1. health and fitness
2. disease
3. cancer

Australasian treatment guidelines for
the management of pancreatic
exocrine insufficiency
March 2010
CONTENTS
Page
Chapter 1 – Introduction
3
Chapter 2 – Pancreatic exocrine insufficiency
5
Chapter 3 – Pancreatic enzyme replacement therapy
11
Chapter 4 – Dietary management
17
Chapter 5 – Pancreatitis: Acute pancreatitis in adults
23
Chapter 6 – Pancreatitis: Chronic pancreatitis in adults
28
Chapter 7 – Pancreatitis: Childhood pancreatitis
38
Chapter 8 – Post surgery: Bowel resections
43
Chapter 9 – Post surgery: Gastrectomy
47
Chapter 10 – Post surgery: Parenchymal reduction
53
Chapter 11 – Pancreatic exocrine insufficiency in cystic fibrosis
58
Chapter 12 – Unresectable pancreatic cancer
73
Chapter 13 – Coeliac disease
77
Chapter 14 – Diabetes mellitus
80
Chapter 15 – Human immunodeficiency virus
83
Chapter 16 – Irritable bowel syndrome
86
Chapter 17 – Conclusion
88
Chapter 1
Introduction
The pancreas, by way of the various enzymes that it produces and secretes into the
gastrointestinal tract, has a major role in digestion and hence normal nutrition. The release
of pancreatic enzymes is orchestrated by an interplay of neural and hormonal factors which
respond to the delivery of food into the gastrointestinal system. An imbalance in these
events often leads to malnutrition and symptoms associated with malabsorption of nutrients.
This imbalance may be brought about by disease of the pancreas or as a consequence of
surgery on the upper gastrointestinal tract or pancreas.
Some of the effects of malnutrition and malabsorption can be reversed by the adequate
administration of pancreatic enzymes. The availability of pancreatic enzymes and an
improved understanding of their role in relieving symptoms of malabsorption and
malnutrition of patients with these disorders have led to the development of these treatment
guidelines.
A group of clinicians representing disciplines of medicine involved with patients with
pancreatic exocrine insufficiency was convened to write these guidelines. The group
undertook this task under the auspices of the Australasian Pancreatic Club with the aim of
publicising the guidelines to the wider medical community for their use.
Financial support for the committee’s activities was provided to the Australian Pancreatic
Club and the committee members by an unrestricted educational grant from Solvay. Grey
Healthcare provided assistance for research of the world literature and in medical writing of
the guidelines.
In developing the guidelines evidence was sourced from Medline, EMBASE and the
Cochrane library. Each of the findings and recommendations were categorised according to
the available level of evidence, as defined by Sackett et al (Table 1). Where levels of
evidence could not be found, the opinion of the group was used to provide guidance. This
is noted as level 5 evidence.
It is the hope of the committee that where evidence is lacking, these guidelines may serve
as the impetus for future research in the management of pancreatic exocrine insufficiency.
Table 1. Levels of evidence
Level of evidence
1
2
3
a
Systematic review of randomised controlled trials
b
Individual randomised controlled trial
a
Systematic review of cohort studies
b
Individual cohort study or low-quality randomised controlled trial
c
Outcomes research
a
Systematic review of case-control studies
b
Individual case-control study
4
Case series or poor-quality cohort or case-control studies
5
Expert opinion
Reference
1.
Sackett DL et al. Evidence-based medicine: How to practice and teach EBM. 2nd ed:
Churchill Livingstone.
Chapter 2
Pancreatic exocrine insufficiency
Introduction
The pancreas is a glandular organ located in the upper abdomen behind the stomach
(Figure 1). Its head is connected to the duodenum by the main pancreatic duct and the
accessory pancreatic duct (Figure 2). The pancreas serves two major functions. It is an
endocrine organ producing insulin and glucagon to regulate blood sugar levels. In addition,
it is a digestive organ that secretes digestive enzymes and bicarbonate into the duodenum
via a ductal system.
Pancreatic exocrine excretion
Pancreatic enzymes, particularly lipase, amylase, trypsin and chymotrypsin, play a critical
role in macronutrient digestion. Pancreatic enzyme secretion is predominately stimulated by
exposure of the duodenal mucosa to nutrients, in particular lipids.
After ingesting a meal, pancreatic enzyme secretion can be divided into three phases (Table
1).1 During the first phase, enzyme delivery into the duodenum increases rapidly and
reaches maximal levels within 30 to 60 minutes. In the second phase, enzyme secretion
decreases to a slightly lower level and then remains stable for 2 to 3 hours. At the end of the
digestive period, enzyme secretion returns to baseline levels, usually 3 to 4 hours
postprandially. The extent and duration of pancreatic enzyme secretion depends on the
caloric content, nutritional composition and physical properties of the meal.
Table 1. Pancreatic enzyme secretion into the duodenum1
Lipase (U/min)
Amylase (U/min)
Trypsin (U/min)
Phase I
maximal secretion
Phase II
stable secretion
Phase III
baseline secretion
3000-6000
500-1000
200-1000
2000-4000
500
150-500
1000
50-250
50-100
Figure 1. The pancreas and nearby organs
Reproduced from the National Cancer Institute.
Figure 2. The pancreas anatomy
Reproduced from the National Cancer Institute.
Pancreatic exocrine insufficiency
Pancreatic exocrine insufficiency occurs when amounts of enzymes secreted into the
duodenum in response to a meal are not sufficient to maintain normal digestive processes.
There are three main reasons why sufficient pancreatic enzymes may not be available:1
1. Insufficient capacity of the pancreas to synthesise enzymes due to loss of or injury to the
pancreatic parenchyma
2. Reduced stimulation of enzyme production due to postcibal asynchrony
3. Impaired delivery of enzymes to the duodenum due to obstruction of the pancreatic duct
Due to the high reserve capacity of the pancreas and compensatory mechanisms that partly
substitute for the loss of pancreatic enzymes, clinical symptoms of pancreatic exocrine
insufficiency do not usually manifest until duodenal lipase levels fall below 5-10% of normal
postprandial levels.1,2
The main clinical consequence of pancreatic exocrine insufficiency is fat maldigestion and
malabsorption resulting in steatorrhoea. Steatorrhoea is characterised by frothy, foul
smelling and buoyant stools due to their high fat content. Other symptoms may also include
abdominal pain, flatulence and weight loss in adults or lack of weight gain in children. If left
untreated, fat maldigestion may lead to low circulating levels of micronutrients, fat-soluble
vitamins and lipoproteins, which have been related to high morbidity due to increased risk of
malnutrition-related complications and cardiovascular events.3,4
Diagnosis of pancreatic exocrine insufficiency
Pancreatic exocrine function is difficult to assess because the organ and its secretions are
relatively inaccessible. However, it is important to be able to differentiate
malabsorption/maldigestion due to pancreatic causes from other causes and to assess the
efficacy of treatment. Pancreatic exocrine function can either be tested directly or indirectly.
Direct tests involve collecting pancreatic secretions via duodenal intubation with the
pancreas stimulated with exogenous hormones or intestinal nutrients. Although direct tests
are the most sensitive and specific methods to assess pancreatic exocrine function, their
cost and invasive nature limit their routine use in clinical practice.
Indirect tests are cheaper and easier to administer, but are less sensitive and less specific
because they are designed to detect abnormalities secondary to loss of pancreatic function.
Indirect tests can be divided into 4 categories – faecal tests, breath tests, urinary tests and
blood tests.
Faecal tests
The 3-day faecal fat test is considered the gold standard for diagnosing and quantifying
steatorrhoea, although it does not distinguish between pancreatic and nonpancreatic
causes. The method most commonly used is the Van de Kramer method.5 Adults consume
a diet containing 100 g of fat for 3-5 days.6 Children meticulously weigh their food and
maintain careful dietary records in order to calculate the mean daily fat intake. Stools are
collected over 72 to 96 hours and pooled for analysis. Steatorrhoea is present if more than
7% of ingested fat is excreted in patients over 6 months of age or more than 15% in patients
under 6 months of age.6,7 The odious nature of this test for both patients and laboratory
technicians makes it an unpopular choice.
Determination of steatocrit can be used to measure faecal fat. Homogenised faeces are
centrifuged at 15,000 rpm for 15 minutes causing the lipid and aqueous phases to separate
from each other and from the stool residue.8 A lipid phase representing less than 10% of
volume is considered normal in patients older than 6 months of age. Perchloric acid can be
added to the faecal homogenate to improve sensitivity of the test.9,10 The acid steatocrit
method correlates closely with the 3-day faecal fat test.11,12
Faecal chymotrypsin is measured photometrically after solubilising chymotrypsin with a
detergent.13 It is convenient, reproducible and sensitive, and can reliably differentiate
between pancreatic-sufficient and pancreatic-insufficient patients. Faecal chymotrypsin has
been validated by showing good correlation with direct secretion tests following hormonal
stimulation with CCK-secretin.14,15
Faecal elastase-1 is measured using an ELISA assay, and has been found to be both more
sensitive and specific than faecal chymotrypsin in detecting pancreatic insufficiency.16-18 As
such, the use of this test is becoming more prevalent in clinical practice. A faecal elastase
level less than 200 mcg/g stool is indicative of mild pancreatic exocrine insufficiency, and
less than 100 mcg/g stool of severe pancreatic exocrine insufficiency.
Microscopic examination of stool for fat globules may be used as a crude screening test for
malabsorption. A simple qualitative technique utilises the Sudan III stain in which neutral fat
globules are visualised under the microscope. If fat globules are present, then it may be
prudent to perform additional tests.
Breath tests
Radiolabelled breath tests take advantage of the fact that ingested lipids are predominantly
hydrolysed by pancreatic lipases in the small intestine, absorbed as free fatty acids and
monoglycerides, and transported to the liver, where oxidative metabolism liberates carbon
dioxide. Three different trigylcerides have commonly been used – trioctanoin, tripalmitate
and triolein. Triolein breath tests appear to be more specific than the others.19 However,
triolein breath tests have not been fully validated against the 3-day faecal fat test for
confirming the presence of fat malabsorption.20,21 In addition, they do not differentiate
between pancreatic and nonpancreatic causes of fat malabsorption. The clinical use of
radiolabelled breath tests for the diagnosis of pancreatic exocrine insufficiency is still limited
due to expensive substrates and long test periods with many samples.
Urine tests
Urine tests use nonabsorbable substrates that are specifically cleaved by pancreatic
enzymes. This results in the release of a rapidly absorbable marker that is conjugated in the
liver and excreted in urine. Two substrates have been used – bentiromide and fluorescein
dilaurate.22-24 Following substrate ingestion, urine is collected over a specified time period.
The test is then repeated on a second day to correct for urinary recovery. Urine tests have
been superseded by simpler blood tests with better specificity and sensitivity.
Blood tests
Trypsin is exclusively synthesised by the pancreas and small amounts are released into the
blood as the proenzyme trypsinogen. Measurement of serum immunoreactive trypsinogen is
a sensitive and relatively non-invasive method of screening for pancreatic insufficiency in
older children. It has been validated in children with cystic fibrosis and pancreatic exocrine
insufficiency due to other causes.25,26 Serum trypsinogen levels below 20 ng/mL are
reasonably specific for pancreatic insufficiency in patients over 7 years of age.
Serum immunoreactive trypsinogen is also used as a diagnostic screening test for cystic
fibrosis in infants less than 1 year of age.27 Individuals with cystic fibrosis have elevated
serum immunoreactive trypsinogen levels during the first year of life. The levels fall to
subnormal levels by 6 years of age in those cystic fibrosis patients who are pancreatic
insufficient.
Conclusions
The pancreas plays an important role in macronutrient digestion through the secretion of
digestive enzymes into the duodenum. Pancreatic enzyme secretion reaches maximal
levels within 1 hour following meal ingestion and remains at a lower, but stable level for an
additional 2 to 3 hours before returning to baseline levels. The extent and duration of
pancreatic stimulation depends on the caloric content, nutrient composition and physical
properties of the meal.
Pancreatic exocrine insufficiency occurs when pancreatic enzyme secretion is no longer
sufficient to support normal digestive processes. Steatorrhoea is the main clinical
consequence that if left untreated can result in significant morbidity.
A number of different tests have been developed to diagnose pancreatic exocrine
insufficiency. Direct function tests are the most specific and sensitive tests, but are too
expensive, cumbersome and invasive for routine use in clinical practice. Three-day faecal
fat is the “gold standard” for diagnosing steatorrhoea but is unpopular with patients and lab
technicians. Of the remaining indirect function tests, faecal elastase-1 and serum
trypsinogen are most commonly used.
In clinical practice, the diagnosis of pancreatic exocrine insufficiency is usually based on an
assessment of the patient’s clinical state, a self-report of bowel movements and weight loss
in adults or failure to thrive in children. Pancreatic enzyme replacement therapy can be
trialled, and symptom improvement would support a diagnosis of pancreatic exocrine
insufficiency.
References
1.
Keller J and Layer P. Gut 2005; 54(Suppl VI): vi1-vi28.
2.
DiMagno EP et al. N Engl J Med 1973; 288: 813-15.
3.
Domínguez-Muñoz JE. Curr Gastroenterol Rep 1007; 9: 116-22.
4.
Montalto G et al. Pancreas 1994; 9: 137-38.
5.
Van de Kramer JK et al. J Biol Chem 1949; 177: 347-55.
6.
Thompson JB et al. J Lab Clin Med 1969; 73: 521-30.
7.
Fomon SJ et al. Am J Clin Nutr 1970; 23: 1299-313.
8.
Colombo C et al. J Pediatr Gastroenterol Nutr 1987; 6: 926-30.
9.
Van den Neucker AM et al. Acta Paediatr 2001; 90: 873-75.
10.
Wagner MH et al. J Pediatr Gastroenterol Nutr 2002; 35: 202-05.
11.
Van den Neucker et al. Clin Biochem 2002; 35: 29-33.
12.
Amann ST et al. Am J Gastroenterol 1997; 92: 2280-84.
13.
Kaspar P et al. Clin Chem 1984; 30: 1753-57.
14.
Bonin A et al. J Pediatr 1973; 83: 594-600.
15.
Brown GA et al. Arch Dis Child 1988; 63: 785-89.
16.
Walkowiak J et al. Pediatrics 2002; 110(1 Pt 1):e7.
17.
Loser C et al. Gut 1996; 39: 580-86.
18.
Glasbrenner B et al. Eur J Gastreneterol Hepatol 1996; 8: 1117-20.
19.
Newcomer AD et al. Gastroenterology 1979; 76: 6-13.
20.
Pedersen NT et al. Scand J Clin Lab Invest 1991; 51: 699-703.
21.
Dumasy V et al. Am J Gastroenterol 2004; 99: 1350-54.
22.
Scharpe S and Iliano L. Clin Chem 1987; 33: 5-12.
23.
Toakes PP. Gastroenterology 1983; 85: 565-69.
24.
Mitchell CJ et al. Scan J Gastrenterol 1979; 14: 737-41.
25.
Durie PR et al. Pediatr Res 1986; 20: 209-13.
26.
Moore DJ et al. Gut 1986; 27: 1362-68.
27.
Couper RT et al. J Pediatr 1995; 127: 408-13.
Chapter 3
Pancreatic enzyme replacement therapy
Introduction
The primary treatment goal for pancreatic exocrine insufficiency is to eliminate
maldigestion/malabsorption and maintain adequate nutrition. Ideally, treatment would
perfectly mimic the exocrine secretory response of a healthy pancreas in terms of the
quantity, composition and timing of luminal enzymatic activity.
Pancreatic enzyme replacement therapy is the mainstay of treatment for pancreatic
exocrine insufficiency. The objective is to deliver sufficient enzymatic activity into the
duodenal lumen simultaneously with the meal in order to restore nutrient digestion and aid
absorption. There are two pancreatic enzyme replacement agents available in Australia –
Creon® and Panzytrat®.
Creon® is a porcine pancreatic enzyme extract encapsulated in minimicrospheres with a
pH-sensitive coating. The minimicrospheres are similar in size to food particles to enable
them to mix homogenously with the chyme (0.7-1.6 mm diameter). Creon is available in four
different strength capsules (Table 1).
Table 1. Minimum enzyme activities in each Creon capsule
Lipase (BP units)
Amylase (BP units)
Protease (Ph Eur Units)
Creon 5,000
Creon 10,000
Creon 25,000
Creon 40,000
5,000
4,000
300
10,000
8,000
600
25,000
18,000
1,000
40,000
25,000
1,600
Panzytrat® 25000 is a porcine pancreatic enzyme preparation of encapsulated entericcoated microtablets. The microtablets are uniform in size and shaped for maximum contact
surface area (2 mm diameter convex spheres of thickness 1.90-2.10 mm) Each capsule
contains no less than lipase 25,000 BP units, amylase 22,500 BP units and protease 1,250
Ph Eur Units.
Both preparations contain a pH-sensitive coating to allow the enzymes to mix with the
chyme while being protected from inactivation by gastric acid. The intact enzymes then
pass into the alkaline pH of the duodenum where the enteric coating rapidly dissolves and
the enzymes are released.
Several factors influence the effectiveness of pancreatic enzyme replacement therapy:
• Variations in enzyme content
• Size of the enzyme particles
• Dissolution properties of the enteric coating
These factors need to be taken into consideration when reviewing the literature and making
recommendations for appropriate dosing regimens. They can also influence the
bioequivalence of different formulations.
Enzyme content
Units of measurement for pancreatic enzyme content and activity vary internationally. The
conversion factors for units of enzyme activity are shown in Table 2. The quality and content
of a product or formulation must conform to the description laid out in the relevant
pharmacopoeia. Since enzymes are sensitive proteins, their activity is degraded with time.
Measured enzyme activities are generally higher than the declared activities to ensure the
required minimum activity at the end of shelf life.
Table 2. Conversion factors for units of enzyme activity1
European
Pharmacopoeia
Lipase
Amylase
Protease
1
1
1
Federation
Internationale
Pharmaceutique
1
1
1
British
Pharmacopoeia
United States
Pharmacopoeia
1
1
1*
1
4.15
62.5
*Only free protease for pancreatin; total protease for pancreatic extract (pancrelipase).
Particle size
Theoretically, enzyme particles that are too large may not empty from the stomach as
quickly as smaller food particles. The dissociation of duodenal passage of nutrients and
enzymes could prevent their ability to aid digestion. Two studies have investigated the
effects of enzyme particle size on gastric transit time. Another two studies compared the
effectiveness of microspheres and minimicrospheres on fat excretion.
A study in 26 healthy subjects was conducted to identify the size of spheres that would
empty from the stomach with food and to determine whether different meals altered the
size.2 This study showed that sphere size was a more important determinant of sphere
emptying than meal size. Gastric transit time was inversely related to sphere diameter. Onemillimetre spheres emptied consistently faster than 2.4 or 3.2 mm spheres when ingested
together with either 420 g or 100 g meals. The ideal sphere size was 1.4 +/- 0.3 mm in
diameter to empty at the same rate as the test meal of chicken liver.
Another study compared the gastric transit time of 2 mm microspheres with 1.2 mm
minimicrospheres in pancreatic-insufficient subjects with cystic fibrosis.3 Patients consumed
20 g of free oil in spaghetti meals or 20 g of oil emulsified in a milk meal. This study did not
show a difference in gastric transit time between the two preparations.
The effect of microspheres (1-2 mm diameter) and smaller minimicrospheres (0.7-1.25 mm
diameter) on fat excretion and fat intake was evaluated in a double-blind, randomised,
multicentre, crossover study.4 Twenty-three patients with chronic pancreatitis and faecal fat
excretion of greater than 7.5 g/day during a placebo period were randomly assigned to
receive the two treatments in random order. The results showed that the minimicrospheres
were equally effective as microspheres in improving the coefficient of fat absorption.
Similar results were obtained in a study of 24 cystic fibrosis patients.5 Patients took
microspheres for 14 days and were then randomised to 28 days of microspheres followed
by 28 days of minimicrospheres or vice versa. Stool fat (g/day) and coefficient of fat
absorption were measured at the end of each treatment period, and both products were
found to be therapeutically equivalent.
Taken together, these results suggest that spheres with a diameter of 2 mm or less are
mixed intragastrically with the meal and emptied intact into the duodenum within the chyme.
However, a further decrease in sphere size may not be associated with greater clinical
benefit.
Dissolution properties of the enteric coating
All digestive enzymes are susceptible to acid degradation, especially lipase. Modern
preparations protect enzymes from denaturation with a pH-sensitive enteric coating. The
polymer coatings of these preparations are designed to release the enzymes when exposed
to the higher pH environment of the duodenum. If enzyme release takes too long after
exposure to the intestinal milieu, then the digestive action may be delayed. Therefore, the
physicochemical properties of the enteric coating are crucial for the efficacy of enzyme
therapy.
Duodenal pH is normally between 6 and 7, but after a meal, it drops to around 5.5. In vitro
studies show that the coating of most preparations dissolves over a variable period of time
at a pH 5.0-6.0.6-8 Most preparations show more than 90% dissolution within 30 minutes at
pH greater than 6.0.
These results suggest that even if enzyme preparations have equivalent enzyme content,
they may not be equivalent with respect to their release of enzymatic activity.
Adjunct therapy for acid suppression
The pH of the duodenum in patients with pancreatic disease may be even lower than
normal due to bicarbonate deficiency.9 It has been shown that duodenal pH declines to less
than 4 after 100 minutes postprandially in some patients with pancreatic exocrine
insufficiency due to chronic pancreatitis.10 This lower pH may impair the release of entericcoated pancreatic enzymes and reduce their effectiveness. In theory, acid suppression may
improve fat absorption by providing a duodenal environment more conducive to efficient
enzyme function.
