1. 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

2. 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

3. 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

4. Pancreatic Calcifications

5. 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

6. 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?

7. 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

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

9. Postprandial Duodenal Lipase in Health and Chronic Pancreatitis DiMagno EP et al, N Engl J Med 1977;296:
Lipase, U/min
CP (Pancreatin Supplementation)
Health (Secretion)
cumulative 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

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

11. Chronic Pancreatitis: Alcohol Use and Loss of Function DiMagno et al, N Y Acad Sci 1975;252:200-710 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.

12. 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

13. 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

14. 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

15. 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

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

17. 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?

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

19. Pancreatic Enzyme Replacement
Individual dosing (severity of the disease, composition of food, body weight)
~ ( units/g lipase units) digest 1 g of fat
Adults: at least ( ) units of lipase per main meal, 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:

20. 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

21. 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

22. 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

23. 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

24. 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 and units of lipase per main meal, and units per snack
Response to enzyme therapy may be monitored through measurement of fecal elastase