Best Practice & Research Clinical Gastroenterology
Volume 24, Issue 3 , Pages 337-347 , June 2010

Pancreatic enzyme replacement therapy in chronic pancreatitis

  • E.C.M. Sikkens, MD

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +31 (10) 70 31073.
  • ,
  • D.L. Cahen, MD, PhD

      Affiliations

    • Tel.: +31 (10) 70 35946.
  • ,
  • E.J. Kuipers, Md, PhD (Professor)

      Affiliations

    • Tel.: +31 (10) 70 34681.
  • ,
  • M.J. Bruno, MD, PhD (Professor)

      Affiliations

    • Tel.: +31 (10) 70 35946; fax: +31 (10) 70 34682.

References 

  1. Keller J, Layer P. Human pancreatic exocrine response to nutrients in health and disease. Gut. 2005 Jul;54(Suppl. 6):vi1–vi28
  2. Bruno MJ. Maldigestion and exocrine pancreatic insufficiency after pancreatic resection for malignant disease: pathophysiology and treatment. Pancreatology. 2001;1(Suppl. 1):55–61
  3. Kamisawa T, Egawa N, Inokuma S, et al. Pancreatic endocrine and exocrine function and salivary gland function in autoimmune pancreatitis before and after steroid therapy. Pancreas. 2003 Oct;27(3):235–238
  4. Layer P, Yamamoto H, Kalthoff L, et al. The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology. 1994 Nov;107(5):1481–1487
  5. Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol. 2006 Aug;4(8):1010–1016quiz 934
  6. Finkelberg DL, Sahani D, Deshpande V, et al. Autoimmune pancreatitis. N Engl J Med. 2006 Dec 21;355(25):2670–2676
  7. Whitcomb DC, Lowe ME. Human pancreatic digestive enzymes. Dig Dis Sci. 2007 Jan;52(1):1–17
  8. Carriere F, Barrowman JA, Verger R, et al. Secretion and contribution to lipolysis of gastric and pancreatic lipases during a test meal in humans. Gastroenterology. 1993 Sep;105(3):876–888
  9. Moreau H, Sauniere JF, Gargouri Y, et al. Human gastric lipase: variations induced by gastrointestinal hormones and by pathology. Scand J Gastroenterol. 1988 Nov;23(9):1044–1048
  10. Granger M, Abadie B, Marchis-Mouren G. Limited action of trypsin on porcine pancreatic amylase: characterization of the fragments. FEBS Lett. 1975 Aug 15;56(2):189–193
  11. Layer P, Go VL, DiMagno EP. Fate of pancreatic enzymes during small intestinal aboral transit in humans. Am J Physiol. 1986 Oct;251(4 Pt 1):G475–G480
  12. Holtmann G, Kelly DG, Sternby B, et al. Survival of human pancreatic enzymes during small bowel transit: effect of nutrients, bile acids, and enzymes. Am J Physiol. 1997 Aug;273(2 Pt 1):G553–G558
  13. Layer P, Jansen JB, Cherian L, 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;98(5 Pt 1):1311–1319
  14. Keller J, Runzi M, Goebell H, et al. Duodenal and ileal nutrient deliveries regulate human intestinal motor and pancreatic responses to a meal. Am J Physiol. 1997 Mar;272(3 Pt 1):G632–G637
  15. Layer P, von der Ohe MR, Holst JJ, et al. Altered postprandial motility in chronic pancreatitis: role of malabsorption. Gastroenterology. 1997 May;112(5):1624–1634
  16. Lankisch PG, Lembcke B, Wemken G, et al. Functional reserve capacity of the exocrine pancreas. Digestion. 1986;35(3):175–181
  17. Layer PH, DiMagno EP. Natural histories of alcoholic and idiopathic chronic pancreatitis. Pancreas. 1996 Apr;12(3):318–320
  18. Layer PKJ. Intestinal transit of chyme and its regulatory role: clinical implications. In:  Lankisch PG,  Dimagno EP editor. Pancreatic disease: state of the art and future aspects of research. Springer; 1999;p. 112–120
  19. Layer P, Peschel S, Schlesinger T, et al. Human pancreatic secretion and intestinal motility: effects of ileal nutrient perfusion. Am J Physiol. 1990 Feb;258(2 Pt 1):G196–G201