Several different classes of agents have been used to evaluate the role of acid suppression
in the treatment of pancreatic exocrine insufficiency (Table 3). In general, the results have
been mixed, and there is limited evidence that these agents improve fat absorption in
patients with pancreatic exocrine insufficiency on enzyme therapy. However, they may be
useful in patients who continue to experience symptoms of pancreatic exocrine
insufficiency, particularly steatorrhoea, despite enzyme therapy.
Table 3. Acid-suppressing agents evaluated for pancreatic exocrine insufficiency
Class
Antacids
Agent
Bicarbonate
Hydroxides
H2-receptor antagonists
Cimetidine
Metiamide
Famotidine
Ranitidine
Proton pump inhibitors
Omeprazole
Lansoprazole
Prostaglandin analogues
Enprostil
Misoprostol
A 6-week, double-blind, placebo-controlled crossover trial evaluated the efficacy of
misoprostol (100 µg, 4 times daily) in improving fat absorption in 17 children with cystic
fibrosis already on pancreatic enzyme therapy.11 Misoprostol did not further improve fat
absorption in those patients who had >90% absorption on enzyme therapy alone. However,
a significant improvement with misoprostol was observed in those with <90% absorption on
standard enzyme therapy.
These results are in agreement with another study involving 11 cystic fibrosis patients with
faecal fat excretion >10% while on enzyme therapy.12 This double-blind, placebo-controlled
crossover study evaluated the effect of gastric acid inhibition by 20 mg omeprazole. Adjunct
therapy with omeprazole resulted in a significant reduction in faecal fat excretion.
The efficacy of omeprazole was also evaluated in another randomised, crossover study
involving 15 patients with cystic fibrosis who had residual steatorrhoea despite high-dose
pancreatic enzyme supplements (≥10,000 lipase/kg/day).13 In this study, omeprazole
significantly improved fat digestion and absorption. Median faecal fat loss decreased from
13 g/day to 5.5 g/day with a similar improvement noted when fat absorption was calculated.
The coefficient of fat absorption was 87% without omeprazole versus 94% with omeprazole.
Recommended doses
In healthy individuals, the amount of digestive enzymes released postprandially far exceeds
the amount required for normal digestive function. In pancreatic exocrine insufficiency,
between 5% and 10% of normal cumulative enzyme outputs may be enough to aid digestion
and improve clinical symptoms.
The relationship between dose of pancreatic enzymes required and the presence of
malabsorption and maldigestion is not linear. Therefore, doses need to be individually
titrated to the lowest effective dose.
In adults, the initial dose recommended is 25,000 to 40,000 units lipase with each meal.1,14
The dose can then be titrated up to a maximum of 75,000 to 80,000 units lipase per meal.
In children, 500 to 4,000 units lipase per gram of dietary fat may be given.15 Alternatively,
the amount of enzymes may be calculated based on bodyweight; using this method,
children under the age of 4 years may be given 1,000 units lipase per kilogram bodyweight
per meal. Children greater than 4 years of age may be given 500 units lipase per kilogram
per meal. The enzyme doses should be halved for snacks.16
In infants, 500 to 1,000 units lipase per gram of dietary fat is recommended.15 Alternatively,
infants may be given 2,000 to 4,000 units lipase per breastfeed or 120 mL of infant
formula.16
In infants and children, the maximum dose recommendation is 10,000 units of lipase per
kilogram per day.16
The efficacy of pancreatic enzyme replacement therapy for specific conditions is described
in subsequent chapters.
Summary
Pancreatic enzyme replacement therapy is the main pharmacological treatment for
pancreatic exocrine insufficiency. Modern preparations contain pancreatic extract
encapsulated in microtablets or (mini)microspheres with pH-sensitive enteric coating. The
enzymes mix intragastrically with the chyme while being protected from acid degradation by
the enteric coating. The enzymes are then emptied from the stomach simultaneously with
the chyme. The higher pH in the duodenum dissolves the enteric coating, releasing the
enzymes at the appropriate site for digestion and absorption. Not all pancreatic enzyme
replacement agents are equivalent, although the therapeutic implications of the differences
are not yet clear.
Patients with pancreatic exocrine insufficiency should be commenced on the lowest
recommended dose of pancreatic enzymes and then increased and titrated to the lowest
effective dose. In adults, the maximum recommended dose is 75,000 to 80,000 units lipase
per meal. In infants and children, the maximum recommended dose is 10,000 units lipase
per kilogram per day. Acid-suppressing agents may be trialled in those patients who
continue to experience symptoms of pancreatic exocrine insufficiency despite high-dose
enzyme therapy.
References
1.
Layer P et al. Curr Gastroenterol Rep 2001; 3: 101-08.
2.
Meyer JH et al. Gastroenterology 1988; 94(6): 1315-25.
3.
Meyer JH and Lake R. Pancreas 1997 15(3): 226-35.
4.
Halm U et al. Aliment Pharmacol Ther 1999; 13(7): 951-57.
5.
Patchell CJ et al. J Cyst Fibros 2002; 1(4): 287-91.
6.
Gan KH et al. Aliment Pharmacol Ther 1996; 10(5): 771-75.
7.
Case CL et al. Pancreas 2005; 30(2): 180-83.
8.
Littlewood JM et al. J Pediatr Gastroenterol Nutr 1988; 7(Suppl 1): S22-29.
9.
Keller J and Layer P. Gut 2005; 54: 1-28.
10.
DiMagno EP et al. N Engl J Med 1977; 296: 1318-22.
11.
Robinson P and Sly PD. J Pediatr Gastroenterol Nutr 1990; 11: 37-40.
12.
Heijerman HG et al. Dig Dis Sci 1993; 38: 1-6.
13.
Proesmans M and De Boeck K. Eur J Pediatr 2003; 162: 760-63.
14.
Dominguez-Munoz JE. Curr Gastroenterol Rep 2007; 9: 116-22.
15.
Anthony H et al. J Paediatr Child Health 1999; 35(2): 125-29.
16.
Baker SS. Ther Clin Risk Manag 2008; 4(5): 1079-84.
Chapter 4
Dietary management
Introduction
The management of patients with pancreatic exocrine insufficiency (PEI) is a complex issue.
Patients need to be assessed to determine if enzyme therapy is required, what dosage to
prescribe and be constantly monitored for compliance. A nutritional assessment of patients
with PEI is essential due to the weight loss in adults or lack of weight gain in children
associated with malabsorption, and the potential nutritional deficiencies that can occur.
The involvement of a dietician to oversee dietary management is critical. The role of the
dietician is to make an initial assessment of the nutritional adequacy of the patient’s diet.
Dietary advice can then be specifically tailored to improve energy and protein intake, and
ensure the diet is nutritionally adequate in vitamins and minerals. The dietician can also play
a role in ongoing patient management by monitoring dietary compliance, nutritional
deficiencies and enzyme therapy compliance.
Nutritional assessment
Aetiology of PEI
It is important to understand the underlying aetiology of PEI so that nutritional management
can address both the PEI and also any specific needs associated with the disease state.
Nutritional management differs according to different aetiologies, particularly in the
monitoring of nutritional parameters, the recommendations for meal size and frequency and
the potential need for nutritional supplementation.
Detailed diet history
A detailed diet history is essential to establish the patient’s baseline diet. This enables an
estimation of the patient’s total energy, fat and protein intake. Some important questions
need to be answered so that the dietician can formulate dietary goals and strategies to
address problem areas.
• Is the patient following a low, normal or high fat diet?
• Is the patient’s protein and total energy intake adequate to facilitate weight gain or
prevent weight loss?
• Does the patient consume three large meals per day or smaller meals with snacks in
between?
Weight assessment
Weight loss in adults or lack of weight gain in children is common in PEI due to
malabsorption and the patient’s fear of eating. Weight loss is usually gradual in chronic
pancreatitis and occurs in the early stages of the disease before steatorrhoea develops. In
contrast, weight loss is rapid in pancreatic cancer. Up to 90% of patients with pancreatic
cancer present with weight loss and malabsorption at the time of diagnosis.1
In children with cystic fibrosis (CF), malnutrition continues to be a major clinical problem
with stunted growth evident in most patient populations. Data from the Australasian CF Data
Registry from 2002 indicate that 12% of children and adolescents were below the 5th
percentile for height and 10% were below the 5th percentile for weight.2 Underweight
remains prevalent in CF into adulthood, with 8% of adults having a body mass index (BMI)
less than 18 kg/m2, and a further 23% with a BMI between 18 and 20 kg/m2.
Ensuring adequate growth in children and preventing weight loss in adults are paramount to
any dietary management. In adults, BMI is a common method of assessing the weight
status of populations and also individuals. BMI can have its limitations in individuals due to
variations in lean body mass, skeletal mass and frame, and hence should always be used
with some caution. Assessing the weight history of the patient when they have been well,
together with BMI will allow a logical target weight to be set for an individual. For children,
locally available growth charts are used as targets until 18 years of age.
Monitoring body composition may be a better indicator of nutritional status and enable
deteriorations in nutritional status to be detected earlier. In adults, a more direct assessment
of muscle mass and protein status is mid arm muscle circumference (MAMC). MAMC
requires an upper arm girth measurement and tricep fat fold. The muscle circumference is
then estimated using an equation and the result is compared using a centile chart. MAMC is
very useful in conditions where body weight is not a good indicator of nutritional status, such
as in liver disease if significant ascites is present, and hence weight is not an accurate
measurement. MAMC has been used as a nutritional assessment tool in PEI in adults. In a
trial of post-pancreaticojejunostomy patients who took enzyme therapy for PEI, 9 out of 11
patients weighed < 90% of their ideal weight for height.3 However, only 2 patients had
MAMC outside the normal range, and hence weight loss was reflected by a decrease in
body fat not muscle mass. This is very useful information to the dietician to determine what
weight is being lost – fat mass or lean mass, as preservation of lean body mass is the more
important issue. Whilst MAMC is a good indicator of protein status and lean muscle mass, it
does require an experienced and trained person to take the necessary measurements
accurately.
Similarly, various skin fold measurements on the body may provide information as to
changing fat mass in adults. In children, skin folds for detecting changes in body
composition over time are unreliable because their fat free mass is constantly changing.
Dual-energy X-ray absorptiometry (DXA) is a superior method to measure body
composition, but is more expensive and more invasive.
Nutritional testing
Fat malabsorption due to PEI can result in deficiencies in fat-soluble vitamins (A, D, E and
K). It is recommended that fat-soluble vitamins be measured at the time of diagnosis and
monitored annually in patients with PEI. Vitamins should be supplemented in those patients
with levels below the reference range.
Vitamin B-12 deficiency may be observed, particularly post-gastrectomy as intrinsic factor in
the stomach facilitates vitamin B-12 absorption in the terminal ileum. Hence any surgery
that reduces intrinsic factor and gastric acidity will reduce vitamin B-12 absorption.
Iron deficiency may occur, particularly in surgical procedures where the duodenum has
been bypassed, the primary site for iron absorption. Reduced gastric acidity also impairs
conversion of ferric iron to the more absorbable ferrous form, so again, any gastric reduction
surgery or proton pump inhibitor use will affect the ability of iron to be absorbed.
Dietary recommendations for PEI
Dietary fat intake
Historically, dietary fat intake has been restricted in patients with PEI to minimise fat
malabsorption and reduce steatorrhoea. Diets containing as low as 20 g of fat per day have
been prescribed.4 However, low fat diets are lower in total energy, and restricting fat intake
also reduces intake of fat-soluble vitamins, which are already malabsorbed in PEI.
Furthermore, it appears lipase activity during small intestinal transit requires the presence of
dietary triglycerides.5,6 In an experimental model of PEI in dogs, fat digestion and absorption
were higher when enzyme supplements were taken with a high fat diet compared with a low
fat diet.7
Studies in humans have successfully used high fat diets with adequate pancreatic enzyme
replacement therapy (PERT) with good results. A randomised, double-blind, placebocontrolled trial showed that lipase-deficient chronic pancreatitis patients do not require a fat
restricted diet when adequate enzyme therapy is prescribed.8 In this study, patients
consumed at least 100 g of dietary fat per day. Another randomised, placebo-controlled trial
evaluated the effects of PERT in combination with dietary counselling in patients with
unresectable pancreatic cancer.9 Patients were encouraged to consume as much fat as they
could tolerate, and to divide energy intake across 6 eating occasions. Patients receiving
enzyme therapy consumed 8.42 MJ per day compared with 6.66 MJ per day in placebo
patients.
Today, fat restriction is no longer recommended in the dietary management of patients with
PEI. Once dietary fat intake is established, the dietician can counsel patients to consume at
least a normal fat intake (e.g. 30% energy from fat). A higher fat intake may be
recommended for some patients such as those having difficulty gaining or maintaining
weight. Adequate fat intake will increase total energy intake and fat-soluble vitamin intake.
PERT should be taken with all meals since they are likely, and should be encouraged, to
contain at least some fat content. However, enzymes do not need to be taken with fat free
snacks such as fruit, jelly, lollies, juices, cordial etc.
MCT
The use of medium chain triglycerides (MCT) in the dietary management of PEI patients has
been controversial. MCTs have two important features that can theoretically make them
useful for managing PEI. First, they do not require pancreatic enzymes or bile for
absorption. Second, they do not stimulate pancreatic exocrine secretion. Few human
studies have evaluated the therapeutic efficacy of MCTs in clinical practice.
A cross-over study evaluated the absorption of MCTs with and without PERT in 6 patients
with severe PEI due to chronic pancreatitis.10 The patients consumed a low-fat diet to which
butter or MCT oil was added, with and without PERT. Each diet was consumed for a period
of 5 days. In the absence of PERT, steatorrhoea was substantial with both diets, although
less with MCT oil compared with butter. However in the presence of PERT, steatorrhoea
was the same with both diets. These results are supported by other studies showing PERT
improved the absorption of MCTs in children with cystic fibrosis and in a patient on an
elemental diet after total pancreatectomy.11,12
MCTs do not provide any clear nutritional advantage over the usual long-chain triglycerides
when PERT is used to manage PEI. They are poorly tolerated in many patients and can
induce side effects such as abdominal pain, nausea and diarrhoea. In addition, MCT oil is
heat sensitive, and therefore cannot be used for frying, baking or roasting. They are best
used when added to salads, or used as a spread or as an addition to foods already cooked.
The benefit of MCTs is that of additional energy intake. They may be trialled in patients
whose symptoms persist despite enzyme therapy or when weight gain is very difficult.
Meal frequency and size
Nutrient intake is logically better distributed across 6 or more smaller meals throughout the
day. The main reason for this is a smaller meal or snack with suitable enzyme therapy will
reduce the amount of fat in the meal that can be malabsorbed. Larger meals may not be
appetising to a patient with PEI due to nausea or anorexia, and require significant gastric
mixing followed by simultaneous gastric emptying of the chyme with the enzymes. This
mixing of chyme with pancreatic enzymes is considered more efficient when smaller meals
or snacks are consumed.
Smaller, more frequent meals are often better tolerated by the patient. This regime may
improve the energy, protein and micronutrient content of the diet, and therefore facilitate
weight gain and nutritional improvements.
Alcohol abstinence
With any PEI, alcohol abstinence is crucial as alcohol inhibits gastric lipase secretion, and
therefore contributes to fat malabsorption.4 In chronic pancreatitis, there are studies that
claim that PEI may be reversible after cessation of alcohol use.13,14 Other studies found that
PEI is progressive regardless of whether alcohol is continued or not.15,16 However, the
deterioration of pancreatic function with time was much more marked in patients who
continued to consume alcohol than in those who abstained.15 This indicates that continual
alcohol abuse can cause more severe and rapid pancreatic damage.
Timing of enzyme intake
Timing related to meals can influence the effectiveness of pancreatic enzymes.
Theoretically if enzymes are taken before the meal, enzymes may be emptied from the
stomach before the meal is emptied, and therefore only part of the meal may be adequately
digested. If enzymes are taken after the meal, some of the meal may be emptied before the
enzymes, and so again digestion may be incomplete. Enzymes taken with or during the
meal theoretically would be the best approach.
A study of 24 patients with PEI evaluated the effectiveness of enzyme therapy administered
just before, during or just after meals.17 Patients were treated with 40,000 IU of lipase for
three consecutive 1-week crossover periods. Fat digestion before and during the three
treatment periods was evaluated. The results showed that fat digestion tended to be higher
when capsules were taken during or immediately after the meal.
Summary
Routine nutritional assessment of patients with PEI is essential due to the potential impact
that malabsorption can have on nutritional status. Patients should be referred to a dietician
for nutrition counselling. Dieticians should encourage patients to avoid alcohol, to eat small
meals frequently, to consume at least a normal fat diet and to take PERT during or
immediately after meals and snacks. MCTs may be considered in patients with persistent
malabsorption despite enzyme therapy and with inadequate weight gain or further weight
loss. Patients should have their vitamin status monitored annually and supplementation
administered as required.
Tips for increasing energy intake
•
Use full fat dairy products rather than reduced fat products
•
Use spreadable fats (eg. butter, margarine, peanut butter, cream cheese, mayonnaise)
wherever possible on crackers, on vegetables, in mashed potato, in sandwiches. Mono or
polyunsaturated fats are preferred due to cardiovascular benefits over saturated fats
•
Fry meat, chicken, fish and vegetables in plenty of mono or polyunsaturated oil or margarine
•
Enjoy high fat snacks such as nuts, seeds, cheese & crackers, dips, chips, cake and biscuits
•
Have high fat desserts after meals (eg. cheesecake, puddings, ice cream, custard)
•
Make sure main meals include a generous portion of protein (eg. meat, fish, chicken, eggs,
tofu/vegetable protein)
•
Enjoy nutritious low fat foods (fruit, dried fruit, vegetables, bread) but try to consume with
additional fats such as margarine, nuts, cream or butter
•
Make up fortified milk (add skim milk powder to fresh milk) to increase protein and energy,
and use on cereal, in tea and coffee, to make custards and desserts, etc
•
Use commercially available supplements if still struggling to gain weight
Recommendations for the dietary management of PEI
Recommendations
Level of
evidence
Patients with PEI should be referred to a dietician for nutrition counselling
5
Patients with PEI should abstain from alcohol
3a
Patients should be counselled to consume at least a normal fat intake (e.g. at
least 30% energy from fat)
5
Patients should be encouraged to consume smaller and more frequent meals
5
Oral PERT should be taken with or immediately after meals
2b
Medium chain triglycerides can be trialed in patients who fail to gain or to
maintain adequate body weight in order to increase energy intake
5
Fat-soluble vitamins should be measured at the time of diagnosis, and
annually thereafter, and supplemented as required
5
References
1.
Smith RC et al. Int J Pancreatol 1991; 8: 253-62.
2.
Cystic Fibrosis Australia, Cystic fibrosis in Australia and New Zealand 2002: Annual
Report from the Australasian Cystic Fibrosis Data Registry. 2004, Cystic Fibrosis
Australia: Sydney.
3.
Van Hoozen CM et al. Pancreas 1997; 14: 174-80.
4.
Domínguez-Muñoz JE. Curr Gastroenterol Rep 2007; 9: 116-22.
5.
Holtmann G et al. Am J Physiol 1997; 273: G553-58.
6.
Thiruvengadam R and DiMagno EP. Am J Physiol 2988; 255: G476-81.
7.
Suzuki A et al. Gastroenterology 1999; 116: 431-37.
8.
Safdi M et al. Pancreas 2006; 33: 156-62.
9.
Bruno MJ et al. Gut 1998; 42: 92-96.
10.
Caliari S et al. Scand J Gastroenterol 1996; 31(1): 90-94.
11.
Durie PR et al. J Pediatr 1980; 96: 862-64.
12.
Caliari S et al. Scand J Gastroenterol 1993; 28: 749-52.
13.
Begley CG and Roberts-Thomson IC. Dig Dis Sci 1985; 30(12): 1117-20.
14.
Garcia-Puges AM et al. Gastroenterology 1986: 91(1): 17-24.
15.
Gullo L et al. Gastroenterology 1988; 95(4): 1063-68.
16.
Nagata A et al. Digestion 1986; 33(3): 135-45.
17.
Domínguez-Muñoz JE et al. Aliment Pharmacol Ther 2005; 21: 993-1000.
Chapter 5
Pancreatitis: Acute pancreatitis in adults
Introduction
Acute pancreatitis is a common inflammatory disease of the pancreas triggered by the
unregulated activation of trypsin within pancreatic acinar cells. Many aetiologies for acute
pancreatitis exist, the most common being gallstones and alcohol abuse.1 In approximately
10% of cases, no cause is identifiable.2-7
The incidence in Australia has not yet been reported, but overseas estimates range from 5.4
to 79.8 per 100,000 adults.1 Most episodes of acute pancreatitis are mild and without
complications. Approximately 15-20% of patients develop severe disease with local and/or
systemic complications. Overall, the mortality in acute pancreatitis is approximately 5%, but
is higher in severe cases involving pancreatic necrosis, especially if infected, and
multisystem organ failure.8
Pancreatic exocrine function
The impact of an episode of acute pancreatitis on pancreatic exocrine function is a subject
of debate. The data are difficult to interpret with studies involving patients with acute
pancreatitis of varying severity and underlying aetiology. Furthermore, the studies employed
different techniques to test for pancreatic exocrine function and measurements were
undertaken at different stages of recovery.
When taken together, the data support the fact that some patients have pancreatic exocrine
dysfunction for a period of time after acute pancreatitis. Pancreatic exocrine insufficiency
occurs more frequently in patients with alcohol as the aetiological factor, and in those
recovering from severe episodes versus mild episodes, and in those who developed
necrosis or pseudocyst.9,10
Early phase
Limited data are available on exocrine pancreatic function in the early phase of acute
pancreatitis. The interdigestive pancreatic secretion was studied by a duodenal intubation
perfusion technique in eight patients with acute pancreatitis within 72 hours of symptom
onset.11 The results showed that exocrine pancreatic secretion in the early phase of mild-tomoderate acute pancreatitis remained within the normal range.
