1. health and fitness
2. disease
3. cholesterol

Pediatric Pulmonology 41:35–49 (2006)
Diagnosis and Treatment of Intestinal
Malabsorption in Cystic Fibrosis
James M. Littlewood, MB, ChB, MD,* Susan P. Wolfe, BSc (Hons),
and Steven P. Conway, MB, BS, MA
Summary. Intestinal malabsorption is severe and of early onset in virtually all people who have
cystic fibrosis. The main cause is deficiency of pancreatic enzymes. Bicarbonate deficiency,
abnormal bile salts, mucosal transport problems, motility differences, and anatomical structural
changes are other contributory factors. Effective treatment should allow a normal to high-fat diet to
be taken, control symptoms, correct malabsorption, and achieve a normal nutritional state and
growth. Appropriate pancreatic enzyme replacement therapy will achieve normal or near-normal
absorption in most people with cystic fibrosis. Early identification and treatment of intestinal
malabsorption is critical to achieving optimal nutritional status. The occurrence of fibrosing
colonopathy in a few patients on very high doses of those enzymes which have the copolymer
Eudragit L30 D55 in their covering resulted in guidelines in the UK to avoid doses equivalent to more
than 10,000 IU lipase per kg per day, and also to avoid preparations containing this copolymer in
children and adolescents. For patients not responding to 10,000 IU lipase per kg per day review of
adherence to treatment, change of enzyme preparation, variation in time of administration, and
reduction in gastric acid may improve absorption. The importance of early investigation to exclude
other gastrointestinal disorders as a cause of the patient’s symptoms, rather than merely
increasing the dose of enzymes, is stressed. With modern pancreatic enzymes in doses up to or
only slightly in excess of 10,000 IU lipase per kg per day, adequate control of gastrointestinal
symptoms and absorption can be achieved, and a normal nutritional state and growth rate
maintained in most people with cystic fibrosis. Pediatr Pulmonol. 2006; 41:35–49.
ß 2005 Wiley-Liss, Inc.
Key words: pancreatic enzymes; cystic fibrosis; malabsorption; nutrition.
INTRODUCTION
Intestinal malabsorption in cystic fibrosis (CF) is of
early onset. In one series of screened infants, malabsorption affected 59% of infants by 7 weeks, 79% by 6 months,
and 92% by age 1 year.1 Eventually 95% of people with CF
in Northern Europe become pancreatic-insufficient (PI),
i.e., they have insufficient pancreatic function to achieve
normal intestinal absorption of fat, and will therefore
require pancreatic enzyme replacement therapy (PERT)
from an early age. However, only 85% of patients
attending the Toronto CF clinic are PI; this is a reflection
of the unusually high incidence of so-called ‘‘mild’’
mutations (R117H, R2334W, R347P, A455E, and
P574H), which are more likely to occur in patients who
are pancreatic-sufficient (PS).2 Multiple factors contribute
to the intestinal malabsorption (see Table 1). Deficiency of
pancreatic enzymes is the most important.3–5 The
pathological changes in the pancreas of duct obstruction
and destruction of acinar cells occur as a result of
abnormalities of the gene product, the cystic fibrosis
transmembrane regulator (CFTR). This leads to abnormal
transmembrane fluid and electrolyte movement. A
deficiency of pancreatic bicarbonate reduces duodenal
ß 2005 Wiley-Liss, Inc.
pH, inactivating pancreatic enzymes and precipitating bile
salts.6–8 There is increased fecal loss of bile salts9 and a
relative increase in glycine-conjugated and a decrease in
taurine-conjugated bile salts.10 Glycine-conjugated bile
salts are less effective at lipid solubilization. Intestinal
mucosal ion transport abnormalities affecting both water
and electrolyte transport appear to be related to the basic
CFTR defect.11 Impaired mucosal uptake and transport of
long-chain fatty acids may occur.12,13 There is also altered
motility, with an increased small bowel transit time.14,15
Regional Paediatric Cystic Fibrosis Unit, St. James’s University Hospital,
Leeds, UK.
This article is extensively reworked and updated from Paediatr Drugs
2000;2:205–222 (published by Adis International, Ltd.).
*Correspondence to: James M. Littlewood, M.B., Ch.B., M.D., Regional
Paediatric Cystic Fibrosis Unit, St. James’s University Hospital, Leeds LS9
7TF, UK. E-mail: [email protected]
Received 31 March 2005; Revised 31 March 2005; Accepted 1 June 2005.
