid that is produced by pancreatic ducts cells *[1], *[7]. Trypsinogen is the most important zymogen because it becomes trypsin, the key enzyme that activates all other zymogens. Trypsin, chymotrypsin, amylase and
Pathophysiology
The pancreas has a large functional reserve and clinically evident EPI occurs only when 90% of the function is lost and the secretion of pancreatic enzymes is less than 10% of normal *[11], [16]. Because of a decrease in lipase, trypsin and amylase activity, maldigestion of fat, proteins and carbohydrates occurs. Malabsorption of fat precedes malabsorption of proteins and carbohydrates and is clinically more apparent *[11], [17], [18]. The decrease in pancreatic lipolytic activity cannot be
Symptoms and complications
In CP patients with EPI, maldigestion of dietary macronutrients (fat, proteins and carbohydrates) leads to malnutrition which is associated with various health problems. Maldigestion of fat results in steatorrhoea, which causes symptoms such as foul-smelling, voluminous, greyish, fatty stools, abdominal cramps, bloating and chronic abdominal pain [25]. In addition, steatorrhoea may cause weight loss due to the loss of the highest dietary source of calories (fat contains 38 kJ/g, carbohydrates
Diagnosis
The pancreatic exocrine function can be tested in an invasive or a non-invasive manner. With invasive testing, which is considered to be the golden standard, pancreatic enzymes are measured in pancreatic juice that is collected from the duodenum after intubation (intraduodenal lipase output after intravenous administration of 1 U/kg CCK; normal value, >90 kU/h) [42]. Pancreatic enzyme stimulation in these tests can be either direct, by means of the intravenous administration of hormones like
Treatment
The treatment of EPI in CP consists of the oral administration of a combination of pancreatic enzymes during meals [59]. Every patient with EPI and maldigestion, independent of the degree of steatorrhoea and presence or absence of associated symptoms, should receive PERT [60], *[61]. The main focus in the management of EPI is to prevent weight loss, EPI related symptoms, vitamin deficiencies, and to improve the nutritional status [25], [62]. The most important clinical parameter to monitor
Pancreatic enzyme replacement therapy (PERT)
The exogenous pancreatic enzymes currently used, are primarily extracted from porcine sources. These preparations, also called pancrelipase or pancreatin, contain a variable mixture of protease, lipase and amylase depending on the brand. Various pancreatin preparations are available consisting of capsules containing mini-microspheres, pellets or micro-tablets of less than 2 mm in size. They are designed to promote an adequate intragastric mixture of exogenous enzymes with chyme [63], [64], [65],
Diet and dosage recommendations
Despite the absence of an easy applicable and objective method to establish the adequate dose of oral pancreatic enzymes in EPI, some general guidelines can be given to accomplish a patient tailored administration schedule [73]. In the past, the restriction of fat was the only way to reduce steatorrhoea, but with the introduction of PERT, this is no longer advocated. Instead, the dose of PERT is tailored to the fat intake of the patient. In general, the recommended dosage of PES for a main meal
When treatment fails
In case of treatment failure, several causes should be considered. A common cause for treatment failure is under dosing of pancreatic enzymes. The practical and reasonable first step therefore is to increase the dose of pancreatic enzymes guided by fat resorption and clinical response, up to a maximum of 10,000 IU lipase/kg/day. This latter recommendation stems from treating children with cystic fibrosis. Evidently, in adult patients with exocrine insufficiency such high dosages are not reached.
Toxicity and side effects
Very few side effects have been observed when using PERT. High doses of enzymes can induce transient nausea, bloating, diarrhoea and hypersensitivity. Only one serious adverse event has been reported. In January 1994, Smyth et al described five children with CF in which a colonic obstruction developed due to fibrosing colonopathy (FC) after using very high doses of the enteric-coated micro-minisphere preparations [81], *[82]. The mechanism underlying this phenomenon remains unclear. Although
Bovine enzymes
In patients who refuse to consume porcine products for religious or other cultural reasons, bovine enzymes appear to be an attractive alternative [84]. However, bovine preparations contain about 75% less lipase activity compared to porcine and human pancreatic extracts. Hence, a considerable greater amount of tablets needs to be taken to treat EPI in comparison with porcine preparations. Furthermore, there are some concerns about transmittable pathogens which can cause diseases as
Summary
Clinically evident EPI occurs when 90% or more of the pancreatic function is impaired and the secretion of pancreatic enzymes is less than 10% of normal. It is of great importance to actively look for EPI, recognise it as early as possible, and start PERT to avoid malnutrition related morbidity and mortality. The most readily available and easiest test for a clinician to detect EPI is the FET. Every patient with EPI and maldigestion, independent of the degree of steatorrhoea and presence or
Conflict of interest
Mrs E.C.M. Sikkens has received an unrestricted research grant from “Axcan Pharma Inc., Canada”.
References (96)
Maldigestion and exocrine pancreatic insufficiency after pancreatic resection for malignant disease: pathophysiology and treatment
Pancreatology
(2001)- et al.
The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis
Gastroenterology
(1994 Nov) - et al.
Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience
Clin Gastroenterol Hepatol
(2006 Aug) - et al.
Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans
Gastroenterology
(1993 Sep) - et al.
Limited action of trypsin on porcine pancreatic amylase: characterization of the fragments
FEBS Lett
(1975 Aug 15) - et al.
Feedback regulation of human pancreatic secretion. Effects of protease inhibition on duodenal delivery and small intestinal transit of pancreatic enzymes
Gastroenterology
(1990 May) - et al.
Altered postprandial motility in chronic pancreatitis: role of malabsorption
Gastroenterology
(1997 May) - et al.