In a more recent study of 75 patients with their first episode of acute pancreatitis, faecal
elastase-1 was determined on the day of refeeding, which was on average 11.2 days after
the attack.12 Abnormal faecal elastase values were found in 9 out of the 75 patients. The
results were not significantly related to severity.
Convalescent phase
Impaired exocrine pancreatic function has been noted in the convalescent period after acute
pancreatitis. Exocrine pancreatic function was analysed in 53 patients who had recovered
from their first attack of necrotising pancreatitis.13 After 4 weeks, 74% had mild-to-moderate
insufficiency, while 26% suffered from severe impairment. After 12 to 18 months, 80-85%
had pancreatic insufficiency, with severe insufficiency measured in 5-10%.
In a study of 30 patients with acute pancreatitis, pancreatic function was abnormal in all
patients at various time intervals in the convalescent period.14 Two to 6 months after the
attack, 4 out of 6 patients still had abnormal results. Results were improved or normal in 12
of 15 patients who were retested after 1 year.
A recent study of 54 patients with alcoholic acute pancreatitis found that exocrine
dysfunction was present in 39% of patients early after their first episode.15 After 2 years,
only 9% still had pancreatic exocrine dysfunction.
In another study, 18 patients surviving at least 1 month after necrosectomy for acute
necrotising pancreatitis were followed up.16 At the time of discharge from hospital, 13
patients had pancreatic exocrine insufficiency. After 6 weeks, 9 of these patients still had
exocrine insufficiency that continued for 6 months. By 18 months, 7 of these 9 patients had
resolution of symptoms, but steatorrhoea persisted in 2 patients.
The pancreatic exocrine function of 75 patients who had a single attack of acute pancreatitis
was studied.10 Among the 36 patients with alcoholic pancreatitis, 29 had impaired
pancreatic function between 4 and 18 months after the episode. Of the 39 patients with
biliary pancreatitis, only 9 had pancreatic insufficiency. When the tests were repeated 1 year
later 18 out of 23 patients with alcoholic pancreatitis continued to have pancreatic
insufficiency, whereas only 4 out of 26 patients with biliary pancreatitis showed insufficiency.
A prospective cohort study in 39 patients with severe acute biliary pancreatitis evaluated the
influence of necrosectomy on pancreatic exocrine function after 12 months.17 Most of the
patients with necrosectomy had an abnormal exocrine pancreatic function, with
steatorrhoea in 25%. By comparison, exocrine function was abnormal in only 13.3% of
patients without surgery, with no cases of steatorrhoea.
Another prospective study assessed pancreatic exocrine function in 23 patients recovering
from a first attack of acute pancreatitis and evaluated its relationship to severity of attack
and extent of pancreatic necrosis.9 Pancreatic exocrine insufficiency occurred in 6 out of 7
patients recovering from severe attacks compared with 2 out of 16 patients recovering from
mild attacks. All 5 patients who developed pancreatic necrosis or pseudocyst developed
pancreatic exocrine insufficiency whereas only 3 out of 18 patients who did not develop
necrosis or pseudocyst had exocrine insufficiency. The development of pancreatic exocrine
insufficiency was strongly correlated with the extent of pancreatic necrosis.
In contrast to the above studies, a study of 63 patients with acute biliary pancreatitis found
no deficiency in pancreatic exocrine function at 1, 6 or 12 months after the episode.18
Long-term follow up
Pancreatic exocrine function gradually improves following an episode of acute pancreatitis.
The length of time for the recovery appears to depend on the severity of the episode, with
the more severe cases having the longest recovery phase.
The late outcome of acute alcoholic pancreatitis was studied in 47 patients with moderate
clinical course.19 Pancreatic exocrine function was impaired in nearly two-thirds of patients 4
to 7 years after the acute episode. Similar results were observed in 34 patients who had
recovered from biliary or post-ERCP acute pancreatitis after an average of 4.6 years followup.20 In a retrospective study, 35 patients with severe acute pancreatitis were followed up
for a median time of 7 years.21 Nine patients had signs of severe exocrine dysfunction. In
another study of 30 patients who had completed at least 6 months of recovery, 12 had
abnormal faecal fat excretion.22 There was a higher frequency of pancreatic exocrine
insufficiency in the first year after recovery, and incidence decreased as duration of followup increased.
A long-term follow up of 27 patients treated with conservative surgery of necrohaemorrhagic
pancreatitis showed that an almost complete recovery of the exocrine function is achieved
within 4 years.23 Similar results were reported in 28 patients with infected pancreatic
necrosis treated with necrosectomy.24 During a follow up 2 to 8 years after discharge,
median stool elastase-1 concentrations were in the normal range.
In contrast, a study of 63 patients who underwent pancreatic necrosectomy found that onequarter developed exocrine insufficiency during a median follow up of 28.9 months.25
Similarly, a long-term study evaluating the outcomes after operative treatment of necrotising
pancreatitis found that one-quarter developed clinical pancreatic exocrine insufficiency
during the mean follow up of 5 years.26 Normal pancreatic function was associated with 27%
parynchymal necrosis suggesting that pancreatic insufficiency varies with the extent of
necrosis.
Another study found that 2 of 21 patients who underwent necrosectomy for severe
necrotising pancreatitis developed pancreatic exocrine insufficiency as a late complication.27
A follow-up study of nine patients with infected pancreatic necrosis treated with catheter
drainage and necrosectomy evaluated pancreatic exocrine function after 30 months.28 Mildto-moderate exocrine dysfunction was found in 5 patients, severe restriction of exocrine
pancreatic function in 2 patients and normal function in 1 patient.
Pancreatic enzyme replacement therapy
There has only been one clinical trial investigating pancreatic enzyme supplementation in
acute pancreatitis.29 The study was a double-blind, prospectively randomised, placebocontrolled trial including 23 patients with proven acute pancreatitis. Patients were given 3
capsules 4 times per day, providing a daily total of 7,800 units of protease, 96,000 units of
lipase, and 108,000 units of amylase. The patients took the enzymes for a minimum of 5
days. Those predicted to have a severe attack or those who developed complications
received enzymes for 10 days. There were no significant differences in pain scores,
analgesic requirements, length of hospital stay or incidence of complications compared with
placebo. Based on these results, there is no evidence to support the use of pancreatic
enzyme supplements in the initial stages of acute pancreatitis.
However, pancreatic exocrine function seems to be impaired at least during the first 6 to 18
months after acute pancreatitis, if not longer in the more severe cases. Most studies
reported dysfunction based on biochemical analysis, so the incidence of clinically-relevant
insufficiency is not clear. Therefore, it is recommended that all patients recovering from
acute pancreatitis should be monitored for pancreatic exocrine insufficiency. Those who
have suffered from an acute necrotising attack should be given potent oral pancreatic
enzymes and then an evaluation be made later in the recovery period whether or not the
patient has pancreatic steatorrhoea.
Conclusion
Acute pancreatitis is an inflammatory disease associated with significant morbidity and
mortality. While there is no evidence to support the use of pancreatic enzyme replacement
therapy during the initial stages of acute pancreatitis, the data do support the fact that some
patients have pancreatic exocrine dysfunction for a period of time after acute pancreatitis.
Therefore patients should be monitored for pancreatic exocrine insufficiency for at least 6 to
18 months and treated with oral pancreatic enzymes as indicated. Since the length of time
for the recovery of exocrine function appears to depend on the severity of the episode, it
may be prudent to supplement those recovering from an acute necrotising attack with oral
pancreatic enzymes and then evaluate exocrine function later in the recovery period.
Recommendations for pancreatic enzyme replacement therapy in acute pancreatitis
Recommendations
There is no evidence to support the use of pancreatic enzyme replacement
therapy in the initial stages of acute pancreatitis
Patients recovering from an episode of acute pancreatitis should be
monitored for pancreatic exocrine insufficiency for at least 6 to 18 months
Patients recovering from an acute necrotising attack should be
supplemented with oral pancreatic enzymes and then their exocrine
function evaluated later in the recovery period
Level of
evidence
1b
2b
5
References
1.
Lankisch PG. Epidemiology of acute pancreatitis. In: Buchler MW, Uhl W, Friess H,
Malfertheiner P, eds. Acute Pancreatitis: Novel Concepts in Biology and Therapy.
London: Blackwell Science Ltd, 1999; 145-53.
2.
Lankisch PG et al. Int J Pancreatol 1997; 22: 235-36.
3.
Maes B et al. Eur J Gastroenterol Hepatol 1999; 11: 891-96.
4.
Bank S and Indaram A. Gastroenterol Clin North Am 1999; 28: 571-89.
5.
Halvorsen FA and Ritland S. Scand J Gastroenterol 1996; 31: 411-14.
6.
Grendell JH. Gastroenterol Clin North Am 1990; 19: 843-48.
7.
Tarnasky PR and Hawes RH. Gastrointest Endosc Clin North Am 1998; 8: 13-37.
8.
Banks PA et al. Am J Gastroenterol 2006; 101: 2379-400.
9.
Boreham B and Ammori BJ. Pancreatology 2003; 3: 303-08.
10.
Migliori M et al. Pancreas 2004; 28: 359-63.
11.
Dominguez-Munoz JE et al. Scand J Gastroenterol 1995; 30(2): 186-91.
12.
Pezzilli R et al. Hepatobiliary Pancreat Dis Int 2009; 8: 316-19.
13.
Bozhurt T et al. Hepatogastroenterology 1995; 42: 55-58.
14.
Mitchell CJ et al. Scand J Gastroenterol 1983; 18: 5-8.
15.
Pelli H et al. Pancreatology 2009; 9: 245-51.
16.
Bavare C et al. Indian J Gastroenterol 2004; 23: 203-05.
17.
Sabater L et al. Pancreas 2004; 28: 65-68.
18.
Pareja E et al. Pancreatology 2002; 2: 478-83.
19.
Malecka-Panas E et al. Mater Med Pol 1996; 28: 64-68.
20.
Symersky T et al. JOP 2006; 7: 447-53.
21.
Appelros S et al. Eur J Surg 2001; 167: 281-86.
22.
Gupta R et al. J Gastrointest Surg 2009; 13: 1328-36.
23.
Angelini G et al. Digestion 1984; 30: 131-37.
24.
Reszetow J et al. Pancreas 2007; 35: 267-72.
25.
Connor S et al. Surgery 2005; 137: 499-505.
26.
Tsiotos GG et al. Br J Surg 1998; 85: 1650-53.
27.
Tzovaras G et al. Dig Surg 2004; 21(1): 41-46.
28.
Endlicher E et al. Hepatogastroenterology 2003; 50: 2225-28.
29.
Patankar RV et al. HPB Surgery 1995; 8: 159-62.
Chapter 6
Pancreatitis: Chronic pancreatitis in adults
Introduction
Chronic pancreatitis is the persistent damage of pancreatic tissue and function due to
various aetiologies. It is characterised by progressive and irreversible damage to both the
exocrine and endocrine components of the pancreas.1 Its reported incidence in
industrialised countries ranges from 3.5 to 10 per 100,000 people.2, 3
Aetiology
Alcohol is considered the primary cause of chronic pancreatitis, and accounts for 60-70% of
all cases.2, 4 However, its aetiology varies with geographical location. There is a body of
evidence suggesting that alcoholic pancreatitis may begin as acute pancreatitis, with
recurrent episodes of acute necroinflammation leading to irreversible loss of pancreatic
structure and function (the “necrosis-fibrosis hypothesis”).2
Other aetiological factors may include hyperlipidaemia, hereditary factors, autoimmune
disease, congenital pancreatic anomalies (eg. pancreatic divisum, cystic fibrosis) and
hyperparathyroidism.1-3, 5 In about 10-30% of chronic pancreatitis, no identifiable cause can
be found and a diagnosis of idiopathic chronic pancreatitis is made.3, 4 However, recent
research indicates that a significant percentage of these patients may have an identifiable
cause for their condition.
Pathology
Pancreatic fibrosis, acinar atrophy, chronic inflammation, distorted and blocked pancreatic
ducts are key pathological features of chronic pancreatitis.3 Histological changes from
normal pancreatic architecture include irregular fibrosis, acinar cell loss, islet cell loss and
inflammatory cell infiltrates.6
At the early stage, there are scattered foci of fat necrosis, lobular and periductal fibrosis,
protein plugs within side branches of the main pancreatic duct and formation of calculi. In
the advanced stage, stricturing and dilatation of pancreatic ducts may occur. In the late
stage, the pancreatic endocrine tissue is involved, leading to loss of endocrine cells.5
Symptoms
This progressive loss of pancreatic parenchyma eventually leads to impairment of exocrine
and endocrine functions, and subsequent malabsorption.4 The three key clinical features of
chronic pancreatitis are pain, maldigestion and diabetes.3
Abdominal pain is usually, but not always, the initial manifestation of chronic pancreatitis.
Typically, the pain is epigastric or periumbilical in location and may radiate to the back and
into the chest or flanks. Although recurrent or continuous pain is considered an important
symptom of chronic pancreatitis, a subgroup of patients may have no pain at all, presenting
instead with symptoms of pancreatic insufficiency.
Maldigestion is a relatively late manifestation of chronic pancreatitis. It does not become
clinically evident until digestive enzyme output is reduced to less than 10% of normal
secretion.7 In general, maldigestion of fat occurs earlier than that of carbohydrate or proteins
because secretion of lipase decreases more rapidly than that of amylase or proteases.8 As
such, steatorrhoea is the predominant manifestation of maldigestion, with overt cases
occurring in about 30% of patients with chronic pancreatitis.9 Marked steatorrhoea may be
associated with weight loss.
Diagnosis
The diagnosis of chronic pancreatitis relies on relevant symptoms, imaging of pancreatic
structure and assessment of pancreatic function. In general, advanced stages of chronic
pancreatitis may be easily diagnosed by imaging procedures whereas diagnosis of early
disease presents a considerable challenge. Histology could be considered the gold
standard for pathological diagnosis of chronic pancreatitis, but it is difficult to justify biopsies
to obtain pancreatic tissue in clinical practice. The next best diagnostic methods to
demonstrate changes consistent with chronic pancreatitis are endoscopic ultrasound (EUS)
or magnetic resonance cholangiopancreatography (MRCP). The advantage of endoscopic
ultrasound is that tissue can be obtained for histological evaluation; however, it is an
invasive procedure and the results are highly operator dependent. Computed axial
tomography (CT) scan or endoscopic retrograde cholangiopancreatography (ERCP) can
also be used.
The biochemical, structural and functional parameters used to assist in the diagnosis of
chronic pancreatitis are outlined in Table 1.
Table 1: Patient assessment for chronic pancreatitis
Parameter
Interpretation
Surgical biopsy
The diagnostic gold standard of early stage disease, but rarely
available
Used to identify an acute episode of the disease in patients with
pain
Levels may be low in pancreatic insufficiency and may not be
raised with acute flares of the disease
Cannot be used in isolation to diagnose chronic pancreatitis due
to low sensitivity
Used for the diagnosis of steatorrhoea
Alleviation of steatorrhoea with pancreatic enzymes would
suggest a pancreatic cause
Most useful parameter for determining the efficacy of treatment
of maldigestion
Calcification on abdominal x-ray and associated steatorrhoea
would make chronic pancreatitis likely
First procedure usually performed in patients with suspected
chronic pancreatitis
Operator dependent
More sensitive than abdominal x-ray for calcification
Clarity of images often confounded by bowel gas
Widely used
Useful for outlining pancreatic and surrounding anatomy
Sensitive in the detection of pancreatic calcification
Can detect ductular abnormalities although ERCP and MRCP
are more sensitive
Useful for detecting/excluding pancreatic neoplasms and cystic
lesions
May eventually supersede ERCP as a noninvasive alternative
Useful in patients at high risk of developing post-ERCP
pancreatitis or where the pancreatic duct is inaccessible as a
result of surgery
Can outline ductal and parenchymal changes
Can be combined with secretagogues to provide structural as
well as functional data
Possibly most sensitive procedure to detect chronic pancreatitis
although analysis of accuracy is ongoing
Unclear diagnostic role in early stage disease
Used for identification of ductular structural abnormalities
Most common imaging modality for planning intervention
(endoscopic or surgical)
Serum levels of lipase or
amylase
Analysis of fat in stools
Abdominal x-ray
Transabdominal ultrasound
Abdominal CT
Magnetic resonance
cholangiopancreaticography
(MRCP)
Endoscopic ultrasonography
(EUS)
Endoscopic retrograde
cholangiopancreatography
(ERCP)
All patients with painful established chronic pancreatitis should undergo an upper
gastrointestinal endoscopy, abdominal CT scan and ERCP/MRCP in order to detect a
potentially reversible cause of pain, such as peptic ulcer, pseudocyst or common bile duct
stricture.
Classification
Chronic pancreatitis may be separated into 4 different stages based on disease
presentation (Table 2). It is important to note that patients may not experience every stage
of illness.
Table 2: Classification of chronic pancreatitis3
Stage
Symptoms
I
A pre-clinical stage with absent or uncharacteristic symptoms
II
Recurrent acute episodes of pancreatitis without definite signs of chronic pancreatitis
on imaging
III
Further recurrent episodes with intermittent or constant pain in between and signs of
chronic pancreatitis on imaging
IV
Final stage mostly without acute flares and absence or decreased frequency of pain,
possibly associated with evidence of endocrine and exocrine insufficiency
Associated morbidity and mortality
Up to 70% of patients with calcific pancreatitis develop diabetes.2 Diabetes develops late in
the disease course of chronic pancreatitis and therefore denotes advanced disease.
Chronic pancreatitis patients have an increased incidence of pancreatic cancer. The risk of
developing pancreatic cancer is 16.5-fold higher in chronic pancreatitis patients than agematched healthy controls.10 Those with hereditary pancreatitis have an even higher risk of
pancreatic cancer. The estimated cumulative risk of pancreatic cancer to age 70 years in
patients with hereditary pancreatitis is as high as 40%.11 There is also a five-fold increase in
relative risk of developing pancreatic cancer in those with tropical pancreatitis.12
Mortality in chronic pancreatitis, particularly alcoholic pancreatitis, is reported to be
approximately 30% higher than that in the age- and sex-matched general population.13 Onefifth of this excess mortality can be directly attributed to pancreatitis itself. The majority are
secondary to the effects of alcohol and/or smoking on the liver, the respiratory and the
digestive systems.
Pancreatic exocrine insufficiency
Pancreatic exocrine insufficiency (PEI) due to chronic pancreatitis is a consequence of
various factors which regulate digestion and absorption of nutrients.14 Although pancreatic
function has been extensively studied, some aspects of secretion and gastrointestinal
adaptation are not well understood. However, it is known that a progressive loss of
pancreatic acinar cell function in chronic pancreatitis does lead to deficiencies in the
secretion of digestive enzymes from the pancreas. This results in maldigestion of nutrients.
PEI after disease onset depends on the type of pancreatitis.3 PEI develops earlier in
alcoholic, tropical and late-onset idiopathic pancreatitis than early-onset idiopathic
pancreatitis. Those with alcoholic pancreatitis generally develop PEI within 5-6 years of
disease onset. Pancreatic exocrine and endocrine insufficiency is usually present at the
time of presentation in 70% of patients with tropical pancreatitis.
The main clinical manifestations of PEI are fat malabsorption (commonly manifesting as
steatorrhea), weight loss, abdominal discomfort and distention.
Overt steatorrhoea occurs in about one-third of patients with chronic pancreatitis.9 Fat
malabsorption also results in a deficit of fat-soluble vitamins (A, D, E and K) with
consequent clinical manifestations.
Evidence clearly shows that malabsorption does occur in patients with chronic pancreatitis.
Further, natural history studies indicate that the clinical diagnoses of steatorrhoea and
exocrine insufficiency are usually not evident until relatively late in the course of the
disease.15 Untreated malabsorption is related to many long-term harmful effects including
weight loss,4 malnutrition and osteoporosis.15 This suggests that malabsorption, even if it is
not
yet
clinically
evident,
merits
therapy.
Management of PEI in chronic pancreatitis
The general principles for the management of chronic pancreatitis are mainly to control
symptoms, improve nutrition and treat complications.5 These principles should be kept in mind
when managing associated PEI.
Pancreatic enzyme replacement therapy (PERT) The cornerstone of therapy for PEI is replacement of pancreatic enzymes to allow for
efficient digestion and nutrient absorption. PERT has been shown to improve fat absorption,
but steatorrhoea may persist.16-18 It is important to note that the efficacy of PERT may be
influenced by a number of factors including type of preparation, enzyme concentration,
dosage schedule and the use of adjuvant therapy to improve bioavailability of enzymes.
A small study with 29 chronic pancreatitis patients was conducted using enteric-coated,
gastric acid resistant minimicrospheres.16 All patients were on a fat-balanced diet across the
three study phases:
• Phase 1: 7-day baseline to assess malabsorption
• Phase 2: 7-day run-in on PERT
• Phase 3: 14-day randomised parallel-group treatment phase of PERT vs placebo
This study showed no statistically significant differences in most PEI symptoms between
treatment arms, but a trend towards improvement in stool frequency and consistency was
observed in PERT-treated patients.16
In a multicentre, randomised, placebo-controlled trial involving 27 patients with chronic
pancreatitis, PERT-treated patients had significantly less steatorrhoea and had an
improvement in stool consistency. Patients on PERT also had a decrease in stool
frequency.17
PERT in painful chronic pancreatitis
The exogenous replacement of pancreatic proteases for pain is based on the concept of
feedback inhibition of pancreatic exocrine secretion.19 As patients with chronic pancreatitis
have decreased protease activity, perpetual pancreatic stimulation may occur.
It has been proposed that PERT can also stimulate receptors in the proximal small intestine
and trigger a negative feedback loop which suppresses baseline pancreatic secretion,
decreasing ductal pressures and therefore decreasing pain.20, 21 Nevertheless, there are
other pathophysiological mechanisms for pain including perineural inflammation and
fibrosis, uninhibited cholinergic stimulation of pancreas secretion and colonic hypermotility.