DOI 10.1002/ppul.20286
Published online 15 November 2005 in Wiley InterScience
(www.interscience.wiley.com).
36
Littlewood et al.
TABLE 1— Factors Contributing to Intestinal Malabsorption
in Cystic Fibrosis
Abnormal CFTR function in pancreatic ducts
Deficiency of pancreatic enzymes
Deficiency of pancreatic bicarbonate
Increased fecal loss of bile salts
Altered ratio of glycine- and taurine-conjugated bile salts
Intestinal mucosal ion transport abnormalities
Uptake and transport of long-chain fatty acids
Altered motility and increased small-bowel transit time
Structural abnormalities from previous surgery
Structural abnormalities from previous gastrointestinal
surgery for meconium ileus (e.g., shortened bowel,
strictures, malrotations, and adhesions) and an excess of
mucus may also be relevant.16
Although malabsorption of both fat and nitrogen is
severe without PERT, carbohydrate malabsorption is
minimal.17 Control of symptoms does not guarantee
control of fat malabsorption.18,19 Also, persistent abdominal signs and symptoms, particularly pain, despite taking
reasonable doses of enzymes, may not be due to
inadequate enzyme treatment but some other cause such
as constipation.20
The control of intestinal malabsorption is but one aspect
of the overall nutritional management of CF, which also
includes provision of an adequate energy intake, avoidance of fat-soluble vitamin deficiencies, and maintenance
of an adequate energy balance by effective treatment of the
respiratory infection.21–24
INVESTIGATION OF
INTESTINAL MALABSORPTION
It is important to document some evidence of intestinal
malabsorption before starting pancreatic enzyme therapy;
subsequently, the presence of pancreatic insufficiency
should be confirmed, ideally by estimating fecal pancreatic elastase 1 (EL1). If clinical signs of malabsorption are
mild or absent, it is advisable to confirm pancreatic
insufficiency before starting enzyme therapy. There
should be some regular measurement of the adequacy of
PERT, as symptoms, weight gain, and growth do not
always correlate with the severity of malabsorption.
It is important to document evidence of pancreatic
abnormality in addition to demonstrating intestinal
malabsorption. Such evidence provides important support
for the diagnosis of CF at all ages. Failure to demonstrate
any pancreatic abnormality would cast doubt on the
diagnosis of cystic fibrosis.
IDENTIFICATION OF A PANCREATIC LESION
Direct pancreatic stimulation tests were the traditional
‘‘gold standard’’ measurements of pancreatic function,
but are not in routine use at most CF centers (see Table 2).
TABLE 2— Identification of Pancreatic Lesion
Direct pancreatic function tests
Fecal chymotrypsin, when not taking pancreatic enzymes
Immunoreactive trypsin, high or low values
Fecal elastase 1, on or off enzymes
Three-day fecal fat estimation
The fluid volume and the bicarbonate and enzyme content
of pancreatic secretions are all reduced in cystic fibrosis.
Fecal chymotrypsin is unfortunately not available in the
UK at present. It is reasonably stable at room temperature
in contrast to the older fecal trypsin tests, and not degraded
by proteolytic enzymes. Levels are low in untreated PI
patients with CF, and provide useful supportive evidence
of a pancreatic abnormality.25 Occasional measurements
of fecal chymotrypsin are useful for monitoring PERT.
Values that remain low on treatment indicate either
inadequate prescription or nonadherence with treatment,
although a normal value does not exclude persisting
significant steatorrhea. Very high values can indicate that
the dose of PERT is excessive. High values also occur if the
patient has rapid intestinal transit. Conversely, constipation may be associated with low values. If low values
persist alongside symptoms of malabsorption, treatments
to reduce gastric-acid secretion may help improve enzyme
efficacy and enable a reduction in enzyme intake.
Blood immunoreactive trypsin (IRT) is raised in young
infants with CF, and levels fall during childhood. Values
are usually low after 10 years of age in people with CF
except in those who are PS, who may remain elevated.26 In
infants with CF identified by neonatal screening, the raised
IRT provides additional evidence of a pancreatic lesion as
well as identifying the affected infant. IRT cannot predict
the onset of pancreatic insufficiency in screened PS
infants.
Fecal pancreatic elastase 1 is a specific human protease
synthesized by the acinar cells, and is now the most
suitable investigation to demonstrate a significant pancreatic lesion. It is stable, unaffected by exogenous
pancreatic enzyme treatment, and correlates well with
stimulated pancreatic function tests.27–29 There may be
some transient mild pancreatic insufficiency associated
with some reduction in EL1 levels in patients with celiac
disease before treatment. This is not to the same degree as
the pancreatic insufficiency associated with cystic fibrosis.30 Fecal pancreatic elastase 1 can be estimated from
a very small specimen of feces. In CF, there is clear
separation between PS patients who have normal values
(>200 mg/g of feces) and PI patients with very low values.