  20. Layer P, Schlesinger T, Groger G, et al. Modulation of human periodic interdigestive gastrointestinal motor and pancreatic function by the ileum. Pancreas. 1993 Jul;8(4):426–432
  21. Read NW, McFarlane A, Kinsman RI, et al. Effect of infusion of nutrient solutions into the ileum on gastrointestinal transit and plasma levels of neurotensin and enteroglucagon. Gastroenterology. 1984 Feb;86(2):274–280
  22. Rosa ESL, Troncon LE, Gallo L, et al. Determinants of accelerated small intestinal transit in alcohol-related chronic pancreatitis. Dig Dis Sci. 2009 Apr 24;
  23. DiMagno EP, Malagelada JR, Go VL, et al. Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules. N Engl J Med. 1977 Jun 9;296(23):1318–1322
  24. Zentler-Munro PL, Fitzpatrick WJ, Batten JC, et al. Effect of intrajejunal acidity on aqueous phase bile acid and lipid concentrations in pancreatic steatorrhoea due to cystic fibrosis. Gut. 1984 May;25(5):500–507
  25. Pasquali C, Fogar P, Sperti C, et al. Efficacy of a pancreatic enzyme formulation in the treatment of steatorrhea in patients with chronic pancreatitis. Curr Therapeut Res – Clin Exp. 1996;57(5):358–365
  26. Rivers JP, Hassam AG. Defective essential-fatty-acid metabolism in cystic fibrosis. Lancet. 1975 Oct 4;2(7936):642–643
  27. Roberts IM. Enzyme therapy for malabsorption in exocrine pancreatic insufficiency. Pancreas. 1989;4(4):496–503
  28. Rosenlund ML, Kim HK, Kritchevsky D. Essential fatty acids in cystic fibrosis. Nature. 1974 Oct 25;251(5477):719
  29. Dutta SK, Bustin MP, Russell RM, et al. Deficiency of fat-soluble vitamins in treated patients with pancreatic insufficiency. Ann Intern Med. 1982 Oct;97(4):549–552
  30. Kalivianakis M, Minich DM, Bijleveld CM, et al. 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. 1999 Jan;69(1):127–134
  31. Lankisch PG, Lembcke B, Goke B, et al. Therapy of pancreatogenic steatorrhoea: does acid protection of pancreatic enzymes offer any advantage?. Z Gastroenterol. 1986 Dec;24(12):753–757
  32. DiMagno EP. A short, eclectic history of exocrine pancreatic insufficiency and chronic pancreatitis. Gastroenterology. 1993 May;104(5):1255–1262
  33. Haaber AB, Rosenfalck AM, Hansen B, et al. Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency. Int J Pancreatol. 2000 Feb;27(1):21–27
  34. Moran CE, Sosa EG, Martinez SM, et al. Bone mineral density in patients with pancreatic insufficiency and steatorrhea. Am J Gastroenterol. 1997 May;92(5):867–871
  35. Dutta SK, Procaccino F, Aamodt R. Zinc metabolism in patients with exocrine pancreatic insufficiency. J Am College Nutr. 1998 Dec;17(6):556–563
  36. Girish BN, Rajesh G, Vaidyanathan K, et al. Zinc status in chronic pancreatitis and its relationship with exocrine and endocrine insufficiency. J Pancreas. 2009;10(6):651–656
  37. Isaksson G, Lundquist I, Ihse I. Effect of dietary fiber on pancreatic enzyme activity in vitro. Gastroenterology. 1982 May;82(5 Pt 1):918–924
  38. Leng-Peschlow E. Interference of dietary fibres with gastrointestinal enzymes in vitro. Digestion. 1989;44(4):200–210
  39. Montalto G, Soresi M, Carroccio A, et al. Lipoproteins and chronic pancreatitis. Pancreas. 1994 Jan;9(1):137–138
  40. Gullo L, Stella A, Labriola E, et al. Cardiovascular lesions in chronic pancreatitis: a prospective study. Dig Dis Sci. 1982 Aug;27(8):716–722
  41. Gullo L, Tassoni U, Mazzoni G, et al. Increased prevalence of aortic calcification in chronic pancreatitis. Am J Gastroenterol. 1996 Apr;91(4):759–761
  42. Perri F, Pastore M, Festa V, et al. Intraduodenal lipase activity in celiac disease assessed by means of 13C mixed-triglyceride breath test. J Pediatr Gastroenterol Nutr. 1998 Oct;27(4):407–410