Of these, only colonic hypermotility due to steatorrhoea and malabsorption would potentially
respond to PERT.22
A meta-analysis in 1997 analysed the available studies and concluded that there was no
significant benefit of pancreatic enzymes for pain relief in painful chronic pancreatitis.23
Since then, a prospective, multicentre, follow-up study of patients with chronic pancreatitis
was conducted to assess quality of life before and after PERT.24 PERT therapy reduced the
extent of steatorrhoea and pain and was associated with a significant improvement in
quality of life.
Therefore, the role of PERT in reducing pain in chronic pancreatitis remains unclear.25 The
American Gastroenterological Association recommends a trial of high-dose pancreatic
enzymes coupled with acid suppression therapy before proceeding with continuous use of
narcotics or invasive treatment.26
Dosage and administration
The relationship between the dose of pancreatic enzymes required and symptoms of
maldigestion is not linear. For efficient digestion, it is essential that the concentration of
enzymes delivered exogenously to the gut represents at least 5% of normal digestive
enzyme output.1 In general, the dose of lipase required with each meal is of the order of
25,000 to 50,000 units.27 Dosing should be with, or immediately following each meal.28
In case of an inadequate response to therapy, compliance should be checked by
measurement of faecal chymotrypsin, although this is not a standardised procedure.29 In the
compliant patient, doses may be doubled or tripled.
Unprotected digestive enzymes are rapidly destroyed by gastric acid. Acid degradation is a
major factor influencing the bioavailability of PERT.30 Several commercial pancreatic
enzyme preparations are available as enteric-coated tablets, capsules or microspheres. The
use of concurrent acid suppression therapy may be a useful adjunct therapy and is
recommended, especially if severe steatorrhoea continues with adequate dosing of
pancreatic enzyme.31
The use of high-strength preparations can reduce pill burden. High doses of PERT have
been associated with the development of fibrosing colonopathy and colonic strictures in
patients with cystic fibrosis.32-34 There is evidence to suggest that these adverse effects
were due to the presence of the methacrylic acid copolymer in the enteric coating rather
than the dose of lipase.35
If compliant patients remain unresponsive to therapy, the diagnosis of PEI needs to be
reviewed. Coeliac disease, (concomitant) bacterial overgrowth, and blind loop syndrome, as
well as giardiasis, need to be excluded or otherwise be treated specifically.29
A treatment algorithm for PERT in patients with PEI associated with chronic pancreatitis is
proposed in Figure 1.
Figure 1: Recommendations for pancreatic enzyme therapy in patients with
pancreatic exocrine insufficiency due to chronic pancreatitis
Pancreatic enzyme replacement therapy
[25,000–50,000 USP U of lipase/meal]
Adequate response
Inadequate response
Check compliance (faecal chymotrypsin) Increase
enzyme dose (2 to 3 times)
Adequate response
Inadequate response
Additional gastric suppression
Adequate response
Inadequate response
Check diagnosis
Bacterial overgrowth, giardiasis, coeliac disease?
Adapted from Domínguez-Muñoz. 2007.30
YES
NO
Specific therapy
Trial low-fat diet or
substitute dietary fat
for medium-chain
triglycerides
Summary
One of the most common causes of PEI is chronic pancreatitis. Alcohol is considered the
primary cause. The progressive loss of pancreatic parenchyma leads to impaired exocrine
function. Malabsorption occurs in the majority of patients with chronic pancreatitis. However,
the clinical diagnoses of steatorrhoea and exocrine insufficiency are usually not evident until
relatively late in the course of the disease. Therefore, early treatment of PEI is warranted.
The efficacy of PERT may be influenced by a number of factors including type of
preparation, enzyme concentration, dosage schedule and the use of adjuvant therapy to
improve bioavailability of enzymes. For the treatment of PEI, 25,000 to 50,000 units of
lipase are required with each meal. PERT should be taken with or immediately following
meals.
In cases of an inadequate response to therapy, doses may be increased two- to three-fold.
If severe steatorrhoea continues with adequate dosing of pancreatic enzyme, adjunctive
acid suppression therapy is recommended. If patients remain unresponsive to therapy,
other possible causes (e.g. bacterial overgrowth) should be considered.
General dietary and nutritional considerations for patients with PEI due to other causes can
be applicable to patients with chronic pancreatitis. Abstinence from alcohol cannot be
overemphasised for patients with chronic pancreatitis.
Dietary counselling, coupled with PERT, in patients with chronic pancreatitis not only
reduced the extent of steatorrhea and pain, but also significantly improved patients’ quality
of life.
Recommendations for pancreatic enzyme replacement therapy in chronic
pancreatitis
Recommendations
Level of
evidence
PEI occurs in almost all patients with chronic pancreatitis, even though
PEI symptoms often do not manifest until the later stages of the disease.
3a
PERT for chronic pancreatitis patients can improve the symptoms of PEI.
3a
PERT for chronic pancreatitis patients can improve quality of life.
4
Generally, the required amount of lipase with each meal 25,000 to 50,000
units.
5
For severe, persisting steatorrhoea, consider the use of adjunct acid
suppressant therapy.
4/5
Patients with chronic pancreatitis should abstain from alcohol.
3a
References
1.
DiMagno EP et al. Chronic pancreatitis. In: Go VLW, DiMagno EP, Gardner JD,
Lebenthal L, Reber HA and Scheele GA, [Editors]. The pancreas: biology, pathobiology
and disease. New York: Plenum Press, 1993: 665–706.
2.
Tandon RK et al. J Gastroenterol Hepatol 2002; 17(4): 508-18.
3.
Witt H et al. Gastroenterology 2007; 132(4): 1557-73.
4.
Dumasy V et al. Am J Gastroenterol 2004; 99(7): 1350-54.
5.
Pancreas Study Group (Chinese Society of Gastroenterology). Chin J Dig Dis 2005;
6(4): 198-201.
6.
Etemad B and Whitcomb DC. Gastroenterology 2001; 120(3): 682-707.
7.
DiMagno EP et al. N Engl J Med 1973; 288(16): 813-15.
8.
DiMagno EP et al. Ann N Y Acad Sci 1975; 252(200-07.
9.
Lankisch PG et al. Lancet 1996; 347(9015): 1620-21.
10.
Lowenfels AB et al. N Engl J Med 1993; 328(20): 1433-37.
11.
Lowenfels AB et al. J Natl Cancer Inst 1997; 89(6): 442-46.
12.
Chari ST et al. Pancreas 1994; 9(1): 62-66.
13.
Levy P et al. Gastroenterology 1989; 96(4): 1165-72.
14.
Pezzilli R. World J Gastroenterol 2009; 15(14): 1673-76.
15.
Forsmark CE. Am J Gastroenterol 2004; 99(7): 1355-57.
16.
O'Keefe SJ et al. J Clin Gastroenterol 2001; 32(4): 319-23.
17.
Safdi M et al. Pancreas 2006; 33(2): 156-62.
18.
Stern RC et al. Am J Gastroenterol 2000; 95(8): 1932-38.
19.
Gupta V and Toskes PP. Postgrad Med J 2005; 81(958): 491-97.
20.
Slaff J et al. Gastroenterology 1984; 87(1): 44-52.
21.
Ihse I et al. Scand J Gastroenterol 1979; 14(7): 873-80.
22.
Winstead NS and Wilcox CM. Pancreatology 2009; 9(4): 344-50.
23.
Brown A et al. Am J Gastroenterol 1997; 92(11); 2032-35.
24.
Czako L et al. Can J Gastroenterol 2003; 17(10): 597-603.
25.
AGA Technical Review: treatment of pain in chronic pancreatitis. Gastroenterology
1998; 115(3): 765-76.
26.
American Gastroenterological Association Medical Position Statement: tratment of pain
in chronic pancreatitis. Gastroenterology 1998; 115(3): 763-64.
27.
Ferrone M et al. Pharmacotherapy 2007; 27(6): 910-20.
28.
Dominguez-Munoz JE et al. Aliment Pharmacol Ther 2005; 21(8): 993-1000.
29.
Keller J and Layer P. Curr Treat Options Gastroenterol 2003; 6(5): 369-74.
30.
Dominguez-Munoz JE. Curr Gastroenterol Rep 2007; 9(2): 116-22.
31.
Marotta F et al. Dig Dis Sci 1989; 34(3): 456-61.
32.
Smyth RL et al. Lancet 1994; 343(8889): 85-86.
33.
Stevens JC et al. J Pediatr Gastroenterol Nutr 1998; 26(1): 80-84.
34.
Pawel BR et al. Hum Pathol 1997; 28(4): 395-99.
35.
Prescott P and Bakowski MT. Pharmacoepidemiol Drug Saf 1999; 8(6): 377-84.
Chapter 7
Pancreatitis: Childhood pancreatitis
Introduction
Acute and chronic pancreatitis in childhood causes occasional death and significant
morbidity globally.1
The incidence of acute pancreatitis in children and adolescence has increased over the past
10 to 15 years,2-6 although it is still less than in adults.7 In contrast with adults, in whom
alcohol or gall stones are the usual causes of acute pancreatitis, the aetiology in children is
diverse (Table 1).1 Most cases of acute pancreatitis in children have a mild course, and
symptoms settle if food and drink are withheld for 3 to 5 days.1
Approximately 13-20% of cases of acute pancreatitis in children have a prolonged course
with persistent symptoms or associated complications.8-10 A protracted course is more
common in children with systemic disease as the underlying cause of the pancreatitis.
Up to 10% of children have recurrent episodes of acute pancreatitis. Recurrence is more
common in children with idiopathic, structural or familial causes.8,11,12
Chronic pancreatitis
Chronic pancreatitis is an inflammatory disorder that results in anatomical changes that
include chronic inflammatory cell infiltration and gland fibrosis, with loss of exocrine and
endocrine function.1 The more common childhood causes are outlined in Table 2.
Chronic pancreatitis can occur as a result of repeated episodes of acute pancreatitis or
following a sentinel acute pancreatitis event of sufficient severity.1 Diagnosis is based on a
combination of clinical features and functional and imaging studies.1 In addition to
abdominal pain, patients may present with steatorrhoea and weight loss resulting from
diminished pancreatic exocrine function. Diabetes mellitus may also occur as insulin and
glucagon producing cells are destroyed in chronic pancreatitis. Paediatric data on the
prevalence and incidence of exocrine and endocrine failure are limited. In adults, exocrine
insufficiency ultimately occurs in 50-80% of patients and diabetes in 40-70% of patients.13,14
Patients with chronic pancreatitis require long-term follow up with emphasis on monitoring
for pancreatic exocrine insufficiency and diabetes mellitus.1
Table 1. Aetiology of acute pancreatitis in children1
Acute pancreatitis
Drugs
Periampullary obstruction
Trauma
Metabolic
Toxin
Miscellaneous
Inflammatory/systemic
diseases
Salicylates
Paracetamol
Cytotoxic drugs (ie. L-asparaginase)
Corticosteroids
Immunosuppresives (particularly azathioprine and 6-MP)
Thiazides
Sodium valproate
Tetracycline (particularly if aged)
Erythromycin
Gallstones
Choledochal cysts
Pancreatic duct obstruction
Congenital anomalies of pancreas (especially pancreas divisum)
Enteric duplication cysts
Epstein-Barr virus
Mumps
Measles
Cytomegalovirus
Influenza A
Mycoplasma
Leptospirosis
Malaria
Rubella
Ascariasis
Cryptosporidium
Blunt injury (handle bar, child abuse, etc)
ERCP
α-1 antitrypsin deficiency
Hyperlipidaemia
Hypercalcemia
Scorpion, Gila monster, tropical marine snakes
Refeeding pancreatitis
Haemolytic-uremic syndrome
Reye’s syndrome
Kawasaki disease
Inflammatory bowel disease
Henoch-Schonlein purpura
SLE
ERCP: endoscopic retrograde cholangiopancreatography, 6-MP: 6-mercaptopurine, SLE: systemic
lupus erythematesus.
Table 2. Aetiology of chronic pancreatitis in children1
Chronic pancreatitis
Chronic pancreatitis in
childhood
Chronic hereditary
pancreatitis diagnosed
mainly in adult life
Cystic fibrosis
Fibrosing pancreatitis
Hereditary chronic pancreatitis
Tropical calcific pancreatitis
Inborn errors of metabolism (particularly branched chain aminoacidemias)
Idiopathic
Hyperlipidaemias
Partial lipodystrophy
Wilson’s disease
Haemochromatosis
α-1 antitrypsin deficiency
Pancreatic enzyme replacement therapy
There is no evidence to support the use of pancreatic enzyme replacement therapy in
children with acute pancreatitis.1
In children with chronic pancreatitis, pancreatic enzyme replacement therapy may be used
for two reasons – to treat pancreatic exocrine insufficiency or to aid pain relief. In theory,
supplemental pancreatic enzymes decrease pain by suppressing the feedback mechanism
that regulates cholecystokinin release.1 Cholecystokinin release results in acinar drive and
potentially contributes to inflammation. Nine clinical trials have evaluated the use of
pancreatic enzyme replacement therapy for painful chronic pancreatitis with varying
results.15-23 Of the six randomised controlled trials, only two studies using non-enteric coated
enzyme preparations reported some reduction in pain.15,17 The other five randomised
controlled trials using enteric-coated supplements did not report significant benefit for pain
reduction.16,18-21 There have been two prospective, observational studies both of which
reported reductions in pain. One used an enteric-coated preparation22 whereas the other
one did not specify the supplement used.23 The variable results with the different
preparations may be explained by the fact that the feedback-sensitive part of the small
bowel is proximally located and that enzymes in enteric-coated preparations are released
only distally.1
In children with pancreatic exocrine insufficiency, pancreatic enzyme replacement therapy
should be used to:
• Correct macro- and micronutrient maldigestion
• Eliminate abdominal symptoms directly attributable to maldigestion
• Establish normal stools and bowel habits
• Sustain normal growth and nutritional status24
Guidelines for dosing are based on those used for children with pancreatic exocrine
insufficiency due to cystic fibrosis.24,25 Infants should be given 500 to 1,000 units lipase per
gram of dietary fat or 2,000 to 4,000 units lipase per breastfeed or 120 mL of infant formula.
In children, 500 to 4,000 units lipase per gram of dietary fat may be given. Alternatively,
children under the age of 4 years may be given 1,000 units lipase per kilogram bodyweight
per meal, whereas those over 4 years of age may be given 500 units lipase per kilogram per
meal. The maximum dose per day should not exceed 10,000 units lipase per kilogram
bodyweight.
Conclusions
Pancreatitis in children often has a different aetiology and natural history than in adults.
Most cases of acute pancreatitis in children have a mild course and symptoms resolve
without incident. In contrast, management of chronic pancreatitis includes aetiological
investigations, adequate pain control and long-term follow up for monitoring and treating
pancreatic exocrine and endocrine insufficiency.
There is no evidence for the use of pancreatic enzyme replacement therapy in the treatment
of acute pancreatitis in children. Supplemental enzymes should be used in patients with
chronic pancreatitis and documented pancreatic exocrine insufficiency. In patients with
painful chronic pancreatitis, pancreatic enzyme replacement therapy may be trialled for pain
relief even in the absence of documented pancreatic exocrine insufficiency.
Recommendations for pancreatic enzyme replacement therapy in childhood
pancreatitis
Recommendations
There is no evidence to support the use of pancreatic enzyme
replacement therapy in acute pancreatitis
Pancreatic enzyme replacement therapy may be trialled in children with
chronic pancreatitis for pain relief
Long-term follow up of children with chronic pancreatitis should include
monitoring for pancreatic exocrine insufficiency
Children with chronic pancreatitis and documented pancreatic exocrine
insufficiency should be treated with pancreatic enzyme replacement
therapy
Recommended doses
For infants: 500-1,000 units lipase per gram of dietary fat OR 2,0004,000 units lipase per breastfeed or 120 mL of infant formula.
For children: 500-4,000 units lipase per gram of dietary fat OR 1,000
units lipase per kilogram bodyweight per meal (<4 years old); 500 units
lipase per kilogram bodyweight per meal (>4 years old). Doses could be
halved if having a snack instead of a full meal.
Maximum dose: 10,000 units per kilogram bodyweight per day
References
1.
Nydegger A et al. J Gastroenterol Hepatol 2006; 21(3): 499-509.
2.
Nydegger A et al. J Gastroenterol Hepatol 2007; 22(8): 1313-16.
3.
Lowe ME and Greer JB. Curr Gastroenterol Rep 2008; 10(2): 128-35.
4.
Lopez MJ. J Pediatr 2002; 140(5): 622-24.
5.
Sánchez-Ramírez CA et al. Acta Paediatr 2007; 96(4): 534-37.
6.
Werlin SL et al. J Pediatr Gastroenterol Nutr 2003; 37(5): 591-95.
7.
Steinberg W and Tenner S. N Engl J Med 1994; 330(17): 1198-1210.
Level of
evidence
5
1b (uncoated
preparations)
2b (coated
preparations)
5
5
5
8.
Benifla M and Weizman Z. J Clin Gastroenterol 2003; 37(2): 169-72.
9.
Kandula L and Lowe ME. J Pediatr 2008; 152(1): 106-10.
10.
DeBanto JR et al. Am J Gastroenterol 2002; 97(7): 1726-31.
11.
Appelros S and Borgström A. Br J Surg 1999; 86(4): 465-70.
12.
Jaakkola M and Nordback I. Gut 1993; 34(9): 1255-60.
13.
Ammann RW et al. Gastroenterology 1984: 86(5 Part 1): 820-28.
14.
Layer P et al. Gastroenterology 1994; 107(5): 1481-87.
15.
Slaff J et al. Gastroenterology 1984; 87(1): 44-52.
16.
Halgreen H et al. Scand J Gastroenterol 1986; 21(1): 104-08.
17.
Isaksson G and Ihse I. Dig Dis Sci 1983; 28(2): 97-102.
18.
Larvin M et al. Gastroenterology 1991; 100: A283.
19.
Campbell D et al. Gastroenterology 1992; 102: A259
20.
Mössner J et al. Digestion 1992; 53(1-2): 54-66.
21.
Malesci A et al. Scand J Gastroenterol 1995; 30(4): 392-98
22.
Czako L et al. Can J Gastroenterol 2003; 17(10): 597-603
23.
Kahl S et al. Pancreatology 2001; 1(2): 129-99
24.
Anthony H et al. J Paediatr Child Health 1999; 35(2): 125-29.
25.
Baker SS. Ther Clin Risk Manag 2008; 4(5): 1079-84
Chapter 8
Post surgery: Bowel resections
Introduction
Bowel surgery involves procedures to remove a diseased part of the large or small intestine.
Bowel resections can be performed using an open surgical approach or laparoscopically.
A small bowel resection is the surgical removal of one or more segments of the small
intestine. Small bowel surgery includes duodenectomy, ileaectomy and jejunectomy. Small
bowel resections may be performed to treat Crohn’s disease, tumours, ulcers, gangrene,
obstruction (e.g. due to incarceration in a hernia) or trauma to the small intestines.
Prognosis for small bowel resection depends on the seriousness of the underlying disease.
Recovery from the surgery varies depending on the initial condition that prompted the
procedure, the patient’s overall health status and the length of the bowel removed. In
general, complete healing is expected without complications.
Pancreatic exocrine insufficiency (PEI)
The small intestines play a significant role in nutritional absorption. Food is mixed with
digestive enzymes in the duodenum, passed through the jejunum and nutrients absorbed
largely in the ileum. If a significant part of the small intestines are removed, malabsorption of
food nutrients occurs.
It is known that numerous changes occur in the remaining alimentary tract to help adapt to
the shortened intestine after extensive small bowel resections. There is mucosal
hyperplasia and an accelerated rate of epithelial cell renewal.1-3 In addition there is
increased proliferation of parietal cells in the gastric glands.4 This is caused by a rise in
gastrin in the plasma.5, 6 Exogenous gastrin and pentagastrin have been recognised to exert
a trophic action upon the exocrine pancreas7, 8 but do not affect the small bowel distal to the
duodenum.9 Thus hypergastrinaemia, induced by intestinal resection, may well alter the size
and composition of the exocrine pancreas.
It has been shown that massive resections of the small bowel can induce a marked increase
of the pancreatic weight in rats.10 The concurrent increase in total protein suggests that
pancreatic growth could not be attributed to increased water content. The rise of total DNA
indicates cellular hyperplasia.10
It is well recognised that a variety of factors influence intestinal adaptation after bowel
surgery.3 Biliary and pancreatic secretions can stimulate growth in the mucosa of the
ileum,11, 12 even after jejunal resection.13 Therefore, it could be assumed that pancreatic
enzyme composition is well preserved after bowel surgery. While total enzyme content may
remain unchanged, specific activities of enzymes (especially of amylase) are markedly
reduced after small bowel resection. Acinar cell hyperplasia may compensate for the
decreased level of enzymes.10
Animal models show that massive small bowel resection provokes hyperplasia, not only in
the stomach and the remaining intestine, but also in the exocrine pancreas.10 After bowel
resections, a decrease in digestive enzymes of the pancreatic tissue, namely amylase,
lipase and chymotrypsinogen have also been detected in animal models. The complex
interaction between secretions of the gut, stomach and pancreas are likely to be interrupted
by the total, or partial, removal of the small bowel.14
Therefore, it is reasonable to expect patients who have had extensive small bowel
resections to experience a degree of PEI. PEI symptoms after bowel resection are nonspecific. Typically, patients can experience abdominal pain, diarrhoea, steatorrhoea, weight
loss, fatigue and malnutrition.