Fecal pancreatic elastase 1 provides evidence of pancreatic insufficiency in screened infants with CF, the test being
reliable after age 2 weeks. When patients are reinvestigated as to pancreatic status, but already taking enzymes, a
low EL1 will confirm the need for enzyme treatment
without having to stop their treatment.31 The test is also
Intestinal Malabsorption in Cystic Fibrosis
useful for annual monitoring of PS patients to identify the
onset of pancreatic insufficiency.32 We consider EL1 the
best indirect measure of pancreatic function, and it has
superseded other indirect pancreatic function tests for
routine use.33
DIAGNOSIS OF INTESTINAL MALABSORPTION
A number of clinical features are associated with
intestinal malabsorption, although objective laboratory
evidence is always required for confirmation (Table 3).
Clinical signs and symptoms may be strongly suggestive of intestinal malabsorption. They are not totally
reliable, and occasional patients have been started on
enzymes because their symptoms were considered to be so
obviously due to malabsorption, although years later they
were shown to be pancreatic-sufficient. If there are
abdominal distension, abdominal discomfort, and loose
oily pale offensive stools (particularly if they contain
orange oil), and the patient is malnourished, it is likely that
there is intestinal malabsorption. However, there are
patients whose symptoms and signs are caused by other
gastrointestinal abnormalities.20 In such patients, demonstrating that intestinal absorption is controlled prevents a
potentially harmful increase in the enzyme dose, and also
prompts a search for another cause for the symptoms.34
Inadequate weight gain and growth in children and
adolescents and a low BMI in adults, particularly if the
appetite is good, suggest intestinal malabsorption. However, other causes should be investigated—particularly
uncontrolled bronchopulmonary infection.21 Even in
people with CF who are known to be PI, a poor nutritional
state may be related more to ineffective control of chest
infections, resulting in an increase in energy requirement
and reduced appetite, rather than to uncontrolled intestinal
malabsorption.
The traditional method for demonstrating fat absorption
is a measurement of fat excretion over a fixed time, usually
a minimum of 3 days, and an estimate of dietary intake of
fat over the same period.35 The fecal collection can be
done at home. A dietary diary is completed by the carer/
patient and used to calculate daily fat intake by the
dietitian. The intake and output of fat are then used to
calculate the percentage fat absorption. Normally the
equivalent of less than 5% of the fat ingested is excreted,
i.e., there is over 95% absorption of dietary fat. The total
daily fecal fat output is less than 7 g per day in healthy
TABLE 3— Diagnosis of Fat Malabsorption
Clinical symptoms and signs
Measurement of weight gain and growth
Fecal fat estimations
Fecal microscopy for fat globules
Acid steatocrit
13
C carbon mixed-triglyceride breath test
37
adults and rarely exceeds 4.9 g in adolescents, 3.1 g in
children, and 4.3 g in infants.36 Unfortunately, as fecal
collection is very unpleasant for patients and carers, and
many laboratories are reluctant to perform the analysis,
the test is largely reserved for research purposes, e.g.,
measuring the effect of a new enzyme preparation.
People with CF are often understandably unwilling to
collect fecal specimens for 3 days. Therefore, a semiquantitative estimate of fecal fat content should be made in
all patients by one of the methods of fecal microscopy
validated by comparison with quantitative measurements.37 These are simple, cheap techniques using
microscopy of a very small amount of feces collected at
home and brought to the clinic. The methods are sensitive
and identify all patients with severe steatorrhea who show
a great excess of neutral fat on microscopy.
An alternative semiquantitative technique is a modification of the original steatocrit method, involving
acidification of the fecal homogenate. Although the
specimen requires centrifugation, the method is wellvalidated, and correlates well with the results of standard
fecal fat estimations.38–40
Finally, the 13 carbon mixed-triglyceride breath test is a
safe, noninvasive way of assessing fat digestion that can be
used repeatedly.41–43 However, the test is expensive and
not widely available at present.