  43. Stevens T, Dumot JA, Zuccaro G, et al. Evaluation of duct-cell and acinar-cell function and endosonographic abnormalities in patients with suspected chronic pancreatitis. Clin Gastroenterol Hepatol. 2009 Jan;7(1):114–119
  44. Taylor JR, Gardner TB, Waljee AK, et al. Systematic review: efficacy and safety of pancreatic enzyme supplements for exocrine pancreatic insufficiency. Aliment Pharmacol Ther. Jan;31(1):57–72.
  45. Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Curr Gastroenterol Rep. 2007 Apr;9(2):116–122
  46. Dominguez-Munoz JE, Iglesias-Garcia J, Vilarino-Insua M, et al. 13C-mixed triglyceride breath test to assess oral enzyme substitution therapy in patients with chronic pancreatitis. Clin Gastroenterol Hepatol. 2007 Apr;5(4):484–488
  47. Iglesias-Garcia J, Vilarino-Insua M, Iglesias-Rey M, et al. Oral pancreatic enzyme supplementation in patients with exocrine pancreatic insufficiency: is it enough to evaluate clinical response?. Gastroenterology. 2003;124(Suppl. 1):A-632
  48. Dominguez-Munoz JE, Hieronymus C, Sauerbruch T, et al. Fecal elastase test: evaluation of a new noninvasive pancreatic function test. Am J Gastroenterol. 1995 Oct;90(10):1834–1837
  49. Amann ST, Bishop M, Curington C, et al. Fecal pancreatic elastase 1 is inaccurate in the diagnosis of chronic pancreatitis. Pancreas. 1996 Oct;13(3):226–230
  50. Sziegoleit A, Krause E, Klor HU, et al. Elastase 1 and chymotrypsin B in pancreatic juice and feces. Clin Biochem. 1989 Apr;22(2):85–89
  51. Beharry S, Ellis L, Corey M, et al. How useful is fecal pancreatic elastase 1 as a marker of exocrine pancreatic disease?. J Pediatr. 2002;141(1):84–90
  52. Loser C, Mollgaard A, Folsch UR. Faecal elastase 1: a novel, highly sensitive, and specific tubeless pancreatic function test. Gut. 1996 Oct;39(4):580–586
  53. Gullo L, Graziano L, Babbini S, et al. Faecal elastase 1 in children with cystic fibrosis. Eur J Pediatr. 1997 Oct;156(10):770–772
  54. Layer P, Keller J, Lankisch PG. Pancreatic enzyme replacement therapy. Curr Gastroenterol Rep. 2001 Apr;3(2):101–108
  55. Goldberg DM. Proteases in the evaluation of pancreatic function and pancreatic disease. Clin Chim Acta. 2000 Feb 15;291(2):201–221
  56. Niederau C, Grendell JH. Diagnosis of chronic pancreatitis. Gastroenterology. 1985 Jun;88(6):1973–1995
  57. Lieb JG, Draganov PV. Pancreatic function testing: here to stay for the 21st century. World J Gastroenterol. 2008 May 28;14(20):3149–3158
  58. Henker J, Hackbarth S, Sprossig C. [Fecal chymotrypsin concentration in childhood. Normal values, specificity, sensitivity]. Helv Paediatr Acta. 1989 Jun;43(5–6):397–404
  59. Dobrilla G. Management of chronic pancreatitis. Focus on enzyme replacement therapy. Int J Pancreatol. 1989;5(Suppl):17–29
  60. Mundlos S, Kuhnelt P, Adler G. Monitoring enzyme replacement treatment in exocrine pancreatic insufficiency using the cholesteryl octanoate breath test. Gut. 1990 Nov;31(11):1324–1328
  61. Bruno MJ, Haverkort EB, Tijssen GP, et al. Placebo controlled trial of enteric coated pancreatin microsphere treatment in patients with unresectable cancer of the pancreatic head region. Gut. 1998 Jan;42(1):92–96
  62. Naikwade SR, Meshram RN, Bajaj AN. Preparation and in vivo efficacy study of pancreatin microparticles as an enzyme replacement therapy for pancreatitis. Drug Dev Ind Pharm. 2009 Apr;35(4):417–432
  63. Dominguez-Munoz JE, Birckelbach U, Glasbrenner B, et al. Effect of oral pancreatic enzyme administration on digestive function in healthy subjects: comparison between two enzyme preparations. Aliment Pharmacol Ther. 1997 Apr;11(2):403–408
