Conservative Treatment and the Role of Replacement

Therapy with Pancreatic Enzymes

Heinz F. HammerAssoc. Prof. of Internal Medicine and

GastroenterologyMedical University Graz, Austria

Exocrine Pancreatic InsufficiencyClinical 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 MaldigestionPancreatic MaldigestionLoss of parenchyma

CP, cystic fibrosis, resection, pancreatic tumours

Inhibition or inactivation of secretionobstruction (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. senileHP ….. 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 MealKeller J et al, Am J Physiol 1997;272:G632-G637

Interdigestive range

0 1 2 3 4 5 60

1000

2000

3000

4000

5000

6000

7000

Lipa

se,

U/m

in

Postprandial h

Lipase

n =14x ± SE

Cumulative postprandial lipase output 500 – 1000 kU

Steatorrhoea and Pancreatic Insufficiency

adapted from Di Magno EP et al. NEJM 1973:288:813

0

1

2

3

4

5

0 1 2 3

Postprandial Duodenal Lipase in Health and Chronic Pancreatitis

DiMagno EP et al, N Engl J Med 1977;296:1318-22

Hours postprandially

Lip

ase,

kU

/min

Health (Secretion)

0

10

20

30

40

0 1 2 3

Lip

ase,

U/m

in

CP (Pancreatin Supplementation)

cumulative 25 - 50 kU Lipase prevent steatorrhoea

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

LipaseTrypsin

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25

% M

axim

al E

nzym

e O

utpu

t

Years Of Alcohol Consumption

Malabsorption Threshold

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

Duodenal Amylase, % normal

Sta

rch

mal

abso

rptio

n %

Salivary amylaseBrush Border Oligosaccharidases

0

20

40

60

80

100

0 20 40 60 80 100 120

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 lipase4.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

• 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

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

• 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

Efficacy of Enzyme Replacement Therapy is Influenced by:

Pancreatic Enzyme Replacement:Choose the Right Product

100.H07

Acid resistant tablets> 2-3 mm: Postprandial retention,no mixing with food

Acid resistant pH-sensitive microspheres

≤2-3mm:mixing with food in

stomach,

prandialemptying,duodenalliberation

Unprotected enzymes: Irreversible Destruction at pH <4

Chronic Pancreatitis and Exocrine Pancreatic Insufficiency

Remaining parenchyma

Increasing need of lipase

Increasing calcifications

Steatorrhoea

Abnormal fecal elastase

Years to decades

Decreasing insulin and glucagon secretion

Decreasing pain

QuestionsAgree 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