As part of their annual review, it is advised that all
patients have ‘‘an assessment of the adequacy of intestinal
absorption by a combination of clinical and laboratory
methods.’’23,44
In summary, EL1 provides the clinician with an
adequate, simple means of identifying pancreatic insufficiency at diagnosis or annually in those who remain
pancreatic-sufficient. Fecal microscopy or acid steatocrit
provide a semiquantitative estimate of the severity of
intestinal fat absorption during pancreatic enzyme treatment. Fecal chymotrypsin gives an approximate indication of the adequacy of PERT. Ideally, timed fecal fat
estimations should be available if required, and the
coefficient of fat absorption should always be measured
if the maintenance of adequate nutritional state and growth
is proving a significant problem, or if gastrointestinal
symptoms are not adequately controlled.
WHO SHOULD RECEIVE PANCREATIC
ENZYME REPLACEMENT THERAPY?
A slender, nonthriving infant with pale oily stools
should be started on enzymes after a fecal specimen has
been sent for fat microscopy, chymotrypsin (if available),
and EL1. Patients with obvious gastrointestinal symptoms
and signs of malabsorption and evidence of a pancreatic
lesion and intestinal malabsorption should receive PERT.
However, where there is doubt and confusion as to the
presence of pancreatic insufficiency and malabsorption, a
38
Littlewood et al.
3-day fecal fat analysis should clarify the situation. When
gastrointestinal symptoms and signs are absent or
minimal, it is reasonable to wait for definite evidence of
malabsorption before commencing enzyme treatment.
Patients who are PI will have an obvious excess of neutral
and split fat on microscopy, an abnormally low fecal
chymotrypsin level, a very low EL1 level, and an increased
3-day fecal fat excretion.
CHOICE OF PANCREATIC
ENZYME PREPARATION
A classification of available types of pancreatic enzyme
preparations is listed in Tables 4 and 5. The occurrence of
fibrosing colonopathy (FC) in the early 1990s45 and the
subsequent recommendations (see below) of the UK
Committee on Safety of Medicines (CSM, 1995) and
North American Consensus Committee (1995)46 will
influence most clinicians in the preparation they choose
for their patients. A UK case-controlled study showed both
dose and preparations to be significant factors in the
development of FC.47 A similar US study found only the
dose of lipase to be a factor.48 The age of the patient,
the clinician’s view on the importance of the copolymer
Eudragit L30 D55 (in the coating of some preparations) as
a factor causing FC (see below), the dose of enzyme that is
required to control malabsorption, the cost, and local
availability will also influence which preparation is used.
In the UK, it is encouraging that there have been only
four further cases of FC reported since 1994.49–52 All were
taking Nutrizym GR, the only standard-strength product
available in the UK that contains the copolymer Eudragit
L30 D55. Despite the rarity of the complication, the
occurrence and severity of the condition had a major
influence on attitudes to pancreatic enzyme treatment.53,54
This subject was reviewed in detail elsewhere.55
In most specialist CF centers in the UK, enzyme
preparations containing the copolymer Eudragit L30 D55
(Pancrease HL, Nutrizym 22 and 10, and Nutrizym GR)
are avoided. Most infants and children now take Creon
Micro, Creon 10,000, or Pancrease. A few parents
preferred their children to continue with Creon 25,000,
and experience with this preparation in one UK specialist
CF center is reassuring.56 Most adults attending CF
specialist centers in the UK are prescribed Creon 25,000,
and some are prescribed Creon 40,000.57
Although opinions remain divided as to the importance
of the copolymer, all are agreed that whichever preparation is used, it is important to use the minimal dose to
achieve acceptable control of symptoms and intestinal
malabsorption. It is disturbing that, in an audit of 17
specialist CF centers by the UK CF Database,58 many
people with CF in the UK appear to be taking enzymes in
doses far in excess of the CSM 1995 recommendations,
which stated that ‘‘it would be prudent not to exceed a
daily dose equivalent to 10,000 IU lipase/kg/day regardless of the preparation used.’’59
Since the first report of FC in 1994, more attention has
been paid to regular monitoring of intestinal malabsorption in a few, but unfortunately not all, specialist CF
centers and clinics. Previously in many instances, the
carer or patient had largely determined the dose of
enzymes according to the presence of bowel symptoms
and signs. Since the description of FC, it is clear that
troublesome pain or other gastrointestinal symptoms
call for investigations at an early stage to determine the
cause. Investigations will usually include a plain abdominal X-ray, an abdominal ultrasound, and contrast
studies. The mistaken belief that recurrent abdominal
pain always indicates a need for more enzymes is now
less common.