  64. Halm U, Loser C, Lohr M, et al. A double-blind, randomized, multicentre, crossover study to prove equivalence of pancreatin minimicrospheres versus microspheres in exocrine pancreatic insufficiency. Aliment Pharmacol Ther. 1999 Jul;13(7):951–957
  65. Stead RJ, Skypala I, Hodson ME, et al. Enteric coated microspheres of pancreatin in the treatment of cystic fibrosis: comparison with a standard enteric coated preparation. Thorax. 1987 Jul;42(7):533–537
  66. Bruno MJ, Borm JJ, Hoek FJ, et al. Gastric transit and pharmacodynamics of a two-millimeter enteric-coated pancreatin microsphere preparation in patients with chronic pancreatitis. Dig Dis Sci. 1998 Jan;43(1):203–213
  67. Lohr JM, Hummel FM, Pirilis KT, et al. Properties of different pancreatin preparations used in pancreatic exocrine insufficiency. Eur J Gastroenterol Hepatol. 2009 Apr 4;
  68. Sax HC, Warner BW, Talamini MA, et al. Early total parenteral nutrition in acute pancreatitis: lack of beneficial effects. Am J Surg. 1987 Jan;153(1):117–124
  69. Gan KH, Geus WP, Bakker W, et al. In vitro dissolution profiles of enteric-coated microsphere/microtablet pancreatin preparations at different pH values. Aliment Pharmacol Ther. 1996 Oct;10(5):771–775
  70. Case CL, Henniges F, Barkin JS. Enzyme content and acid stability of enteric-coated pancreatic enzyme products in vitro. Pancreas. 2005 Mar;30(2):180–183
  71. Aloulou A, Puccinelli D, Sarles J, et al. In vitro comparative study of three pancreatic enzyme preparations: dissolution profiles, active enzyme release and acid stability. Aliment Pharmacol Ther. 2008 Feb 1;27(3):283–292
  72. Geus WP, Eddes EH, Gielkens HA, et al. Post-prandial intragastric and duodenal acidity are increased in patients with chronic pancreatitis. Aliment Pharmacol Ther. 1999 Jul;13(7):937–943
  73. Bruno MJ, Haverkort EB, Tytgat GN, et al. Maldigestion associated with exocrine pancreatic insufficiency: implications of gastrointestinal physiology and properties of enzyme preparations for a cause-related and patient-tailored treatment. Am J Gastroenterol. 1995 Sep;90(9):1383–1393
  74. Dominguez-Munoz JE, Iglesias-Garcia J, Iglesias-Rey M, et al. Effect of the administration schedule on the therapeutic efficacy of oral pancreatic enzyme supplements in patients with exocrine pancreatic insufficiency: a randomized, three-way crossover study. Aliment Pharmacol Ther. 2005 Apr 15;21(8):993–1000
  75. Keller J, Layer P. Pancreatic enzyme supplementation therapy. Curr Treat Options Gastroenterol. 2003 Oct;6(5):369–374
  76. Ramo OJ, Puolakkainen PA, Seppala K, et al. Self-administration of enzyme substitution in the treatment of exocrine pancreatic insufficiency. Scand J Gastroenterol. 1989 Aug;24(6):688–692
  77. Delchier JC, Vidon N, Saint-Marc Girardin MF, et al. Fate of orally ingested enzymes in pancreatic insufficiency: comparison of two pancreatic enzyme preparations. Aliment Pharmacol Ther. 1991 Aug;5(4):365–378
  78. Regan PT, DiMagno EP. Exocrine pancreatic insufficiency in celiac sprue: a cause of treatment failure. Gastroenterology. 1980 Mar;78(3):484–487
  79. Regan PT, Malagelada JR, DiMagno EP, et al. Comparative effects of antacids, cimetidine and enteric coating on the therapeutic response to oral enzymes in severe pancreatic insufficiency. N Engl J Med. 1977 Oct 20;297(16):854–858
  80. Bruno MJ. Treatment of exocrine pancreatic insufficiency in chronic pancreatitis. In:  Lankisch PG,  Dimagno EP editor. Pancreatic disease: state of the art and future aspects of research. Springer; 1999;p. 121–131