Medical management
Following extensive bowel surgery, particularly resections of the small bowel, reduced
endogenous stimulation and postcibal asynchrony may lead to intraluminal pancreatic
enzyme deficiency and reduced nutrient absorption. Pancreatic enzyme replacement
therapy could be prescribed,15 although there are no controlled studies demonstrating a
positive effect of enzyme supplementation in this population.16
Theoretically, the use of pancreatic enzymes together with gastric acid suppression therapy
should enable gastric digestion of nutrients with increased delivery of digestive products in
the small bowel. Because of the superior stimulatory capacity of peptides, amino acids and
free fatty acids compared with macronutrients, conditions for nutrient absorption should be
improved by increased endogenous pancreatic enzyme secretion, delayed gastric emptying
and small intestinal transit as well as mucosal hypertrophy.16
Standard lipase doses of 25,000 to 40,000 IU with regular meals could be prescribed.17 For
smaller meals or snacks, 10,000 IU of lipase should be adequate.18
If PERT is prescribed, it should be administered with meals to allow for adequate mixing of
enzymes and meal nutrients.18 If standard doses do not achieve adequate reduction of
symptoms, the dosage can be increased two to three times. Because of potential side
effects, dosages of more than 75,000 IU of lipase per meal are not recommended.19
Dietary management
Severe nutrient and fluid malabsorption occurs following extensive small bowel resections. It
should be noted that patients with less than 100 cm of residual jejunum generally have a net
secretory response to food, and as such, may lose more fluid than they ingest.
In addition to PEI, bowel resections can lead to malabsorption of fluid, electrolytes, minerals
and other essential nutrients, resulting in malnutrition and dehydration. Individualised and
tailored nutritional management helps to optimise intestinal absorption, leading to nutritional
independence such that a patient can resume as normal a lifestyle as possible.
Some general dietary and nutritional considerations for patients with PEI could be
applicable to this patient population. However, dietary management is complex and should
be individualised based on gastrointestinal anatomy, underlying disease and lifestyle.20
Referral to a dietician is recommended.
Summary
There is limited information in recent published literature around PEI in patients after bowel
surgery. Most studies seem to indicate that PEI does occur after bowel resections,
particularly affecting those patients who have undergone extensive small bowel surgeries.
A host of physiological changes occur in response to the significant anatomical changes
consequent to bowel resections. Animal models indicate that pancreatic hyperplasia,
coupled with a decrease in pancreatic digestive enzymes occur post bowel resections.
These may well explain why these patients experience the symptoms of PEI.
PERT could be prescribed for PEI symptoms in this patient population. However, it is
important to note that there is a lack of robust clinical trials to support this practice.
Theoretically, PERT could be prescribed with gastric acid suppression therapy to enable
gastric digestion of nutrients with increased delivery of digestive products to the small
bowel.
The general principles of dietary and nutritional management could be applicable to patients
who have undergone bowel surgeries. However, clinicians should individualise nutritional
management strategies based on gastrointestinal anatomy, underlying disease and the
patient’s lifestyle.
Recommendations for pancreatic enzyme replacement therapy after bowel surgery
Recommendations
Level of
evidence
Pancreatic hyperplasia and a decrease in pancreatic digestive enzymes
are consequences of bowel surgery.
2a
Patients can develop PEI, especially after extensive small bowel
resections.
2a
Oral PERT doses should be individualised. Generally, the required
amount of lipase is 25,000 to 40,000 units with regular meals, and 10,000
units with small meals and snacks.
5
PERT, together with gastric acid suppression therapy should enable
gastric digestion of nutrients with increased delivery of digestive products
in the small bowel.
5
Dietary management is complex and should be individualised based on
gastrointestinal anatomy, underlying disease, and lifestyle. Referral to a
dietician is recommended.
5
References
1.
Dowling RH and Booth CC. Clin Sci 1967; 32(1): 139-49.
2.
McDermott FT and Roudnew B. Gastroenterology 1976; 70(5 Part 1): 707-11.
3.
Williamson RC. N Engl J Med 1978; 298(26): 1444-50.
4.
Winborn WB et al. Gastroenterology 1974; 66(3): 384-95.
5.
Buxton B. Gut 1974; 15(3): 229-38.
6.
D'Sa A A and Buchanan KD. Gut 1977; 18(11): 877-81.
7.
Johnson LR. Gastroenterology 1976; 70(2): 278-88.
8.
Reber HA et al. J Surg Res 1977; 22(5): 554-60.
9.
Oscarson JE et al. Gastroenterology 1977; 72(5 Pt 1): 890-95.
10.
Haegel P et al. Gut 1981; 22(3): 207-12.
11.
Altmann GG. Am J Anat 1971; 132(2): 167-77.
12.
Williamson RC et al. Surgery 1978; 83(5): 570-76.
13.
Weser E et al. Gastroenterology 1977; 73(3): 524-29.
14.
Gelinas MD et al. J Physiol 1982; 322(1): 71-82.
15.
Layer P and Malle U. Pancreatology 2001; 1(Suppl1): 49-54.
16.
Keller J and Layer P. Gut 2005; 54(Suppl 6): vi1-28.
17.
Layer P et al. Gastroenterology 1994; 107(5): 1481-87.
18.
Keller J and Layer P. Curr Treat Options Gastroenterol 2003; 6(5): 369-74.
19.
Layer P et al. Curr Gastroenterol Rep 2001; 3(2): 101-08.
20.
Matarese LE and Steiger E. J Clin Gastroenterol 2006; 40(Suppl 2): S85-93.
Chapter 9
Post surgery: Gastrectomy
Introduction
Gastrectomy is performed most commonly to treat cancer, bleeding gastric ulcers, polyps
and perforations of the stomach wall. Stomach cancer was the most common form of
cancer worldwide in the 1970s and early 1980s, although the incidence rates vary
substantially across different countries. Although the incidence of gastric carcinoma has
been continuously decreasing over the last decade, it remains the fifth leading cause of
cancer-related mortality in Western countries.1 Gastrointestinal diseases (including gastric
ulcers) affect an estimated 25-30% of the world's population.2
For gastric carcinomas, removal of the tumour (often along with the surrounding lymph
nodes) is the only curative treatment.2
Gastrectomy is the treatment of choice for gastric adenocarcinomas, primary gastric
lymphomas, and rare leiomyosarcomas, with about 60% of patients having total
gastrectomies.1
Occasionally, gastrectomy is also used in the treatment of severe peptic ulcer disease or its
complications. While the vast majority of peptic ulcers are managed with medication, partial
gastrectomy is sometimes required for patients who do not respond satisfactorily to medical
therapy, those who develop a bleeding or perforated ulcer, and those who develop pyloric
obstruction. An antrectomy is most commonly used for severe ulcer disease. For duodenal
ulcers, antrectomy may be combined with vagotomy, to reduce the acid production. In all
types of gastrectomy the pylorus and duodenum are resected.
The Billroth I procedure (remaining portion of the stomach is reattached to the duodenum
proximal to the bile duct and the duct of the pancreas) is performed in cases where a
sufficient portion of the upper duodenum remains intact. If the stomach cannot be
reattached to the duodenum, the stomach and the remaining portion of the duodenum are
closed and either a Billroth II (or Polya) or Roux en Y gastroenterostomy is used to connect
the stomach to the remainder of the GI tract. The latter anastomosis is the preferred
procedure following total gastrectomy.3 The removal of the pylorus can cause food to move
quicker into the small intestine, leading to gastric dumping syndrome.2
Morbidity and mortality following gastrectomy has decreased significantly over the last 2-3
decades.4 Depending on the extent of surgery, the risk for postoperative death after
gastrectomy for gastric cancer is approximately 1-3%.2 However malnutrition as a
consequence of malabsorption is one of the postoperative complications of partial and total
gastrectomy.5
The possible causes of malabsorption following total gastrectomy are most likely
multifactorial.4 Clinically relevant postoperative maldigestion is associated with secondary
pancreatic exocrine insufficiency (PEI) and it occurs irrespective of the type of gastrectomy
procedure.3
Malnutrition and consequent bodyweight loss may be related to the loss of gastric reservoir.
Coupled with this, the mediated centrally hypothalamic factors may also cause appetite
suppression.6 Increased peristalsis and bacterial overgrowth may cause diarrhoea, while
rapid small bowel transit and intestinal malabsorption play a part in causing steatorrhoea.6 If
bacterial overgrowth is suspected, then antibiotics may be indicated.7 Both primary and
secondary PEI contribute to nutritional complications post gastrectomy.8
The physiological functions of the stomach are complex, and its interactions with other
organs are poorly understood.1 Nevertheless, through its mechanical and chemical
processes, the stomach has a unique role in food processing and bioavailability.6
Pancreatic exocrine insufficiency (PEI)
It has long been established that patients develop severe PEI following gastrectomy.9 In one
study, the secretion of bicarbonate, lipase and chymotrypsin into the duodenum was
investigated in 12 patients on an average of 21 months after total gastrectomy. In this study,
14 healthy individuals with no history of digestive disease acted as control subjects. The
results of this study showed a significant reduction in bicarbonate and lipase secretion in
gastrectomy patients. Two-thirds of gastrectomy patients also had steatorrhoea. The
authors concluded that the majority of patients who have undergone gastrectomy have
impaired exocrine function.9
Even though it is known that patients develop PEI after gastrectomy, the causes and
underlying mechanisms remain unclear.3 Both animal and human studies have contributed
to the identification of possible pathophysiological pathways.
Animal studies have shown a close functional interaction between the stomach and the
pancreas.10, 11 After gastrectomy, significant exocrine pancreatic trophism occurs. This is
thought to lead to an increase in amylase and trypsin, and a reduction of lipase in the
pancreas.10, 11
Following partial or total gastrectomy, postcibal asynchrony between gastric emptying and
the discharge of bile and pancreatic enzymes into the small intestine occurs.12
Impaired coordination between secretory and motor functions induces:
• Decreased endogenous stimulation of the pancreas, leading to reduced intraluminal
pancreatic enzymes
• Insufficient mixing of pancreatic juice with the nutrients in chyme
• Reduced contact time for digestion of nutrients
This contributes to malabsorption.12, 13
Decreased gastrin, decreased late postprandial pancreatic polypeptide and increased
cholecystokinin levels have been documented in a study of 15 patients after gastrectomy.1
These findings suggest further mechanisms may contribute to PEI following gastrectomy.
Besides postcibal asynchrony, there appears to be a disruption of the interaction between
the stomach and pancreas. Resections of the stomach result in deterioration of exocrine
pancreatic function, possibly due to denervation of the pancreas following lymph node
dissection and division of the vagus nerves.1
Gastrointestinal symptom control, through effective overall nutritional improvement, can
minimise the impact of gastrectomy on quality of life and body composition.14
Management of PEI after gastrectomy
Gastrectomy leads to disturbance of the exocrine and endocrine function of the pancreas,
resulting in primary and secondary PEI.3 Regardless of the cause of PEI, approximately
70% of patients who have undergone partial gastrectomy, and almost all patients who have
had a total gastrectomy develop PEI postoperatively.3
Pancreatic enzyme replacement therapy (PERT)
In spite of the relevance of PEI on the nutritional status of patients who have undergone
gastrectomy, the number of studies evaluating the use of PERT in this patient population is
limited. Pancreatic enzyme replacement therapy (PERT), combined with a high-energy diet,
distributed over six to eight meals per day can improve postoperative nutritional status and
non-specific symptoms in this patient population.3, 7, 8
A double-blind, crossover study involving 15 patients evaluated the effects of 300 mg of an
enteric-coated pancreatin (10,000 IU lipase; 10,000 IU amylase; 650 IU protease) on
abdominal symptoms, bowel habits, faecal fat excretion and oro-caecal transit time in
patients after total gastrectomy. Patients were treated with either pancreatin or placebo in
two test periods each of seven days. During treatment with pancreatin, stool consistency
was significantly more solid. However, the number of bowel movements and abdominal
symptoms were not affected. Only patients with considerable steatorrhoea, experienced a
significant reduction in faecal fat excretion. The authors concluded that the use of PERT
post-gastrectomy can improve stool consistency and decrease faecal fat excretion in
patients experiencing considerable steatorrhoea.15
A randomised, double-blind, prospective study of 52 patients was conducted to assess the
role of PERT on symptoms, energy intake, bowel habits and fat malassimilation postgastrectomy. Surprisingly, no differences were found between placebo and PERT patient
groups. The authors concluded that PERT confers only marginal improvements in
symptoms and steatorrhoea after gastrectomy.16 However, data from this study did show
that patients on PERT had significant improvement in dyspepsia, significant decrease in
symptoms of early satiety and an overall improvement in general wellbeing.16
Nevertheless, as PEI is a well-established complication following gastrectomy, PERT should
be considered part of postoperative management for these patients.8 Adequate enzyme
substitution prevents maldigestion and improves postoperative nutritional status, as well as
other non-specific gastrointestinal symptoms. 17
Dosing
As there are no strict dosing regimens for gastrectomy patients, the required doses of PERT
should be individually adjusted.3, 8 Clinicians should keep in mind that there is no linear
relationship between the dose of pancreatic enzyme and the symptoms of maldigestion.19
Normally, 25,000 to 40,000 IU of lipase taken with regular meals are considered standard
doses,18 while 10,000 IU of lipase should be supplemented for small meals or snacks.13 The
exact dosages of other pancreatic enzymes are less important for therapeutic efficacy.7
PERT should be administered together with the meal. Otherwise, enzymes and meal
nutrients cannot mix adequately and nutrient digestion and absorption will be impaired.13 If
standard doses do not achieve adequate reduction of steatorrhea, dosage should be
increased two to three times. Because of potential side effects, dosages of more than
75,000 IU of lipase per meal are not recommended.7
Adjunt therapy
The most important clinical goal in PERT is to achieve sufficient lipase activity in the
intestine.3 Acid-unstable lipase is predominantly inactivated by gastric acid and proteases.
Although acid inactivation is not a problem for patients who have undergone total
gastrectomy, those who have had partial gastrectomy still secrete a variable amount of
gastric acid. Accordingly, acid suppressants (e.g. H2 antagonists, proton pump inhibitors)
should be considered as adjunct therapy for these patients.3
Formulation
Patients with accelerated gastric emptying due to gastric resections or gastroenterostomies
should be treated with pancreatin granule or powder preparations.3, 13, 20 Patients with rapid
gastrojejunal transit, including those associated with gastrectomy are characterised as
having a significant decrease in gastric acid secretion. This population is often best treated
with powdered enzyme preparations.7 Powders can be rapidly and safely dispersed in the
hypoacidic stomach and act quickly. The disintegration delay conferred by an enteric
coating is unnecessary and may in fact be detrimental when small-bowel transit is
accelerated.7 When the granules or powdered formulations are not available and the
capsules are not providing sufficient symptom relief, then consideration should be given to
having the patients open the capsules and mix the contents with soft food.
Compliance
If steatorrhea still does not improve, faecal chymotrypsin measurements could be
conducted to determine if patients are compliant with medications. Low activities suggest an
insufficient intake of enzymes. It should be noted that results may not be indicative of noncompliance as there are no standardised normal values for enzyme-treated patients.
Patients on PERT should be carefully evaluated. If symptoms and subjective measures such
as dyspepsia, early satiety and general wellbeing do not improve with PERT, then
discontinuation of treatment should be considered.3
Other nutritional deficiencies associated with gastrectomy
Intrinsic factor in the stomach facilitates vitamin B12 absorption in the terminal ileum.
Following gastrectomy intrinsic function is reduced (in partial gastrectomy) or abolished (in
total gastrectomy). Hence vitamin B12 deficiency arises. In addition, where the duodenum
is bypassed iron deficiency results. Hence, in addition to PERT, gastrectomy patients need
to have vitamin B12 and iron replacement therapy.
Summary
The majority of patients who have undergone partial or total gastrectomy develop a degree
of PEI. This contributes to maldigestion, weight loss and impacts on quality of life. These
patients can benefit from PERT postoperatively. Adequate and appropriate enzyme
substitution may reduce maldigestion and contribute to an improvement in post-gastrectomy
nutritional status and reduce maldigestion.
PERT should be tried and continued if patients respond to treatment and experience an
improvement in general wellbeing.3 Doses should be continually reviewed and
individualised. Concurrent nutritional management, particularly with regard to dietary fat
intake, vitamin B12 and iron supplements also should be implemented.
Recommendations for pancreatic enzyme replacement therapy after gastrectomy
Recommendations
Level of
evidence
The majority of patients who have undergone gastrectomy have a degree
of PEI and may benefit from PERT.
2a
Oral PERT doses should be individualised. Generally, the required
amount of lipase is 25,000 to 40,000 units with regular meals, and 10,000
units with small meals and snacks.
5
Double or triple the dose (up to a maximum of 75,000 units lipase per
meal) if current PERT doses do not adequately improve steatorrhoea.
5
Consider the use of adjunct acid suppressant therapy for patients who
have undergone partial gastrectomy.
5
Patients with accelerated gastric emptying should be prescribed
pancreatin granules or powder preparations.
5
PERT therapy should be discontinued if both symptoms and subjective
measures do not improve with treatment.
5
References
1.
Friess H et al. Am J Gastroenterol 1996; 91(2): 341-47.
2.
Helwick CA and Laberge M. Encyclopedia of Surgery: A guide for patients and
caregivers.
2007.
Accessed
from:
http://www.surgeryencyclopedia.com/FiLa/Gastrectomy.html [Access date: 26/05/2009].
3.
Friess H et al. Pancreatology 2001; 1(Suppl 1): 41-48.
4.
Griffiths A and Taylor RH. Eur J Gastroenterol Hepatol 1999; 11(3): 219-21.
5.
Saito A et al. Hepatogastroenterology 2001; 48(38): 585-89.
6.
Papini-Berto SJ and Burini RC. Arq Gastroenterol 2001; 38(4): 272-75.
7.
Layer P et al. Curr Gastroenterol Rep 2001; 3(2): 101-08.
8.
Friess H et al. Digestion 1993; 54(Suppl 2): 48-53.
9.
Gullo L et al. Scand J Gastroenterol 1979; 14(4): 401-07.
10.
Buchler M et al. Int J Pancreatol 1986; 1(5-6): 389-98.
11.
Malfertheiner P et al. Digestion 1987; 38(3): 142-51.
12.
Keller J and Layer P. Gut 2005; 54(Suppl 6): vi1-28.
13.
Keller J and Layer P. Curr Treat Options Gastroenterol 2003; 6(5): 369-74.
14.
Liedman B et al. Dig Dis Sci 2001; 46(12): 2673-80.
15.
Armbrecht U et al. Aliment Pharmacol Ther 1988; 2(6): 493-500.
16.
Bragelmann R et al. Eur J Gastroenterol Hepatol 1999; 11(3): 231-37.
17.
Sategna-Guidetti C and Bianco L. J Clin Gastroenterol 1989; 11(5): 518-24.
18.
Layer P et al. Gastroenterology 1994; 107(5): 1481-87.
19.
DiMagno EP. Dig Dis Sci 1982; 27(6): 481-84.
20.
Degen LP and Beglinger C. Pancreatology 2001; 1(Suppl 1): 9-13.
Chapter 10
Post surgery: Parenchymal reduction
Introduction
Pancreatectomy is a treatment option for both benign and malignant diseases of the
pancreas. Surgical resections are also indicated for intractable pain associated with chronic
pancreatitis.1
Chronic pancreatitis causes debilitating abdominal pain and insufficiency of both endocrine
and exocrine function. Surgery can relieve pain, manage complications and exclude
cancer.2 Although distal pancreatectomy, pylorus-preserving pancreatico-duodenectomy
(PPPD) and longitudinal pancreaticojejunostomy (LPJ) can provide effective pain relief for
many of these patients, postoperative effects on absorption and nutrition should be carefully
managed.2
Surgical resection offers the only possibility of cure for patients with peri-ampullary and
pancreatic cancer.3-5 Pancreatic cancer most commonly presents at an advanced stage,
and as a consequence, surgical resection is only possible in about 20% of patients.
Surgery, with chemotherapy, is associated with a long-term survival rate of 20-25% at 5
years. The most common operative techniques used for carcinoma in the pancreatic head
are the classic Whipple’s pancreatico-duodenectomy4 and PPPD.6, 7 Left sided resection
(e.g. distal pancreatectomy) is performed for tumours of the body and tail of the pancreas.
Although operative mortality rates are now relatively low (about 3%) in specialised units,3, 8, 9
significant morbidity still occurs in about 30% of patients who undergo pancreaticoduodenectomy.10-12 As the pancreas plays a vital role in food digestion and glucose
homeostasis, pancreatectomy is associated with concerns about the management of the
apancreatic state, particularly in association with endocrine and exocrine insufficiencies as
well as malabsorption.13 The presence of symptoms such as diarrhoea, flatulence and
steatorrhoea substantially affect quality of life, and can lead to progressive weight loss and
malnutrition.14, 15 Gastrointestinal dysmotility can also be a significant clinical problem,
causing symptoms such as delayed gastric emptying, early satiety and enterogastric
reflux.16, 17
Modern approaches to pancreatic surgery, coupled with improvements in postoperative
management have decreased mortality and the risk of surgical complications, resulting in
improved quality of life and a better long-term prognosis. This has resulted in an increasing
number of individuals requiring ongoing nutritional monitoring and support.
Pancreatic exocrine insufficiency (PEI) after pancreatectomy
The degree of alteration of the pancreas’ digestive function post-resection depends on the
amount of pancreatic parenchyma resected and the functional capacity of the residual
pancreas.18 Clinically, this relates to the type of surgical procedure carried out and the
presence of underlying pancreatic atrophy or pancreatitis.
In a cohort of approximately 700 patients, pancreatic parenchymal volume correlated with
body weight, exocrine and endocrine function.19 Partial gastrectomy or antrectomy further
disrupts postprandial synchrony of digestion by impairing the release of gastrin, pancreatic
polypeptide and cholecystokinin. The type of pancreatico-enterostomy can also potentially
influence post-operative exocrine function.