For infants and children, it is recommended that
treatment be started with one of the standard-strength
enzyme preparations, e.g., Creon or Pancrease. In 1995,
the UK Committee on Safety of Medicines advised that
pancreatic enzymes containing the copolymer Eudragit
L30 D55 (Pancrease HL, Nutrizym 22, and Panzytrat
25,000) ‘‘will no longer be indicated for children aged
TABLE 4— Pancreatic Enzyme Preparations
Nonenteric coated powders. Older unprotected extracts Pancrex V, Viokase, Cotazyme powder, or (in capsules) Pancrex and Cotazyme are not
indicated for routine use. In ventilated patients, they can be administered down a nasogastric tube, and omeprazole can be used in an attempt to
protect their activity.
Enteric coated tablets. Pancrex V (Paines & Byrne), Viokase tablets. Neither of these preparations has any place in present-day treatment.
Standard-strength microsphere and minimicrosphere acid-resistant preparations. Cotazyme-S (Organon), Pancrease (Janssen-Cilag), Creon
Micro, and Creon 10,000 (Solvay). Pancrease (introduced into UK in 1983; licensed 1986) and Creon (available in UK since 1985) are
standard-strength preparations, and first choice for infants and all PI patients with cystic fibrosis at diagnosis.
Microtablets. Pancrease HL, Nutrizym 10 and 22, Ultrase MT 6/12/20/24/30 (Eurand), Panzytrat 25,000, and Pancrease MT 4/10/16/25/32
(Nordmark). All these preparations contain copolymer Eduragit L30 D55, implicated as a factor in causation of fibrosing colonopathy.
Granules. Nutrizyme GR (Eurand) granules have contained Eudragit L30 D55 since 1993. This product is still available in UK. Three infants with
CF developed fibrosing colonopathy while taking this preparation.
High-strength pancreatic enzymes (HSPE) (>20,000 IU lipase per capsule). In UK, Pancrease HL and Nutrizym 22 (1992), and in the USA,
Pancrease MT (1993) and Ultrase MT (1992) are microtablets and contain Eudragit L30 D55. Creon 25,000 (1992) and Creon 40,000 (2002)
are minimicrosphere preparations and do not contain Eudragit L30 D55.
Intestinal Malabsorption in Cystic Fibrosis
TABLE 5— Minimum Enzyme Content of Pancreatic Enzyme Preparations
Name
Enteric-coated microspheres
Nutrizyme GR
Pancrease
Pancrecarb MS-4
Pancrecarb MS-8
Pancrecarb MS-16
Creon 20
Ultrase capsules
Enterio-coated minimicrospheres
Creon 5
Creon 10,000
Creon 10
Creon Micro per scoop
Creon 25,000
Creon 40,000
Cotazyme-S
Enteric-coated microtablets
Pancrease MT4
Ultrase MT 12
Nutrizym 22
Nutrizym 10
Pancrease HL
Cotazym S
Pancrease MT 10
Pancrease MT 20
Ultrase MT 20
Nonenteric coated powders
Pancrex V per g powder
Viokase powder
Manufacturer
39
1
Lipase IU
Protease IU
Amylase IU
Merck
Janssen Cilag
McNeil (US)
Digestive Care
Digestive Care
Digestive Care
Solvay
Axcan Scandipharm
10,000
5,000
4,500
4,000
8,000
16,000
20,000
4,500
650
330
25,000
25,000
45,000
52,000
75,000
25,000
10,000 (BP)
2,900
20,000 (USP)
20,000 (USP)
40,000 (USP)
52,000 (USP)
66,400 (USP)
20,000 (USP)
Solvay
Solvay
Solvay
Solvay
Solvay
Organon
5,000
10,000
10,000
5,000
25,000
40,000
10,000
18,750
600
37,000
200
1,000
1,600
750
16,600 (USP)
8,000 (Ph Eur)
33,000 (USP)
3,600 (Ph Eur)
18,000 (Ph Eur)
25,000 (Ph Eur)
7,700 (BP)
McNeil
Axcan Scandipharm
Merck
Merck
Janssen Cilag
Organon
McNeil
McNeil
Axcan Scandipharm
4,000
12,000
22,000
10,000
25,000
8,000
10,000
20,000
20,000
12,000
39,000
1,100
500
1250
30,000
30,000
44,000
65,000
12,000 (USP)
39,000 (USP)
19,800 (BP)
9,000 (BP)
22,500 (BP)
30,000 (USP)
30,000 (USP)
56,000 (USP)
65,000 (USP)
Paines & Byrne
Axcan Scandipharm
25,000
16,800
1,400
70,000
30,000 (BP)
70,000 (USP)
1
Conversion table for units of enzyme activity (u, units). Amylase: 1 Ph Eur u ¼ 1 FIP u ¼ 1 BP u ¼ 4.15 USP u. Lipase: 1 Ph Eur u ¼ 1 FIP u ¼ 1 BP
u ¼ 1 USP u. Protease: There is no direct equivalence between BP and Ph Eur units. This is because assay methods used measure protease in different
ways. BP method only measures ‘‘free’’ protease, while Ph Eur method measures ‘‘bound’’ plus ‘‘free’’ protease. ‘‘Free’’ refers to active protease.