Effect of infusion of nutrient solutions into the ileum on gastrointestinal transit and plasma levels of neurotensin and enteroglucagon
Gastroenterology
(1984 Feb) - et al.
Efficacy of a pancreatic enzyme formulation in the treatment of steatorrhea in patients with chronic pancreatitis
Curr Therapeut Res – Clin Exp
(1996) - et al.
Defective essential-fatty-acid metabolism in cystic fibrosis
Lancet
(1975 Oct 4)
Fat malabsorption in cystic fibrosis patients receiving enzyme replacement therapy is due to impaired intestinal uptake of long-chain fatty acids
Am J Clin Nutr
A short, eclectic history of exocrine pancreatic insufficiency and chronic pancreatitis
Gastroenterology
Effect of dietary fiber on pancreatic enzyme activity in vitro
Gastroenterology
Evaluation of duct-cell and acinar-cell function and endosonographic abnormalities in patients with suspected chronic pancreatitis
Clin Gastroenterol Hepatol
13C-mixed triglyceride breath test to assess oral enzyme substitution therapy in patients with chronic pancreatitis
Clin Gastroenterol Hepatol
Elastase 1 and chymotrypsin B in pancreatic juice and feces
Clin Biochem
How useful is fecal pancreatic elastase 1 as a marker of exocrine pancreatic disease?
J Pediatr
Proteases in the evaluation of pancreatic function and pancreatic disease
Clin Chim Acta
Diagnosis of chronic pancreatitis
Gastroenterology
Early total parenteral nutrition in acute pancreatitis: lack of beneficial effects
Am J Surg
Exocrine pancreatic insufficiency in celiac sprue: a cause of treatment failure
Gastroenterology
Fibrosing colonopathy in cystic fibrosis: results of a case–control study
Lancet
Strictures of ascending colon in cystic fibrosis and high-strength pancreatic enzymes
Lancet
Lipolytic activity of bacterial lipase survives better than that of porcine lipase in human gastric and duodenal content
Gastroenterology
Effect of bacterial or porcine lipase with low- or high-fat diets on nutrient absorption in pancreatic-insufficient dogs
Gastroenterology
Bacterial lipase and high-fat diets in canine exocrine pancreatic insufficiency: a new therapy of steatorrhea?
Gastroenterology
Adenovirus-mediated transfer of human lipase complementary DNA to the gallbladder
Gastroenterology
Human pancreatic exocrine response to nutrients in health and disease
Gut
Pancreatic endocrine and exocrine function and salivary gland function in autoimmune pancreatitis before and after steroid therapy
Pancreas
Autoimmune pancreatitis
N Engl J Med
Human pancreatic digestive enzymes
Dig Dis Sci.
Human gastric lipase: variations induced by gastrointestinal hormones and by pathology
Scand J Gastroenterol
Fate of pancreatic enzymes during small intestinal aboral transit in humans
Am J Physiol
Survival of human pancreatic enzymes during small bowel transit: effect of nutrients, bile acids, and enzymes
Am J Physiol
Duodenal and ileal nutrient deliveries regulate human intestinal motor and pancreatic responses to a meal
Am J Physiol
Functional reserve capacity of the exocrine pancreas
Digestion
Natural histories of alcoholic and idiopathic chronic pancreatitis
Pancreas
Intestinal transit of chyme and its regulatory role: clinical implications
Human pancreatic secretion and intestinal motility: effects of ileal nutrient perfusion
Am J Physiol
Modulation of human periodic interdigestive gastrointestinal motor and pancreatic function by the ileum
Pancreas
Determinants of accelerated small intestinal transit in alcohol-related chronic pancreatitis
Dig Dis Sci
Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules
N Engl J Med
Effect of intrajejunal acidity on aqueous phase bile acid and lipid concentrations in pancreatic steatorrhoea due to cystic fibrosis
Gut
Enzyme therapy for malabsorption in exocrine pancreatic insufficiency
Pancreas
Essential fatty acids in cystic fibrosis
Nature
Deficiency of fat-soluble vitamins in treated patients with pancreatic insufficiency
Ann Intern Med
Therapy of pancreatogenic steatorrhoea: does acid protection of pancreatic enzymes offer any advantage?
Z Gastroenterol
Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency
Int J Pancreatol
Cited by (100)
Enzymatic dispersion of biofilms: An emerging biocatalytic avenue to combat biofilm-mediated microbial infections
2022, Journal of Biological ChemistryExocrine pancreatic insufficiency in long-term follow-up after curative gastric resection with D2 lymphadenectomy: A cross-sectional study: Exocrine pancreatic insufficiency after curative gastric resection
2021, PancreatologyCitation Excerpt :Still, the link between FE-1 level and nutritional blood biomarkers has not been fully investigated in gastric cancer patients. Malnutrition caused by EPI can also lead to increased morbidity and reduced patient quality of life (QoL), and increase mortality [20–23]. Therefore, the correlation between EPI, secondary to a casual condition, and chronic malnutrition resulting from nutrient deficiency and fat malabsorption needs to be an important part of patient care in follow-up.
Construction of food-grade pH-sensitive nanoparticles for delivering functional food ingredients
2020, Trends in Food Science and TechnologyCitation Excerpt :A few bioactive proteins (e.g. enzymes and hormones) are used as functional food ingredients. The lactase enzyme is used to help lactose intolerant patients break down lactose into galactose and glucose within the small intestine (Heyman, 2006); the lipase enzyme helps patients with pancreatitis to digest lipids within the small intestine (Sikkens, Cahen, Kuipers, & Bruno, 2010). The function of bioactive proteins depends on their ability to maintain their original three-dimensional structure.
Mobile health apps: The quest from laboratory to the market
2020, Digital Health: Mobile and Wearable Devices for Participatory Health Applications