  81. Smyth RL, Ashby D, O’Hea U, et al. Fibrosing colonopathy in cystic fibrosis: results of a case–control study. Lancet. 1995 Nov 11;346(8985):1247–1251
  82. Smyth RL, van Velzen D, Smyth AR, et al. Strictures of ascending colon in cystic fibrosis and high-strength pancreatic enzymes. Lancet. 1994 Jan 8;343(8889):85–86
  83. Taylor CJ. Fibrosing colonopathy unrelated to pancreatic enzyme supplementation. J Pediatr Gastroenterol Nutr. 2002 Sep;35(3):268–269
  84. Layer P, Keller J. Lipase supplementation therapy: standards, alternatives, and perspectives. Pancreas. 2003 Jan;26(1):1–7
  85. Krishnamurty DM, Rabiee A, Jagannath SB, et al. Delayed release pancrelipase for treatment of pancreatic exocrine insufficiency associated with chronic pancreatitis. Ther Clin Risk Manag. 2009 Jun;5(3):507–520
  86. Moreau J, Bouisson M, Saint-Marc-Girardin MF, et al. [Comparison of fungal lipase and pancreatic lipase in exocrine pancreatic insufficiency in man. Study of their in vitro properties and intraduodenal bioavailability] Comparaison d’une lipase fungique et d’une lipase pancreatique au cours de l’insuffisance pancreatique exocrine chez l’homme. Etude de leur propriete in vitro et leur biodisponibilite intraduodenale. Gastroenterol Clin Biol. 1988 Nov;12(11):787–792
  87. Schneider MU, Knoll-Ruzicka ML, Domschke S, et al. Pancreatic enzyme replacement therapy: comparative effects of conventional and enteric-coated microspheric pancreatin and acid-stable fungal enzyme preparations on steatorrhoea in chronic pancreatitis. Hepatogastroenterology. 1985 Apr;32(2):97–102
  88. Zentler-Munro PL, Assoufi BA, Balasubramanian K, et al. Therapeutic potential and clinical efficacy of acid-resistant fungal lipase in the treatment of pancreatic steatorrhoea due to cystic fibrosis. Pancreas. 1992;7(3):311–319
  89. Raimondo M, DiMagno EP. Lipolytic activity of bacterial lipase survives better than that of porcine lipase in human gastric and duodenal content. Gastroenterology. 1994 Jul;107(1):231–235
  90. Suzuki A, Mizumoto A, Rerknimitr R, et al. Effect of bacterial or porcine lipase with low- or high-fat diets on nutrient absorption in pancreatic-insufficient dogs. Gastroenterology. 1999 Feb;116(2):431–437
  91. Suzuki A, Mizumoto A, Sarr MG, et al. Bacterial lipase and high-fat diets in canine exocrine pancreatic insufficiency: a new therapy of steatorrhea?. Gastroenterology. 1997 Jun;112(6):2048–2055
  92. Borowitz D, Goss CH, Limauro S, et al. Study of a novel pancreatic enzyme replacement therapy in pancreatic insufficient subjects with cystic fibrosis. J Pediatr. 2006 Nov;149(5):658–662
  93. Borowitz D, Goss CH, Stevens C, et al. Safety and preliminary clinical activity of a novel pancreatic enzyme preparation in pancreatic insufficient cystic fibrosis patients. Pancreas. 2006 Apr;32(3):258–263
  94. Kuhel DG, Zheng S, Tso P, et al. Adenovirus-mediated human pancreatic lipase gene transfer to rat bile: gene therapy of fat malabsorption. Am J Physiol Gastrointest Liver Physiol. 2000 Nov;279(5):G1031–G1036
  95. Maeda H, Danel C, Crystal RG. Adenovirus-mediated transfer of human lipase complementary DNA to the gallbladder. Gastroenterology. 1994 Jun;106(6):1638–1644
  96. Layer P, Keller J. Pancreatic enzymes: secretion and luminal nutrient digestion in health and disease. J Clin Gastroenterol. 1999 Jan;28(1):3–10

PII: S1521-6918(10)00040-5

doi: 10.1016/j.bpg.2010.03.006

Best Practice & Research Clinical Gastroenterology
Volume 24, Issue 3 , Pages 337-347 , June 2010