Due to the early deactivation of pancreatic enzymes by gastric acid, deterioration in
pancreatic exocrine function in patients who have undergone PPPD with pancreaticogastrostomy is greater,13, 20 and can be overcome with the administration of acid
suppressive therapy.21
Compared to patients with a normal residual pancreas, pancreatic function of those with
chronic pancreatic disease is often impaired, even before any type of resection is carried
out. In these patients, exocrine and endocrine pancreatic function deteriorates progressively
after a major resection and aggressive replacement is required.13
Pancreatic enzyme replacement therapy
Most patients who have major pancreatic resections have a degree of exocrine
insufficiency. Pancreatic enzyme replacement therapy (PERT) may be an important part of
the long-term management of some of these patients. The key clinical issue is identifying
those patients that require enzyme replacement. Symptoms of pancreatic insufficiency may
not be obvious, and sequelae of malnutrition such as osteoporosis due to deficiency of the
fat-soluble vitamin, Vitamin D, may not become apparent for many years.
In patients where PEI is identified or suspected, adequate PERT reduces malnutrition,
normalises biochemical indices of malnutrition, assists a patient to recover much of their
original body weight and improves their overall quality of life.22, 23
There is limited information concerning the routine use of PERT, and there are no data that
define a threshold for the requirement of replacement therapy. Furthermore, objective
measures of pancreatic insufficiency have not proven to be clinically useful at this point in
time.
Individualised treatment is required
Patients can have different degrees of exocrine pancreatic insufficiency. The dosage of
pancreatic enzymes should therefore be titrated to symptoms of an individual patient.22, 24, 25
All patients should be monitored and screened for symptoms and signs of inadequate
replacement. These include weight loss, diarrhoea, steatorrhoea and stool fat excretion in
excess of 15 g/day.22
Efficacy, dose and administration
To date, there is a paucity of robust randomised clinical trials concerning the use of PERT
post-pancreatectomy. Moreover, existing studies utilise only small sample sizes.
A study evaluating the efficacy of PERT post-pancreatectomy involved 11 patients. After
surgery, all patients received 4 weeks of daily individualised dosing of pancreatin. Patients
were then randomised to receive a further 4 weeks of pancreatin or placebo. Intestinal
absorption and nutritional status were measured at baseline, 4 weeks and 8 weeks. Results
showed that pancreatin supplementation significantly improved total energy and increased
the absorption of dietary fat. The study also indicated advantages of continuing therapy.2
In a randomised study involving 39 patients who had undergone total or partial
pancreatectomy, both high-dose and standard-dose pancreatin were equally effective for
the treatment of PEI. However, the authors noted that improved approaches are required for
managing fat malabsorption in this group of patients.27
Contrary to general belief, the relationship between the dose of pancreatic enzymes
required and symptoms of maldigestion is not linear. In general, the required amount of
lipase to be delivered to the small intestine with each meal is in the order of 25,000 to
50,000 units.22, 28, 29 Acid supprssion therapy may be a useful adjunct therapy and is
recommended, especially if severe steatorrhoea continues with adequate dosing of
pancreatic enzymes.22, 28, 30
Summary
In summary, major pancreatic resections not only impair pancreatic function but also the
function of the entire upper gastrointestinal tract. This may adversely affect the nutritional
status and the overall quality of life of these individuals. Current literature suggests that with
advances in surgical techniques and post-operative care (including optimal pancreatic
enzyme replacement), the majority of these patients will have good outcomes with minimal
gastrointestinal symptoms, will be able to maintain adequate weight and achieve a high
quality of life. It is important that pancreatic enzyme insufficiency after pancreatectomy is
suspected, and an individual’s nutritional status (including serum levels of vitamins and
minerals) is closely monitored so that appropriate treatment can be provided.
Recommendations pancreatic enzyme replacement therapy after pancreatectomy
Recommendations
Level of evidence
Different pancreatic resections are associated with different
risks of PEI. All patients who have undergone pancreatic
surgery should be screened for PEI.
3a
Long-term oral PERT for patients with PEI can improve
quality of life.
4
Oral PERT doses should be individualised. Generally, the
required amount of lipase with each meal 25,000 to 50,000
units.
5
For severe, persisting steatorrhoea, consider the use of
adjunct acid suppressant therapy.
4/5
References
1.
Heidt DG et al. J Gastrointest Surg 2007; 11(2): 209-16.
2.
Van Hoozen CM et al. Pancreas 1997; 14(2): 174-80.
3.
Buchler MW et al. Arch Surg 2003; 138(12): 1310-14; discussion 15.
4.
Diener MK et al. Ann Surg 2007; 245(2): 187-200.
5.
Yeo CJ et al. Ann Surg 1995; 221(6): 721-31; discussion 31-3.
6.
Traverso LW. Adv Surg 1999; 32(23-39.
7.
Traverso LW. Swiss Surg 2000; 6(5): 259-63.
8.
Trede M et al. Ann Surg 1990; 211(4): 447-58.
9.
Yeo CJ et al. Ann Surg 1997; 226(3): 248-57; discussion 57-60.
10.
Bassi C et al. Dig Surg 2001; 18(6): 453-57; discussion 58.
11.
Gouma DJ et al. Ann Surg 2000; 232(6): 786-95.
12.
Richter A et al. World J Surg 2003; 27(3): 324-29.
13.
Kahl S and Malfertheiner P. Best Pract Res Clin Gastroenterol 2004; 18(5): 947-55.
14.
McLeod RS. Ann Oncol 1999; 10(Suppl 4): 281-84.
15.
McLeod RS et al. Am J Surg 1995; 169(1): 179-85.
16.
Closset J and Gelin M. Acta Chir Belg 2003; 103(3): 338-39.
17.
Williamson RC et al. Surgery 1993; 114(1): 82-86.
18.
Falconi M et al. Br J Surg 2008; 95(1): 85-91.
19.
Nakamura Y et al. Pancreatology 2005; 5(4-5): 422-31.
20.
Jang JY et al. World J Surg 2002; 26(3): 366-71.
21.
Toyota N et al. Hepatogastroenterology 1998; 45(22): 1005-10.
22.
Braga M et al. Int J Pancreatol 1989; 5(Suppl): 37-44.
23.
Czako L et al. Can J Gastroenterol 2003; 17(10): 597-603.
24.
Layer P et al. Curr Gastroenterol Rep 2001; 3(2): 101-08.
25.
Morrow JD. Am J Med Sci 1989; 298(5): 357-59.
26.
Dominguez-Munoz JE. Curr Gastroenterol Rep 2007; 9(2): 116-22.
27.
Neoptolemos JP et al. Int J Pancreatol 1999; 25(3): 171-80.
28.
Ferrone M et al. Pharmacotherapy 2007; 27(6): 910-20.
29.
Keller J and Layer P. Curr Treat Options Gastroenterol 2003; 6(5): 369-74.
30.
Marotta F et al. Dig Dis Sci 1989; 34(3): 456-61.
Chapter 11
Pancreatic exocrine insufficiency in cystic fibrosis
Introduction
Cystic fibrosis (CF) is an autosomal recessive disease with a wide spectrum of clinical
manifestations leading to premature death. CF has therefore classically been considered a
fatal disease of childhood. However, with improved treatments and better ways of managing
the disease, many people with CF now live well into adulthood.
The most common signs and symptoms in children include progressive damage to the
respiratory system and chronic disorders of the digestive system. Adults with CF experience
medical problems affecting the respiratory, digestive and reproductive systems.
CF is considered one of the most common lethal genetic conditions affecting approximately
1 in 2,500 Caucasian life births.1 The incidence of CF is less common in other ethnic
groups.2
Genotype and phenotype
Since the discovery of the gene responsible for CF on the long arm of chromosome 7,3 over
1,500 mutant alleles have been identified.4 Twenty-four mutant alleles have been identified as
being responsible for 84% of CF cases.5, 6 The most common mutation is the deletion of a
phenylalanine residue in the cystic fibrosis transmembrane conductance regulator (CFTR)
protein.5 This mutation results in a severe reduction in CFTR function.
The CFTR gene plays a role in chloride ion transportation. The flow of chloride ions
regulates water intracellularly, thereby ensuring the production of thin, freely-flowing mucus.
Mutations in the CFTR gene disrupt the function of chloride channels at the apical surface of
epithelial cells (Figure 1). In addition, there is also dysregulation of other transporters (e.g.
chloride-coupled bicarbonate transport and sodium channel activity). As a result, thick, high
salt fluids are present in the extracellular space of many major organs (e.g. lung, pancreas).
Clinically, this mutation leads to the classic CF phenotype of raised sweat chloride,
recurrent respiratory infection with bronchiectasis and early-onset pancreatic insufficiency.5
Figure 1: Schematic representation of CFTR structure
Reproduced from www.cfgenetherapy.org.uk.
7
The clinical manifestations of CF can vary greatly between affected individuals8, and largely
depends on the amount of normal CFTR function. A classification system based on the
functional effect that genotype has on production of CFTR could indicate a biological
mechanism by which genotype could affect mortality (Table 1). Patients with CFTR
genotypes associated with severely reduced CFTR production (Class I to III) have a very
similar severe phenotype and are associated with higher mortality rates than patients with a
CFTR genotype associated with some residual CFTR function (Class IV and V).4
Table 1: Classification system and functional effect on CFTR
Risk
stratification
High risk of
CFTR
genotype
Class of
mutation
I
II
III
Low risk of
CFTR
genotype
IV
V
Functional effect of mutation
Defective protein production with premature
termination of CFTR production. Produces few or no
functioning CFTR chloride channels
Defective trafficking of CFTR so that it does not reach
the apical surface membrane where it is intended to
function
Defective regulation of CFTR even though it is able to
reach the apical cell surface
CFTR reaches the apical surface but conduction
through the channel is defective
Associated with reduced synthesis of function CFTR
Adapted from McKone et al. 2003.5
Diagnosis and screening
About 80-100 new diagnoses of CF are made annually in Australasia.9
In Australia and New Zealand, all newborn babies are screened for CF using the
immunoreactive trypsinogen test (IRT). A blood sample is taken three days after birth, and
analysed for a specific protein called trypsinogen. If positive, genetic testing of the CFTR
gene is done. A sweat test is also carried out to measure the amount of salt in the sweat,
and it is with this test that a diagnosis is made. About 95% of babies with CF are identified
with newborn screening.10
While newborn screening for CF is universal in Australia and New Zealand, this may not be
the case in other parts of the world. In unscreened populations, diagnosis of CF is based on
a clinical phenotype accompanied by elevated sweat chloride.
Prognosis
There are over 3,000 people living with CF in Australia.9 Of these, two-thirds are children
and adolescents. The long-term survival for children with CF has improved significantly in
recent years, with a predicted mean life expectancy of about 40 years.11, 12
The factors contributing to improved survival include earlier diagnosis with newborn
screening, improved management of respiratory infections and importantly, an improvement
in nutritional status.11, 13
Pancreatic function CF patients
The CFTR gene is expressed in many tissues including the pancreas. The pancreas is
vulnerable to luminal concentration defects due to the high protein content in the ducts.14
The viscous secretions can cause luminal obstruction of ducts leading to acinar cell
destruction, fibrosis and pancreatic exocrine insufficiency (PEI).15
Pancreatic function in CF patients is classified into two distinct phenotypes:
1. Pancreatic sufficient: adequate endogenous pancreatic exocrine function to provide
normal absorption
2. Pancreatic insufficient: these patients require exogenous pancreatic exocrine enzymes
to maintain adequate absorption of nutrients
Most CF patients are pancreatic insufficient either at the time of diagnosis or as the disease
progresses. Only 5-15% of affected individuals retain some level of pancreatic function.16
There is a clear correlation between genotype and pancreatic function.14 Those with Class I
and Class II mutations tend to experience an early decline in pancreatic function.
A study of 78 CF patients identified in a newborn screening program showed that 37% are
pancreatic sufficient. These children had growth that was close to normal and comparable
to growth in children with severe pancreatic insufficiency who received oral enzyme therapy.
Pancreatic insufficiency subsequently developed in one in five of these patients at 3 to 36
months of age.17
These data indicate that a proportion of pancreatic sufficient infants can lose their residual
pancreatic function over time. CF patients identified at birth should be continually monitored.
Growth measurements and indirect tests for pancreatic exocrine function should be
routinely conducted.
Consequences of PEI in CF
It has been shown that mortality in CF is related to phenotype and class of mutations with
those classified with Class I and II mutations having higher mortality rates than those with
Class III, IV and V.4
Although chronic pulmonary disease is the major cause of mortality in CF, significant
morbidity is attributed to gastrointestinal dysfunction, particularly PEI. PEI results in the
inability to properly digest food due to the lack of pancreatic digestive enzymes.
Maldigestion, and hence malabsorption of nutrients and poor nutrition, due to PEI occurs in
approximately 85% of CF patients.18-20
Maldigestion in CF affects energy and protein availability, and without treatment,
gastrointestinal losses of fat and nitrogen are severe. This causes energy and protein
deficits leading to growth failure and protein catabolism.19 Fat malabsorption is the most
important digestive malfunction in PEI. In addition, micronutrient absorption could be
affected. This is because fat-soluble vitamins require normal or near normal processes for
fat absorption.
Prolonged, untreated PEI is associated with a poorer prognosis long term. A study of 72 CF
patients with normal fat absorption found that pancreatic sufficient patients generally have
significantly better lung function, milder clinical symptoms, lower sweat chloride and less gut
and liver complications than those with symptoms of PEI.21
Benefits of good nutritional management
Evidence in the literature demonstrates the importance of improving the nutritional status of
CF patients. This was highlighted in a comparison of nutritional management policies in
Canada and the United States.22, 23
Corey et al. conducted a study involving over 1,000 patients from two CF clinic populations
in Boston and Toronto. Demographic data were not significantly different between the two
populations. The Toronto clinic had abandoned the traditional low fat, high energy diet in
favour of more liberal use of both fat and pancreatic enzyme replacement. Data showed that
patients in Toronto tended to be taller, heavier and had a higher median age than those at
the Boston clinic. Although progressive pulmonary disease is the major cause of mortality in
cystic fibrosis, the differences in growth and survival in these two patient groups, with very
similar age-specific pulmonary function, suggest the potential benefits of aggressive
nutritional management.22
Following the dissemination of the results of this study, CF clinics in the United States
adopted the Canadian approach to nutritional management in CF patients. The effects of
this intervention were evaluated about 10 years later.23
In the subsequent trial the growth status of the CF populations in the United States and
Canada were evaluated. This study involved analyses of CF Patient Registries of both
countries. Results show that children with CF in Canada had significantly higher mean
height and weight than those in the United States. Although mean height was similar for
adults with CF in both populations, weight and percentage of ideal weight was significantly
better for Canadian adult CF patients than their American counterparts. Nevertheless, the
authors observed substantially smaller differences in the growth indices of CF patients
between the United States and Canada compared with results from the 1980s.23
These findings demonstrated significant improvements in growth and survival of CF patients
following the adoption of good nutritional management strategies. Growth failure and
chronic malnutrition, once considered acceptable and inevitable consequences of CF,
should now be regarded as preventable with appropriate nutritional management.
Diagnosis of PEI in CF
The specific details of different diagnostic tests for PEI are discussed in Chapter 2 of these
guidelines. This section focuses on tests used clinically to diagnose PEI in CF patients.
Exocrine pancreatic function is notoriously difficult to assess. Practically, the pancreas (and
its secretions) is relatively inaccessible and direct assessment requires duodenal intubation
to collect pancreatic secretions. There are three categories of exocrine pancreatic function
tests:
1) Direct tests – assess the secretory capacity of the exocrine pancreas
2) Indirect tests – detect abnormalities secondary to loss of pancreatic function
3) Blood tests – rely on the small but significant amounts of enzymes and enteroendocrine
hormones synthesised by the pancreas in systemic circulation
Direct tests are the most sensitive and specific measurements of exocrine pancreatic
function. However, these tests are invasive and expensive. Furthermore, the results are
poorly reproducible. Indirect and blood tests are most frequently used because these tend
to be inexpensive and easy to administer. However, these are less sensitive and not as
specific as direct tests. Ideally, 3-5 day faecal fat balance studies (indirect test) should be
used because there is evidence of a good correlation with pancreatic stimulation tests
(direct test).24
The 3-5 day faecal fat balance study involves meticulous weighing of food and careful
dietary records to calculate mean daily fat intake. Stools collected over 72-96 hours are
pooled and refrigerated. Steatorrhoea is present if more than 7% of ingested fat is excreted.
As infants below 6 months of age have immature pancreatic and biliary secretions, test
results are only considered abnormal if they excrete in excess of 15% of ingested fat.
Faecal fat balance studies should ideally be conducted at diagnosis. If CF is detected
through newborn screening, it should be noted that 40% of neonatal CF patients are
pancreatic sufficient. However, many of these patients may lose their residual pancreatic
function over time such that only 10-15% remain pancreatic sufficient by mid-childhood. In
light of this, faecal fat balance studies should be repeated if the patient is not gaining
adequate weight and have symptoms suggesting fat malabsorption. This is not as much an
issue for those patients not diagnosed through newborn screening because these patients
are usually pancreatic insufficient upon initial diagnosis as steatorrhoea is often one of the
main symptoms at presentation.
Due to the odious nature of faecal fat balance studies for both patients and laboratory staff,
it has fallen into disfavour with some clinicians. Faecal elastase and microscopic
assessments are practical alternatives to faecal fat balance studies. Faecal elastase-1 is a
simple test which could be used to predict response to pancreatic enzyme supplementation
in patients with chronic, unexplained diarrhoea with a clinical suspicion of pancreatic
insufficiency.25 Microscopic examination of stools may reveal meat fibres, neutral fat
droplets or free fatty acid crystals, suggesting partial fat hydrolysis. Steatorrhoea could be
quantified by counting the number and size of fat globules.26
The recommended frequency of monitoring is based on the natural history of the disease in
the screened population. Weight and height should be measured every 2-3 months. Every
4-6 months, an indirect test for PEI should be performed. If CF patients do not appear to be
gaining adequate weight, the frequency of these tests should be increased.
Pancreatic enzyme replacement therapy (PERT) in CF
CF patients with gastrointestinal problems related to inadequately controlled intestinal
absorption secondary to PEI may experience symptoms including neonatal meconium ileus,
distal intestinal obstruction syndrome, constipation and acquired megacolon, rectal prolapse
and rarely pancreatitis. If the intestinal malabsorption is well controlled with an effective
pancreatic enzyme preparation, distal intestinal obstruction syndrome, constipation and
rectal prolapse are less frequently observed.27
Pancreatic enzyme replacement therapy (PERT) is indicated in those with documented fat
malabsorption or PEI as established by a pancreatic stimulation test. The objectives of
PERT replacement are to:
• Correct macro- and micronutrient maldigestion
• Eliminate abdominal symptoms directly attributable to maldigestion
• Establish normal stools and bowel habits
28
• Sustain normal growth and nutritional status
Evidence-based practice recommendations for nutritional-related management of CF
patients with pancreatic insufficiency advocate the use of non-generic (ie. branded)
proprietary pancreatic enzyme preparations to ensure efficacy in the treatment of CF-related
PEI.29
Dosing
The severity of PEI can vary enormously from patient to patient. Therefore, PERT doses
should be individualised.28 There are two primary approaches to PERT dosing:
1.
Based on bodyweight
2.
According to fat intake
Patients should be commenced on the minimum dose. Doses can then be uptitrated based
on weight gain and bowel signs to ascertain the lowest effective dose.28
Signs and symptoms of malabsorption such as pain, excessive gas, frequency and stool
consistency are not indications for dose adjustments. PEI is not the main cause of
abdominal pain and increasing the dose of PERT does not alleviate these symptoms.15
Similarly, increasing doses of PERT does not improve patients’ subjective sense of
“gassiness”. Therefore, this is also not an appropriate marker for dosing.15 Number of stools
per day is the same between pancreatic sufficient and insufficient patients and PERT dosing
does not affect frequency of stools.15 Constipation is a common complaint of PEI patients.
No correlation was observed between constipation and PERT dose suggesting that
constipation cannot be used as a marker for inappropriate PERT dosing. The commonlyheld belief that constipation is a consequence of high enzyme doses is also not supported
by evidence.15
PERT dosing for infants based on fat intake is 500-1,000 units lipase per gram of dietary
fat.28 Alternatively, infants may be given 2,000-4,000 units lipase per breastfeed or 120 mL
of infant formula.15 The infant’s mouth should be swept after administration of PERT to
prevent ulceration in the alkaline salivary environment.
In children, 500-4,000 units lipase per gram of dietary fat may be given.28 For dosing based
on bodyweight, those under the age of 4 years may be given 1,000 units lipase per kilogram
bodyweight per meal; whereas those above 4 years old may be given 500 units lipase per
kilogram per meal. If patients are having a snack rather than a full meal, these doses could
be halved.15
In the early days, PERT was thought to be free of major complications and side effects.
Increasingly, there is recognition of fibrosing colonopathy and its association with very high
doses of PERT.30-32
In view of this, the maximum dose recommendation is 10,000 units of lipase per kilogram
per day.15
Administration issues
Pancrealipase tablets or capsules should not be crushed or chewed. Patients who are
unable to swallow capsules may be prescribed delayed release capsules containing enteric
coated microspheres or microtablets. The content of these capsules could be sprinkled on
soft food that does not require chewing (e.g. apple sauce, gelatin, pureed fruits). It should
be noted that the contents of these capsules should not be sprinkled on foods with a pH
above 7.3 (such as milk, custard or ice cream) as the protective enteric coating can dissolve
at high pH.15
Enteral feeding is indicated if ongoing comprehensive assessments of CF patients indicate
that nutritional status is deteriorating or failing to improve.1 The appropriate dosing regimen
of PERT with enteral tube feeding has yet to be determined. Possible options for PERT
dose calculations are suggested in Table 2.33 Enzyme microspheres and tablets should not
be crushed prior to delivery via the feeding tube.
