Conservative Treatment and the Role of Replacement Therapy with Pancreatic Enzymes Heinz F. Hammer Assoc. Prof. of Internal Medicine and Gastroenterology Medical University Graz, Austria

Exocrine Pancreatic Insufficiency Clinical Problems Abdominal pain, steatorrhoea, meteorism Weight loss - malnutrition Deficiency of fat soluble vitamins (esp. Vit D) Diabetes mellitus Obstruction Biliary duodenal Disease related complications pancreatic carcinoma

Pancreatic Maldigestion Loss of parenchyma CP, cystic fibrosis, resection, pancreatic tumours Inhibition or inactivation of secretion obstruction (papillary or head tumours), decreased endogenous stimulation (celiac disease, Crohn’s, diabetes mellitus) inactivation (ZES) Postcibal asynchrony gastric surgery, short bowel, Crohn’s, diabetes adaped from Keller & Layer, GUT 2005, 54 (Suppl. 6): vi9-29

Pancreatic Calcifications

Red Flags for Exocrine Pancreatic Insufficiency: Disappearance of Pain and Appearance of Calcifications Lankisch MR, Mayo Clin Proc. 2001;76:242-51 IJCP .. idiopath. Juvenile, ISCP .. idiopath. senile HP ….. Hereditäre, ACP … alkoholische

Enzyme Replacement Therapy Pancreatic physiology: what do you need to know about pancreatic secretion in order to understand enzyme replacement therapy Treatment Which dosage? Are all products the same?

Lipase Output After a Mixed Meal Keller J et al, Am J Physiol 1997;272:G632-G637 Cumulative postprandial lipase output 500 – 1000 kU l 1 2 3 4 5 6 1000 2000 3000 4000 5000 6000 7000 Lipase, U/min Postprandial h Lipase n =14 x ± SE JK from my group could show that the duration of the pancreatic postprandial response, defined by the return of secretion into the id range, correlates quite well with the duration of the motor response, i.e., the fed pattern Interdigestive range

Steatorrhoea and Pancreatic Insufficiency adapted from Di Magno EP et al. NEJM 1973:288:813

Postprandial Duodenal Lipase in Health and Chronic Pancreatitis DiMagno EP et al, N Engl J Med 1977;296:1318-22 Lipase, U/min CP (Pancreatin Supplementation) Health (Secretion) cumulative 25 - 50 kU Lipase prevent steatorrhoea Lipase, kU/min 4 - 6 fold increase over fasting secretion for the duration of the digestive period Which components cause stimulation? For one, protein and their breakdown products Hours postprandially

Digestion of Fat is the Determining Factor in Pancreatic Insufficiency Lipase secretion is lost faster than secretion of other enzymes

Chronic Pancreatitis: Alcohol Use and Loss of Function DiMagno et al, N Y Acad Sci 1975;252:200-7 10 20 30 40 50 60 70 80 90 100 5 15 25 % Maximal Enzyme Output Years Of Alcohol Consumption Malabsorption Threshold Lipase Trypsin Which could be corrected by supplementing enzymes This suggested that intraileal nutrients might play a role, e.g. a shift of balance between stimul duod nutr and inhibit ileal nutrient.

Digestion of Fat is the Determining Factor in Pancreatic Insufficiency Lipase secretion is lost faster than secretion of other enzymes In contrast to other enzymes, there is no adequate endogenous substitution for lipase

Duodenale Amylase and Starch Malabsorption Layer P et al, Gastroenterology 1986;91:41-48 100 80 Salivary amylase Brush Border Oligosaccharidases 60 Starch malabsorption % 40 20 20 40 60 80 100 120 Duodenal Amylase, % normal

Digestion of Fat is the Determining Factor in Pancreatic Insufficiency Lipase secretion is lost faster than secretion of other enzymes In contrast to other enzymes, there is no adequate endogenous substitution for lipase Fast luminal destruction of lipase (Layer P et al, Am J Physiol 1986;251:G475) Lipase: < 5% reach the ileum Trypsin: 20% reach the ileum Amylase: >35% reach the ileum

Digestion of Fat is the Determining Factor in Pancreatic Insufficiency Lipase secretion is lost faster than secretion of other enzymes In contrast to other enzymes, there is no adequate endogenous substitution for lipase Fast luminal destruction of lipase Fast destruction of lipase in luminal pH < 4.0 in chronic pancreatitis

Intraduodenal pH in Chronic Pancreatitis DiMagno EP et al, N Engl J Med 1977;296:1318-22 pH 4 = irreversible destruction of Lipase

Enzyme Replacement Therapy Pancreatic physiology: what do you need to know about pancreatic secretion in order to understand enzyme replacement therapy Treatment Which dosage? Are all products the same?

Effect of Pancreatic Enzymes on Fecal Fat Cochrane Database of Systematic Reviews 2009; CD006302

Pancreatic Enzyme Replacement Individual dosing (severity of the disease, composition of food, body weight) ~ 2.000 (1000 - 4000 units/g lipase units) digest 1 g of fat Adults: at least 40 000 (20 000-75 000) units of lipase per main meal, 10 000- 25 000 units per snack Administration with every meal or snack in individual portions during the meal, or short time after starting Layer, P. et al Current Gastroenterological Reports, 2001, 3: 101-108

Pancreatic Enzyme Replacement Response to enzyme therapy may be monitored through an assessment of symptoms or, more objectively, through 72-hour stool weight quantification, or even better 72-hour stool fat quantification

Efficacy of Enzyme Replacement Therapy is Influenced by: Denaturation of enzymes (lipase!) by gastric acid Improper timing of enzymes Coexisting small-intestinal mucosal disease Rapid intestinal transit Noncompliance Alternate diagnosis (eg. pancreatic cancer) Effects of diabetes: disturbance of motility, stasis, bacterial overgrowth, impairment of mucosal regeneration and villus function

Pancreatic Enzyme Replacement: Choose the Right Product Unprotected enzymes: Irreversible Destruction at pH <4 Acid resistant pH-sensitive microspheres ≤2-3mm: mixing with food in stomach, prandial emptying, duodenal liberation Acid resistant tablets > 2-3 mm: Postprandial retention, no mixing with food

Chronic Pancreatitis and Exocrine Pancreatic Insufficiency Decreasing insulin and glucagon secretion Increasing need of lipase Steatorrhoea Increasing calcifications Abnormal fecal elastase Decreasing pain Remaining parenchyma Years to decades

Questions Agree or Disagree? Pancreatic calcifications indicate that exocrine pancreatic insufficiency is likely to be present. Appearance of pain in chronic pancreatitis should make you suspicious of pancreatic insufficiency to develop Enzyme replacement therapy needs to replace 10 % of normal postprandial lipase output in order to prevent steatorrhoea Digestion of protein is the determining factor in pancreatic insufficiency Adults should receive between 20 000 and 75 000 units of lipase per main meal, and 10 000- 25 000 units per snack Response to enzyme therapy may be monitored through measurement of fecal elastase