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
7000
Lipase, U/min
6000
5000
4000
3000
2000
l
ll
l
l l
l l ll
l
l
l
Lipase
l
ll l
l
l
l
l
l
l
1000
Interdigestive range
ll
l
0
0
1
2
3
4
5
6
Postprandial h
n =14
x ± SE
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
Health
(Secretion)
CP
(Pancreatin Supplementation)
40
Lipase, U/min
Lipase, kU/min
5
4
3
2
cumulative 25 - 50 kU Lipase
prevent steatorrhoea
30
20
10
1
0
0
0
1
2
3
0
1
Hours postprandially
2
3
Digestion of Fat is the Determining
Factor in Pancreatic Insufficiency
1.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
% Maximal Enzyme Output
100
90
80
70
60
50
40
Trypsin
30 Lipase
20
10 Malabsorption Threshold
0
0
5
10
15
20
Years Of Alcohol Consumption
25
Digestion of Fat is the Determining
Factor in Pancreatic Insufficiency
1.Lipase secretion is lost faster than secretion
of other enzymes
2.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
Starch malabsorption %
100
80
Salivary amylase
Brush Border Oligosaccharidases
60
40
20
0
0
20
40
60
80
100
120
Duodenal Amylase, % normal
Digestion of Fat is the Determining
Factor in Pancreatic Insufficiency
1.Lipase secretion is lost faster than secretion
of other enzymes
2.In contrast to other enzymes, there is no
adequate endogenous substitution for lipase
3.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
1.Lipase secretion is lost faster than secretion
of other enzymes
2.In contrast to other enzymes, there is no
adequate endogenous substitution for lipase
3.Fast luminal destruction of lipase
4.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
1 00 .H07
Acid resistant
pH-sensitive
microspheres
≤2-3mm:
mixing with food in
stomach,
prandial
emptying,
duodenal
liberation
Unprotected enzymes:
Irreversible
Destruction at pH <4
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