Adjunct therapy
PERT improves the nutritional status and decreases maldigestion due to PEI in patients
with CF. In spite of adequate PERT doses, many patients with CF continue to experience
gastrointestinal symptoms of PEI (in particular steatorrhoea). This contributes to malnutrition
and weight loss.34
Orally administered PERT can be inactivated by gastric acid.35 Studies have suggested that
drug therapy which reduces gastric acid, including H2 receptor antagonists and proton pump
inhibitors may improve the effectiveness of PERT.36
A recent Cochrane review found little evidence that the use of adjunctive agents that reduce
gastric acidity in CF patients can improve fat absorption and gastrointestinal symptoms. Of
the assessed acid-suppressing agents, proton pump inhibitors seemed to have the most
promising role as an adjunct to PERT therapy for CF patients. However, further research is
required to ascertain the duration of treatment and the risks of pneumonia, gastroenteritis
and bacterial overgrowth associated with its use. At present, there appears to be insufficient
evidence to indicate whether these adjunctive agents can improve nutritional status, lung
function, quality of life or survival in patients with CF.34
Considering the potential role of adjunctive therapy, an approach to address the lack of
clinical response to PERT is proposed in Figure 2.
Table 2: Proposed PERT dosing regimens for CF patients using enteral tube feeding
Plan A
Estimate the amount of fat in the total
volume of feed to be delivered
Plan B
Estimate the amount of fat to be delivered
every three hours
Step 2
Divide the total amount of fat by the
individual’s recommended pancreatic
enzyme dose to determine the number of
capsules required for the whole feed
Divide the total amount of fat by the
individual’s recommended pancreatic
enzyme dose to determine the number of
capsules required every three hours
Step 3
Possible dosing options:
Possible dosing options:
Single: take one dose, as determined in
step 2, prior to commencing the feed14
Single: take one dose, as determined in
step 2, prior to commencing the feed
Double: take 50% of the dose determined
in step 2 prior to going to sleep, if more
than one hour has lapsed, or whenever
14
voluntarily awake through the night
Double: as per the single option plus take
the same dose again prior to going to
sleep, if more than one hour has lapsed,
or whenever voluntarily awake through
the night
Step 1
Multiple: if feeding for longer than six
hours, take additional 50% of doses if
voluntarily awake at anytime after this
Adapted from Stapleton et al. 1999.
33
Multiple: if feeding for longer than six
hours, take additional doses as
determined in step 2, if voluntarily awake
at anytime after this
Figure 2: Proposed approach to lack of clinical response to PERT
Pancreatic enzyme replacement therapy
Based on body weight or fat intake
Adequate response
Inadequate response
• Steatorrhoea
• Poor weight gain
Adequate compliance
Fat balance study shows
continued malabsorption
Check compliance
If poor address
Increase dose by small
increments
Avoid exceeding max ‘safety’
dose of 100,000 U lipase/kg/day
Add proton pump
inhibitor
Adequate response
Trial for 6 months and monitor
Inadequate response
• Stool check for Giardia lamblia
• Coeliac serology
• Breath test for bacterial overgrowth
• Liver disease
Long-term management and monitoring for PEI
Periodic nutritional assessments should include a collation of anthropometric measures
(height, weight and head circumference); dietary intake, biochemical assessments and a
review of bowel habit and function. Deterioration in parameters of nutritional status should
be detected early, before growth and lung function are compromised.
Anthropometric measurements should be regularly assessed (Table 3). It is important to
note that adults may lose height over time due to ageing, osteoporosis or kyphosis.1 A
thorough assessment of dietary intake should be conducted at least once a year. In very
young children, dietary intake assessments should be more frequently assessed. Table 4
highlights the key areas of dietary assessment in CF patients.1
Table 3: Suggested minimum frequency for recording anthropometric measurements
Measurement
Infants (0-2 yrs)
Children (2-18 yrs)
Adults (>18 yrs)
1-2 weekly until
thriving, then monthly
-
-
-
3 monthly
Annually
1-2 weekly until
thriving, then monthly
1-2 weekly until
thriving, then monthly

Every clinic visit*
Every clinic visit*
-
-

-


-
BMI
-


Plot on BMI centile
chart
-

-
Height (supine/length)
Height (standing)
Weight
Head circumference
Plot on appropriate
growth chart
% IBW
†
Adapted from Stapleton et al. 2006.1
* Fortnightly if clinic visits are more frequent than this.† If growth has cease; otherwise 3 monthly until
cessation of growth is demonstrated (consider that growth may continue up to 20 years in males with CF).
% IBW: percentage ideal body weight, BMI: body mass index.
Table 4: Key areas of dietary intake assessment in CF patients
Key areas of assessment
 Energy intake
 Fat intake
 Food preferences and variety
 Meal pattern and behaviours
 Knowledge and attitudes about nutrition,
including body image
 PERT: dosage; adherence and gastrointestinal
symptoms
 Supplements: vitamins and minerals, oral and
enteral nutritional supplements
 Sodium and fluid intake
 Nutrition-related complementary
Purpose
 Energy balance and affect on weight
 Energy dentistry, PERT adequacy
 Adequacy of micronutrient intake
 Fibre intake
 Target areas for change
 Adequacy of PERT regimen
 Adequacy of micronutrient intake
 Contribution to energy and nutrient intakes
 Hydration and sodium
 Contribution to micro- and macronutrient
intake
Adapted from Stapleton et al. 2006.1
Biochemical tests provide important information regarding the nutritional status of those with
CF. All patients should be assessed at diagnosis and subsequently on a routine basis. If
there is a risk of deterioration in nutritional status, or if there is a change in treatment, then
the frequency of biochemical assessments should be increased.1
Other nutritional assessment in CF patients should also include a review of bowel habits
and function. Information regarding relevant lifestyle factors including exercise and physical
activity should also be collected.1
The Australasian Clinical Practice Guidelines for Nutrition in Cystic Fibrosis provides
discusses these management and monitoring strategies in detail.
Summary
CF is a common lethal genetic disorder caused by mutations in the gene that encodes the
CFTR protein. CFTR mutations disrupt the function of water and chloride ion transportation
at a cellular level leading to classic CF phenotypes such as raised sweat chloride, recurrent
respiratory infection with bronchiectasis and early-onset pancreatic insufficiency. The
majority of babies with CF are diagnosed at birth through newborn screening. The long-term
survival for children with CF has improved significantly. With early diagnosis, appropriate
management of respiratory infections and improved nutrition, most CF patients live well into
adulthood.
About 85% of CF patients are pancreatic insufficient by early childhood. There is evidence
that a proportion of infants determined to be pancreatic sufficient at birth will lose their
residual pancreatic function over time. Without treatment, gastrointestinal losses of fat and
nitrogen can be severe. This causes growth failure and protein catabolism. Fat
malabsorption, the most important digestive malfunction in PEI, affects macro- and
micronutrient absorption. Prolonged, untreated PEI is associated with a poorer prognosis
long term. This highlights the importance of nutritional management and PERT.
PERT is indicated in those with documented fat malabsorption or PEI as established by a
pancreatic stimulation test. PERT dosing should be individualised. CF patients with PEI
should be started on the lowest recommended dose and uptitrated based on weight gain
and gastrointestinal symptoms to ascertain the lowest effective dose. Excessive doses of
PERT is associated with fibrosing colonopathy. Therefore doses should not exceed 10,000
units of lipase per kilogram bodyweight per day or 6,000 units per kilogram bodyweight per
meal.
The role of acid suppressing agents in improving fat absorption and gastrointestinal
symptoms of CF patients is still under debate. Proton pump inhibitors appear to have a
promising role as an adjunct to PERT therapy for CF patients. However, further research is
required to ascertain the duration of treatment and the risks of pneumonia, gastroenteritis
and bacterial overgrowth associated with its use.
Recommendations for pancreatic enzyme replacement therapy in cystic fibrosis
Recommendations
Level of
evidence
Good nutritional management of CF patients can prevent growth failure
and chronic malnutrition.
1b
PERT doses should be individualised based either on bodyweight or fat
intake. Doses can be titrated based on weight gain and bowel signs.
5
Recommended doses
5
For infants: 500-1,000 units lipase per gram of dietary fat OR 2,0004,000 units lipase per breastfeed or 120 mL of infant formula.
For children: 500-4,000 units lipase per gram of dietary fat OR 1,000
units lipase per kilogram bodyweight per meal (<4 years old); 500 units
lipase per kilogram bodyweight per meal (>4 years old). Doses could be
halved if having a snack instead of a full meal.
Maximum dose: 10,000 units per kilogram bodyweight per day or 6,000
units per kilogram bodyweight per meal.
Enteral feeding is indicated if ongoing comprehensive assessments of
CF patients indicate that nutritional status is deteriorating or failing to
improve.
5
Pancrealipase tablets and capsules should not be crushed, chewed or
sprinkled on foods with a high pH.
5
Branded PERT preparations should be used to ensure efficacy.
2a
PPIs may have a role in decreasing gastric acidity and improving fat
absorption and gastrointestinal symptoms in CF patients on PERT.
5
Long-term management and monitoring for PEI in CF patients should
include ongoing periodic nutritional assessments.
3
References
1.
Stapleton D et al. Australasian clinical practice guidelines for nutrition in cystic fibrosis.
2006.
2.
CF Foundation. Annual data report. National Patient Registry; 1994.
3.
Riordan JR et al. Science 1989; 245(4922): 1066-73.
4.
McKone EF et al. Chest 2006; 130(5): 1441-47.
5.
McKone EF et al. Lancet 2003; 361(9370): 1671-76.
6.
Mickle JE and Cutting GR. Med Clin North Am 2000; 84(3): 597-607.
7.
UK cystic fibrosis gene therapy consortium. Accessed from: www.cfgenetherapy.org.uk
[Access date: 7/12/2009].
8.
Kerem E and Kerem B. Pediatr Pulmonol 1996; 22(6): 387-95.
9.
Cystic Fibrosis Australia. Cystic Fibrosis in Australia and New Zealand 2002. Annual
report from the Australasian Cystic Fibrosis Data Registry. Sydney: Cystic Fibrosis
Australia; 2004.
10.
Cystic Fibrosis Australia. Cystic Fibrosis National Website. 2009. Accessed from:
www.cysticfibrosis.org.au [Access date: 4/6/2009].
11.
Thomas CL et al. Med J Aust 2008; 188(3): 135-39.
12.
Elborn JS et al. Thorax 2000; 55(5): 355-58.
13.
Merelle ME et al. Eur Respir J 2001; 18(2): 306-15.
14.
Tizzano EF and Buchwald M. Ann Intern Med 1995; 123(4): 305-08.
15.
Baker SS. Ther Clin Risk Manag 2008; 4(5): 1079-84.
16.
Centers for Disease Control and Prevention. Cystic fibrosis: Clinical validity. Office of
Public Health Genomics; 2007.
17.
Waters DL et al. N Engl J Med 1990; 322(5): 303-08.
18.
Littlewood JM. Br Med Bull 1992; 48(4): 847-59.
19.
Pencharz PB and Durie PR. Clin Nutr 2000; 19(6): 387-94.
20.
Kalivianakis M and Verkade HJ. Nutrition 1999; 15(2): 167-69.
21.
Gaskin K et al. J Pediatr 1982; 100(6): 857-62.
22.
Corey M et al. J Clin Epidemiol 1988; 41(6): 583-91.
23.
Lai HC et al. Am J Clin Nutr 1999; 69(3): 531-38.
24.
Gaskin KJ et al. Gastroenterology 1984; 86(1): 1-7.
25.
Elphick DA and Kapur K. Pancreatology 2005; 5(2-3): 196-200.
26.
Drummey GD et al. N Engl J Med 1961; 264(1): 85-87.
27.
Littlewood JM et al. Pediatr Pulmonol 2006; 41(1): 35-49.
28.
Anthony H et al. J Paediatr Child Health 1999; 35(2): 125-29.
29.
Stallings VA et al. J Am Diet Assoc 2008; 108(5): 832-39.
30.
Smyth RL et al. Lancet 1994; 343(8889): 85-86.
31.
Pawel BR et al. Hum Pathol 1997; 28(4): 395-99.
32.
Stevens JC et al. J Pediatr Gastroenterol Nutr 1998; 26(1): 80-84.
33
Stapleton D et al. Aust J Nutr Dietetics 1999; 56(2): 91-96.
34.
Ng SM and Jones AP. Cochrane Database Syst Rev 2003; 2003(Issue 2): Art no.:
CD003424.
35.
Zentler-Munro PL et al. Gut 1985; 26(9): 892-901.
36.
DiMagno EP. Best Pract Res Clin Gastroenterol 2001; 15(3): 477-86.
Chapter 12
Unresectable pancreatic cancer
Introduction
Pancreatic cancer is considered an “orphan cancer” because of its high mortality. It is the
fourth most common cause of cancer death in Western societies. The prevalence and death
rates are almost equal. In NSW during 2005, there were 750 new cases and 667 deaths
from pancreatic cancer.1 Nationwide, there were 2,026 deaths from pancreatic cancer in
2005, 964 of which were in men and 1,062 in women.2
Pancreatic cancer has one of the worst overall outcomes of any cancer. Less than 5% of
affected patients are alive five years after initial diagnosis.3 Only 10-20% of all patients with
pancreatic carcinomas are eligible for potentially curative resections. Consequently, for the
vast majority of these patients, only palliative treatment options remain.4
Palliative treatment of patients with unresectable pancreatic carcinomas is important.5
Palliative treatment mainly aims to prevent or treat obstructive jaundice, duodenal
obstruction and pain. Many clinicians fail to give adequate attention to pancreatic exocrine
insufficiency, which contributes to ongoing weight loss. About 90% of patients with
pancreatic carcinomas report weight loss at the time of diagnosis.4
Pancreatic exocrine insufficiency (PEI)
Cancer cachexia and weight loss are features of many cancers with a complex aetiology
that can be divided into primary or secondary tumour effects. Primary tumour effects
causing metabolic abnormalities include increased glucose production, increased whole
body protein breakdown and increased lipolysis and depletion of body fat stores.6
These effects can be augmented by secondary tumour effects such as intestinal obstruction
due to tumour expansion or side effects of cancer treatment such as nausea induced by
chemotherapy. Another pertinent secondary effect for the pancreatic cancer patient
population is impeded flow of pancreatic juice due to mechanical obstruction of the
pancreatic duct in patients with cancer of the pancreatic head region.
About 90% of patients with pancreatic cancer experience weight loss at the time of
diagnosis.7 Weight loss in pancreatic cancer patients is associated with maldigestion and
malabsorption due to pancreatic duct obstruction.8,9 In patients with pancreatic carcinoma,
malabsorption is likely a result of destroyed pancreatic tissue which may reduce the
production and delivery of pancreatic enzymes.9 This causes PEI with faecal losses of
energy through steatorrhoea and creatorrhoea.4
Management
Palliative care, including prevention of further weight loss, is important for these patients
and their families. The provision of individualised treatment plans for patients with
distressing nausea, weight loss and pain is a specialised service. The involvement of
palliative care teams provides support and expertise which is greatly appreciated by
patients and their families. They should be introduced to these teams early in the cancer
journey so they are prepared for, and confident about, their symptom control as the tumour
progresses.
Pancreatic enzyme replacement therapy (PERT) can be important for patients with weight
loss associated with pancreatic cancer.10 Enzyme therapy can alleviate some of the
symptoms induced by pancreatic failure.
The main principle of PERT is simulation of the normal physiologic state of exocrine
pancreatic products by exogenous administration during or just after meals.11 PERT can
often relieve many of the symptoms associated with PEI and can allow patients to increase
food intake and improve their nutritional status.12
A prospective, randomised, placebo-controlled study of 21 patients with unresectable
cancer of the pancreatic head region showed that weight loss in these patients can be
reduced by high dose PERT in combination with appropriate dietary counselling.4 However,
PERT improved only moderate-to-severe fat and protein malabsorption. Mild fat or protein
malabsorption in pancreatic cancer patients did not seem to improve with PERT.9 A
separate randomised, double-blind, placebo-controlled trial also found that PERT improved
steatorrhoea and stool consistency.13
Summary
Pancreatic cancer is associated with a poor prognosis. Many patients present at an
advanced stage, when curative surgery is not an option.
About 90% of patients with pancreatic cancer have weight loss at the time of diagnosis.
Weight loss may be exacerbated by maldigestion and malabsorption, as a result of
destroyed pancreatic tissue reducing the availability of pancreatic enzymes. This results in
PEI with associated steatorrhoea. Palliative care should include the control of symptoms
associated with PEI as this can have a significant impact on quality of life.
PERT can often relieve symptoms associated with PEI and can allow patients to increase
food intake and improve their nutritional status. Clinical studies have shown that PERT is
effective and important in the nutritional management of patients with unresectable
pancreatic cancer.
Recommendations for pancreatic enzyme replacement therapy in unresectable
pancreatic cancer
Recommendations
PERT should be used to treat PEI in patients with unresectable pancreatic
cancers in order to maintain weight and improve quality of life.
Level of
evidence
2a
References
1.
Tracey E, Baker D, Chen W, Stavrou E, Bishop J. Cancer in New South Wales:
Incidence, Mortality and Prevalence 2005. Sydney: Cancer Institute, NSW; 2007
[updated 2007; cited 4 August 2008]; Available from:
http://www.cancerinstitute.com.au/cancer_inst/publications/pdfs/cancer-incidencemortality-prevalence-2005.pdf.
2.
Cancer in Australia: an overview, 2008. Australian Institute of Health and Welfare and
Australasian Association of Cancer Registries, December 2008, available at
http://www.aihw.gov.au/publications/index.cfm/title/10607.
3.
Gudjonsson B. Cancer 1987; 60(9): 2284-303.
4.
Bruno MJ et al. Gut 1998; 42(1): 92-96.
5.
Freelove R and Walling AD. Am Fam Phys 2006; 73(3): 485-92.
6.
Heber D and Tchekmedyian NS. Oncology 1992; 49 (Suppl 2): 28-31.
7.
Smith RC, Talley NJ, Dent OF, Jones M, Waller SL. Int J Pancreatol 1991; 8: 253-62.
8.
Perez MM et al. Cancer 1983; 52(2): 346-52.
9.
DiMagno EP et al. Mayo Clinic Proceedings 1979; 54(3): 157-62.
10.
Keller J and Layer P. Gut 2005; 54: 1-28.
11.
Damerla V et al. J Supportive Oncology 2008; 6(8): 393-96.
12.
Anon. Gut 2005; 54(Suppl 5): v1-16.
13.
Safdi M et al. Pancreas 2006; 33(2): 156-62.
Chapter 13
Coeliac disease
Introduction
In Australia, it is estimated that coeliac disease affects about 1 in 100 people.1 It is an
autoimmune disease in which the lining of the small intestine becomes inflamed and
damaged when exposed to even small amounts of gluten. However, other gastrointestinal
organs besides the small intestine may also undergo alteration of structure and function.2
Exocrine pancreatic dysfunction is a frequent finding in patients with untreated coeliac
disease.3 It has been estimated that up to 40% of patients with coeliac disease have some
degree of pancreatic exocrine insufficiency at diagnosis.3-6 This is likely to be due to
impaired secretion and/or release of pancreatic stimulating hormones from the diseased
proximal intestine.7 However, other mechanisms may also be involved. Protein malnutrition
may interfere with the high-level protein synthesis required for generation and secretion of
the pancreatic digestive enzymes.2, 7 It may also lead to structural changes in the pancreas,
including atrophy of acinar cells and pancreatic fibrosis.7
Pancreatic exocrine function
Pancreatic exocrine dysfunction in coeliac disease is usually transient and reversible after
repair of small intestinal damage with a gluten-free diet.4 The intraduodenal lipase activity in
patients with coeliac disease was assessed by means of 13C mixed-triglyceride breath test
following a test meal.8 Four of seventeen patients had impaired pancreatic function. Activity
returned to normal at six and twelve months after the institution of a gluten-free diet.
However, some patients continue to have impaired pancreatic function despite treatment
with a gluten-free diet. One study found that seventeen of forty-six children with coeliac
disease had subnormal faecal chymotrypsin values at the time of diagnosis.9 After
beginning a gluten-free diet, there was a progressive reduction in the percentage of patients
with pancreatic impairment. At 60 days, there were still two children who continued to have
subnormal faecal chymotrypsin values.
Similar results were observed in another study by the same group using faecal elastase to
indirectly measure pancreatic function.10 Ten out of thirty coeliac patients had subnormal
faecal elastase values at diagnosis. After two months on a gluten-free diet, faecal elastase
deficiency persisted in two patients.
Pancreatic exocrine insufficiency has been recognised as a possible cause of poor clinical
response to gluten withdrawal.11-13 Pancreatic function was assessed prospectively in a
group of eighteen treated adult coeliac patients, thirteen of whom were asymptomatic.11 The
para-aminobenzoic acid test indicated pancreatic exocrine insufficiency in three patients, all
of whom had persistent gastrointestinal symptoms.
Another study systematically evaluated patients with presumed non-responsive coeliac
disease to determine the aetiology of persistent and relapsing symptoms.13 Of the forty-nine
patients with a firm underlying diagnosis of coeliac disease and persistent symptoms, six
had pancreatic exocrine insufficiency.
Similar results were observed in a survey of seventy-eight patients with coeliac disease
treated with a gluten-free diet for at least twelve months.12 Thirteen had chronic diarrhoea
after treatment, two of which were diagnosed with steatorrhoea due to pancreatic exocrine
insufficiency.
Another study compared the faecal elastase levels in fifty-seven newly diagnosed coeliac
disease patients, eighty-six treated and asymptomatic coeliac disease patients and sixty-six
treated coeliac disease patients with chronic diarrhoea.14 Thirty percent of the treated
coeliac disease patients with chronic diarrhoea had low faecal elastase levels. This was
significantly more frequent than in the other subgroups (11% in newly diagnosed and 6% in
asymptomatic treated patients).
Taken together, these results suggest that pancreatic exocrine insufficiency is common in
untreated patients with coeliac disease, but is reversible in those patients who have a good
clinical response to a gluten-free diet. However, in those patients with persistent symptoms
after gluten withdrawal, assessment of pancreatic exocrine function is warranted.
Pancreatic enzyme replacement therapy
Pancreatic enzyme replacement therapy has been reported to improve symptoms in
patients with coeliac disease who have persistent symptoms despite gluten withdrawal and
evidence of pancreatic exocrine insufficiency.11, 12 Twenty coeliac disease patients on a
gluten-free diet with chronic diarrhoea and low faecal elastase levels were supplemented
with oral pancreatic enzymes.14 In eighteen, stool frequency significantly reduced from four
per day to one per day. Patients subjectively reported improvements in consistency and
urgency, and all continued treatment with an average follow up of two years.
The validity of pancreatic enzyme replacement therapy in the two months following
diagnosis of coeliac disease was investigated in a randomised, double-blind, placebocontrolled trial.5 Twenty children with a mean age of 14.2 months received a pancreatic
enzyme supplement and twenty with a mean age of 14.5 months received placebo. Only
eight patients in the supplemented group and seven in the placebo group had subnormal
values of duodenal enzyme output. All patients commenced a gluten-free diet with identical
calorie intake. After 30 days, weight gain was significantly greater in the supplemented
group compared with the placebo group. However, there was no significant difference after
60 days.
These results suggest that all infants with coeliac disease, regardless of pancreatic exocrine
function, may benefit from pancreatic enzyme replacement therapy in the period
immediately following diagnosis.
Otherwise, treatment is only warranted in coeliac disease patients (both adults and children)
with persistent symptoms due to pancreatic exocrine insufficiency despite treatment with a
gluten-free diet.
Summary
Pancreatic exocrine insufficiency is common in untreated patients with coeliac disease, but
is reversible in those patients who have a good clinical response to gluten withdrawal.
Patients with persisting symptoms after gluten withdrawal should have their pancreatic
exocrine function assessed. Those found to have pancreatic exocrine insufficiency should
be treated with pancreatic enzyme replacement therapy.
Supplementation with pancreatic enzymes may also benefit infants with coeliac disease in
the period immediately following diagnosis, irrespective of pancreatic function.
Recommendations for pancreatic enzyme replacement therapy in coeliac disease
Recommendations
Level of
evidence
Infants newly diagnosed with coeliac disease may benefit from shortterm pancreatic enzyme replacement therapy
1b
Pancreatic exocrine insufficiency should be assessed in all patients with
coeliac disease whose symptoms persist after gluten withdrawal
2b
Pancreatic enzyme replacement therapy is indicated in all patients with
coeliac disease whose symptoms persist after gluten withdrawal due to
pancreatic exocrine insufficiency
2b
References
1.
Facts about coeliac disease. Gastroenterological Society of Australia. (Accessed
December 14, 2009, at http://www.gesa.org.au/pdf/Coeliac_Disease_4Ed_07.pdf).
2.
Gray GM. Gastroenterology 1997;112:2146-7.
3.
Regan PT, DiMagno EP. Gastroenterology 1980;78:484-7.
4.
Carroccio A et al. Gut 1991;32:796-9.
5.
Carroccio A et al. Dig Dis Sci 1995;40:2555-60.
6.
Carroccio A et al. Dig Dis Sci 1994;39:2235-42.
7.
Freeman HJ. World J Gastroenterol 2007;13:6344-6.
8.
Perri F et al. J Pediatr Gastroenterol Nutr 1998;27:407-10.
9.
Carroccio A et al. Gastroenterology 1997;112:1839-44.
10.
Carroccio A et al. Ital J Gastroenterol Hepatol 1998;30:500-4.
11.
Collins BJ et al. Pancreas 1986;1:143-7.
12.
Fine KD et al. Gastroenterology 1997;112:1830-8.
13.
Abdulkarim AS et al. Am J Gastroenterol 2002;97:2016-21.
14.
Leeds JS et al. Aliment Pharmacol Ther 2007;25:265-71.
Chapter 14
Diabetes mellitus
Introduction
The exocrine and endocrine portions of the pancreas are linked anatomically and
physiologically, and as such, any disease affecting one part has the potential to affect the
other part.1 During the past few decades, numerous reports have described morphological,
histological and functional changes in the exocrine pancreas of patients with diabetes
mellitus.2 However, it is not clear whether these changes are a consequence or cause of
endocrine dysfunction or a result of a pathological process affecting the whole organ.2,3
Pancreatic exocrine function
Pancreatic exocrine insufficiency occurs frequently in patients with diabetes mellitus.
Several case-control studies have compared the levels of faecal elastase in patients with
and without diabetes and have uniformly found lower concentrations in cases than in
controls.4-6 Table 1 summarises the prevalence of low faecal elastase concentrations in
patients with diabetes from population studies. These studies reported a high prevalence in
both type 1 (45-55%) and type 2 diabetes (30-35%).4-8
The clinical impact of low faecal elastase concentrations in patients with diabetes was
investigated in a prospective multicentre study of hospital inpatients with type 1 or type 2
diabetes.3 Patients with low faecal elastase levels (<100 mg/g) were invited to enter a study
on fat digestion. Of the 101 patients who completed the study, only forty-one (40.6%) had
normal fat excretion <7 g/day. In forty patients (39.6%), fat excretion was greater than 10
g/day indicating significant steatorrhoea.
Taken together, these results suggest that patients with type 1 or type 2 diabetes mellitus
should be checked for pancreatic exocrine insufficiency.
Table 1. The prevalence of low faecal elastase concentrations in diabetes mellitus
Hardt et al. 20004
Rathmann et al. 20015
Icks et al. 20016
Hardt et al. 20037
Ewald et al. 20078
Type 1 diabetes
<200
<100
mg/g
mg/g
56.7%
30.0%
45.5%
25.9%
51.1%
28.5%
21.1%
Type 2 diabetes
<200
<100
mg/g
mg/g
35.0%
16.9%
30.3%
11.9%
35.4%
19.9%
-
Controls
<200
<100
mg/g
mg/g
18.1%
4.8%
14.3%
3.7%
13.8%
5.2%
-
Pancreatic enzyme replacement therapy
There have been only a few reports on the use of pancreatic enzyme replacement therapy
in diabetic patients with pancreatic exocrine insufficiency.
The first study was a small randomised crossover trial in which ten insulin-dependent
diabetes patients with chronic pancreatitis and pancreatic exocrine insufficiency were
treated for four days with either pancreatic enzymes or placebo.9 Pancreatic enzyme
replacement therapy did not significantly alter blood glucose levels or the requirement for
insulin. There was a tendency towards smaller oscillations of blood glucose with pancreatic
enzyme replacement therapy than with placebo.
The second study involved patients with tropical calculous chronic pancreatitis and
diabetes.10 During 6 months of pancreatic enzyme replacement therapy, patients showed
considerable improvement in abdominal pain, steatorrhoea and quality of life. There was a
significant reduction in postprandial plasma glucose and glycosylated haemoglobin.
A third study investigated the effects of pancreatic enzyme replacement therapy on food
absorption and blood glucose control in twenty-nine patients with chronic pancreatitis and
faecal fat excretion greater than 10 g/day.11 Eighteen patients had diabetes. After fourteen
days of pancreatic enzyme supplementation, faecal fat and nitrogen excretion decreased
and fat absorption increased.
However, changing treatment from active enzyme
supplementation to placebo or vice versa resulted in problems in blood glucose control.
More recently, the impact of pancreatic enzyme replacement therapy on glucose
metabolism and diabetes treatment was evaluated in a multicentre prospective study of
patients with type 1 diabetes.8 Eighty patients were randomised to receive either pancreatic
enzymes or placebo in a double-blind manner. During the sixteen-week study, there were
no significant differences between groups in parameters of glucose metabolism or in
patients’ symptoms.
Although a significant proportion of diabetic patients seem to have a need for pancreatic
enzyme replacement therapy, the clinical benefit of such use has not yet been established.
Summary
Pancreatic exocrine insufficiency occurs frequently in both type 1 and type 2 diabetes
mellitus. In approximately 60% of patients, the pancreatic exocrine insufficiency can cause
characteristic steatorrhoea, and treatment with pancreatic enzyme replacement therapy
may be indicated. However, a clear clinical benefit of such use has not yet been
established.
Recommendations for pancreatic enzyme replacement therapy in diabetes mellitus
Recommendations
Level of
evidence
Patients with diabetes mellitus should be investigated for pancreatic
exocrine insufficiency
2b
Pancreatic enzyme replacement therapy can be trialled in diabetic
patients with proven impairment of pancreatic exocrine function
4/5
References
1.
Czakó L et al. Pancreatology 2009; 9: 351-59.
2.
Andren-Sandberg A, Hardt PD. J Pancreas (Online) 2008; 9: 541-75.
3.
Hardt PD et al. Dig Dis Sci 2003; 48: 1688-92.
4.
Hardt PD et al. Acta Diabetol 2000; 37: 105-10.
5.
Rathmann W et al. Scand J Gastroenterol 2001; 10: 1056-61.
6.
Icks A et al. Z Gastroenterol 2001; 39: 823-30.
7.
Hardt PD et al. Pancreatology 2003; 3: 395-402.
8.
Ewald N et al. Diabetes Metab Res Rev 2007; 23: 386-91.
9.
Glasbrenner B et al. Z Gastroenterol 1990; 28: 275-79.
10.
Mohan V et al. Int J Pancreatol 1998; 24: 19-22.
11.
O’Keefe SJ et al. J Clin Gastroenterol 2001; 32: 319-23.
Chapter 15
Human immunodeficiency virus
Introduction
Patients with human immunodeficiency virus (HIV) frequently suffer from involuntary weight
loss, chronic diarrhoea and nutrient malabsorption, particularly in the later stages of
disease.1 Fat malabsorption often contributes to this clinical presentation, and is commonly
caused by opportunistic intestinal infection or intestinal mucosa damage.1-3 However,
pancreatic impairment may also play a role.
It was reported that the incidence of chronic pancreatitis was 0.5% in a series of about
1,000 hospitalised HIV patients.1 Usually chronic pancreatitis is due to alcohol, particularly
in those HIV-infected patients with a history of drug abuse.1 It has also been proposed that
HIV infection itself can cause pancreatic exocrine insufficiency.1 4
Autopsy studies have shown morphological abnormalities in the pancreas of patients with
acquired immunodeficiency syndrome (AIDS) caused by HIV,5, 6 and functional studies have
demonstrated a high incidence of abnormalities in HIV-infected patients.7, 8 In addition to
pancreatic diseases affecting the general population, patients with HIV infection can
develop pancreatic disorders from opportunistic infections, HIV-associated neoplasia, and
medications used in treatment.4
Pancreatic exocrine function
Pancreatic exocrine function was first studied in 1990 in 25 HIV-infected patients.9 Fat
malabsorption was evident in 12 of the 25 patients using the 14C-triolein breath test. Three
of the 12 patients had evidence of mild pancreatic exocrine insufficiency based on urinary
recovery of para-amino-benzoic acid.
Another study evaluated the frequency of pancreatic exocrine insufficiency and its
relationship with fat malabsorption in thirty-five HIV-infected patients.8 Twenty-five patients
had evidence of fat malabsorption with the steatocrit test. Nineteen had low faecal elastase
levels.
More recently, faecal elastase was measured in twenty-two HIV-positive patients with
chronic diarrhoea.10 Eight had evidence of pancreatic exocrine insufficiency.
In addition to adults, pancreatic exocrine insufficiency has also been noted in HIV-infected
children.7 Pancreatic function was assessed in forty-seven HIV-infected children without
apparent pancreatic disease. Fourteen had abnormal pancreatic function tests as measured
by faecal elastase and/or chymotrypsin.
These studies suggest that reduced pancreatic exocrine function is frequently present in
both adult and children with HIV infection. It has been estimated that steatorrhoea is due to
pancreatic dysfunction in at least 30% of patients.11 It is likely that pancreatic exocrine
insufficiency is undiagnosed in many patients because diarrhoea that is not secondary to
opportunistic infection is thought to be a normal side effect of treatment or due to small
bowel abnormalities secondary to HIV infection itself.10
Pancreatic enzyme replacement therapy
The effectiveness of pancreatic enzyme replacement therapy in HIV-infected patients with
fat malabsorption has been evaluated in two trials.
In the first open-label trial, 24 consecutive children with HIV infection and fat malabsorption
were recruited.11 All patients had faecal fat loss as determined by elevated steatocrit values.
Six had abnormally low faecal elastase and/or chymotrypsin, suggesting pancreatic
exocrine insufficiency. Patients were treated for two weeks with pancreatic enzyme
replacement therapy at a dose of 1,000 units of lipase per gram of ingested dietary fat. Five
patients did not complete the study due to the onset of abdominal pain during treatment. In
the 19 patients who completed the study, steatocrit values at the end of treatment were
significantly lower than at baseline. Steatocrit values returned to within the normal limit in 8
of the 19 patients.
More recently, a retrospective study was conducted in a cohort of 8 HIV-positive adults with
evidence of pancreatic exocrine insufficiency based on low faecal elastase measurement.10
Seven of the patients were started on oral pancreatic enzyme replacement therapy. All
patients had symptomatic improvement of diarrhoea and steatorrhoea with normal bowel
motions once or twice a day. Four patients required only 10,000 units of lipase per meal to
relieve symptoms, whereas two required 20,000 units and one required 60,000 units.
However, the patient taking 60,000 units of lipase per meal had intolerable abdominal
bloating and had to discontinue treatment. Two other patients also had abdominal bloating,
but it was mild and tolerable.
These results suggest that pancreatic enzyme replacement therapy may be effective in
treating steatorrhoea in HIV-infected patients with fat malabsorption.
Summary
Fat malabsorption is a frequent problem in patients with HIV infection. Steatorrhoea may be
due to pancreatic exocrine insufficiency in approximately 30% of cases. Treatment with
pancreatic enzyme replacement therapy can reduce faecal fat loss and relieve the
symptoms of steatorrhoea in HIV-infected patients with fat malabsorption.
Recommendations for pancreatic enzyme replacement therapy in HIV
Recommendations
Level of
evidence
Faecal fat loss and pancreatic exocrine function should be measured in
HIV-infected patients with chronic diarrhoea
3b
Pancreatic enzyme replacement therapy should be trialled in HIVinfected patients with fat malabsorption
4
References
1.
Cappell MS. Gastroenterol Clin North Am 1997;26:337-65.
2.
Miller TL et al. Gastroenterology 1991;100:1296-302.
3.
Sharpstone D, Gazzard B. Lancet 1996;348:379-83.
4.
Cappell MS, Hassan T. J Clin Gastroenterol 1993;17:254-63.
5.
Dowell SF et al. Mod Pathol 1990;3:49-53.
6.
Bricaire F et al. Lancet 1988;1:65-6.
7.
Carroccio A et al. Gut 1998;43:558-63.
8.
Carroccio A et al. Scand J Gastroenterol 1999;34:729-34.
9.
Kapembwa MS et al. Q J Med 1990;74:49-56.
10.
Price DA et al. HIV Med 2005;6:33-6.
11.
Carroccio A et al. Aliment Pharmacol Ther 2001;15:1619-25.
Chapter 16
Irritable bowel syndrome
Introduction
Irritable bowel syndrome is a common condition affecting as many as one in five Australians
at some point during their lives.1 It is characterised most commonly by abdominal pain and
bloating with abnormal bowel habit. Some patients suffer from constipation, others have
diarrhoea, and many alternate between the two.
It is possible that pancreatic exocrine insufficiency may contribute to diarrhoea-predominant
irritable bowel syndrome.2
Pancreatic exocrine function
The first suggestion that pancreatic exocrine insufficiency may be present in some patients
with irritable bowel syndrome came from a case-control study conducted in 1986.3 In this
study, 14CO2 breath sampling was used to measure the absorption of 14C-triolein from a
standard fat meal. Results from sixty-six patients with gastrointestinal disorders were
compared with sixty controls. Twenty percent of those with irritable bowel syndrome had
subnormal values in the 14C-triolein breath test.
Recently the prevalence of pancreatic exocrine insufficiency was assessed in 314 patients
with diarrhoea-predominant irritable bowel syndrome.2 Nineteen patients (6.1%) had faecal
elastase levels less than 100 mg/g stool indicating severe pancreatic exocrine insufficiency.
The prevalence was significantly higher than in diarrhoea and non-diarrhoea control groups.
Pancreatic enzyme replacement therapy
The efficacy of pancreatic enzyme replacement therapy in diarrhoea-predominant irritable
bowel syndrome was assessed in a case-control study.2 Nineteen patients with faecal
elastase levels below 100 mg/g stool and fifteen patients with normal faecal elastase levels
(>200 mg/g stool) were treated with 30,000 units of lipase three times per day for 12 weeks.
Eighteen patients (94.7%) with low faecal elastase levels and one patient with normal faecal
elastase (6.7%) had a clinically significant response to therapy. Supplementation with
pancreatic enzymes led to significant improvements in stool frequency, stool consistency
and abdominal pain in patients with low faecal elastase levels compared to controls.
The results are supported by a recent case report of a patient with clinical features of
diarrhoea-predominant irritable bowel syndrome who was successfully treated with
pancreatic enzymes.4 In 2002, the patient enrolled in a randomised controlled trial
comparing the efficacy of pancreatic enzyme replacement therapy with that of placebo in
patients with diarrhoea-predominant irritable bowel syndrome. The patient was one of
twenty-five out of thirty-nine patients completing the trial who judged the enzyme
supplementation to be more effective than placebo at reducing postprandial symptoms. She
continued to be successfully treated with enzymes for an additional four years.
Summary
Irritable bowel syndrome is a common condition characterised by abdominal pain, bloating
and abnormal bowel habit. Pancreatic exocrine insufficiency may occur in patients with
diarrhoea-predominant irritable bowel syndrome. Treatment with pancreatic enzyme
replacement therapy may reduce diarrhoea and abdominal pain.
Recommendations for pancreatic enzyme replacement therapy in irritable bowel
syndrome
Recommendations
Level of
evidence
Patients with diarrhoea-predominant irritable bowel syndrome should be
investigated for pancreatic exocrine insufficiency
2b
Pancreatic enzyme replacement therapy can lead to clinically significant
improvements in diarrhoea-predominant irritable bowel syndrome with
evidence of pancreatic exocrine insufficiency
3b
References
1.
Facts about irritable bowel syndrome. Gastroenterological Society of Australia.
(Accessed December 15, 2009, at http://www.gesa.org.au/pdf/IBS_2nd_03.pdf).
2.
Leeds JS et al. Clin Gastroenterol Hepatol 2009; Oct 13 [Epub ahead of print].
3.
Mylvaganam K et al. Gut 1986; 27(11): 1347-52.
4.
Money ME et al. Pancreas 2009; 38(2): 232-233.
Chapter 17
Conclusion
Pancreatic exocrine insufficiency occurs when amounts of enzymes secreted into the
duodenum in response to a meal are not sufficient to maintain normal digestive processes.
This can occur in adults or children as a consequence of numerous diseases, including
chronic pancreatitis, pancreatic cancer, cystic fibrosis or following gastrointestinal surgery
where parts of the gastrointestinal tract have either been removed or bypassed. The main
clinical consequence of pancreatic exocrine insufficiency is fat maldigestion and
malabsorption resulting in steatorrhoea.
There is no standardised method for assessing pancreatic exocrine function, and as such,
there are no defined criteria for diagnosing pancreatic exocrine insufficiency.
Recommendations have been made regarding the medical and dietary management of
patients with pancreatic exocrine insufficiency. Pancreatic enzyme replacement therapy
(PERT) remains the mainstay treatment for pancreatic exocrine insufficiency. Over the
course of the past five decades, PERT has evolved and numerous different formulations
have been developed, evaluated and marketed during that time. The clinical effectiveness
of the medication has improved as better understanding of dose and time of administration
has evolved.
The initial recommended dose of pancreatic enzymes is 25,000 units lipase per meal for
adults or 500 units lipase per gram of dietary fat for children, which can then be uptitrated to
the lowest effective dose. The enzymes should be taken during a meal for optimal action.
Adjunct therapy with acid-suppressing agents may be useful in patients who continue to
experience symptoms of pancreatic exocrine insufficiency despite high-dose enzyme
therapy.
The involvement of a dietician to oversee dietary management is recommended. Patients
should be counselled to consume at least a normal fat diet divided into smaller meals
across six or more eating occasions. Alcohol abstinence should be encouraged as it may
lead to further deterioration in pancreatic exocrine function and exacerbate symptoms of
pancreatic exocrine insufficiency.
Through the development of these guidelines it has become apparent that there is a lack of
good quality clinical evidence for the management of pancreatic exocrine insufficiency.
Recommendations are based primarily on clinical experience rather than high level clinical
evidence. Clearly, further research is needed in order to optimise patient management.
Acknowledgements
Writing Group
•
Prof Andrew Biankin, Pancreatobiliary Surgeon, Garvan Institute, Sydney
•
A/Prof Mark Oliver, Gastroenterologist, Royal Children’s Hospital, Melbourne
•
A/Prof Callum Pearce, Gastroenterologist, Fremantle Hospital, Fremantle
•
Prof James Toouli, Professor of Surgery, Flinders University, Adelaide
•
Prof Jeremy Wilson, Gastroenterologist, SW Sydney Clinical School, Sydney
•
Nick Wray, Dietician, Flinders Private Hospital, Adelaide
These Guidelines were supported by an unrestricted grant from Solvay Pharmaceuticals to
the Australasian Pancreatic Club.