‘‘Bound’’ refers to inactive precursor for protease. When pancreatin is released from enteric-coated granules in gut, inactive ‘‘bound’’ protease
precursor is rapidly converted to active ‘‘free’’ protease. Thus it could be argued that Ph Eur units are a more useful measure.129
15 years and under with cystic fibrosis, and it would be
prudent not to exceed a daily dose equivalent to 10,000 IU
of lipase per kg per day regardless of which preparation is
used’’.59
The US Cystic Fibrosis Foundation/Food and Drugs
Administration Conference of 1995 advised that ‘‘if
enzyme doses of >2,500 IU lipase units per meal or
4,000 IU lipase per gm of dietary fat per day are required
further investigations should be performed; larger doses
should be used with caution.’’46 Also, high-strength
enzyme preparations (i.e., those containing more than
20,000 IU lipase per capsule) were withdrawn from the US
market.
AIMS OF PANCREATIC ENZYME
REPLACEMENT THERAPY
Satisfactory PERT should enable the patient to eat a
normal to high-fat diet and abolish unpleasant gastro-
intestinal symptoms, particularly abdominal pain and
distension. There should be a normal bowel habit and stool
characteristics. A good nutritional state should be maintained, and in infants, children, and adolescents, growth
should be normal.
CONTROL OF MALABSORPTION
ACHIEVED WITH PRESENT-DAY ENZYMES
Considerable control of fat and protein malabsorption
can be achieved in most patients: a coefficient of fat
absorption of over 85% can usually be achieved, and of
over 90% in many patients (normal fat absorption over
95% of fat ingested). These aims should be possible in the
majority of people with CF, using present-day enzyme
preparations with doses equivalent to less than or only
slightly in excess of 10,000 IU lipase/kg/day (Fig. 1). In
most published studies of standard-strength enzymes, a
coefficient of fat absorption of between 85–95% was
40
Littlewood et al.
that doses were previously unnecessarily high in some
people.
DIETARY FACTORS IN THE
CONTROL OF MALABSORPTION
Fig. 1. Daily enzyme dosages (IU lipase/kg/day) of 121 children
attending the Leeds Regional Paediatric Cystic Fibrosis Centre
in 1999. Each data point represents one child. Short horizontal
lines indicate median dosage for each 5-year group.
reported (Table 6). Studies comparing standard- and highstrength enzyme capsules in numbers delivering equivalent amounts of lipase showed similar satisfactory
absorption (Table 7).
Although the fat absorption achieved in the context of
clinical trials is good, in practice, a substantial number of
people with CF do not achieve entirely normal absorption.
Factors influencing the effect of PERT include variations
in the enzyme content of the capsules,60 dissolution
characteristics of the preparation,60 the size of the enzyme
particles and their rate of exit from the stomach,61,62 the
relation of the dose to the fat intake,63 and the timing in
relation to the meals.64 Even at specialist CF centers where
there is a particular interest in the gastroenterological
aspects of CF treatment. For example, in the Toronto CF
Clinic, only one third of patients taking PERT achieved
over 90% fat absorption, one third achieved over 80%
absorption, and a third achieved less than 80%.65 At the
Regional Paediatric CF Centre in Leeds, where 95% of the
patients are PI, the mean fat absorption (þ 1 standard
deviation) achieved with PERT in 0–5-, 5–10-, and 10–
15-year-olds was 89% (12.8), 91% (4.5), and 83% (10.1)
of intake, respectively. In 1999, the mean doses of
enzymes used in Leeds for the 0–5-, 5–10-, 10–15-,
and over 15-year-old groups were 8,038, 6,832, 6,847,
and 5,186 IU lipase per kg per day (Fig. 1), respectively.
Nitrogen absorption is usually adequately controlled on enzymes.66,67 Carbohydrate malabsorption is
minimal.17
In specialist CF centers where fat absorption is not
monitored regularly, even by semiquantitative methods,
it is likely that a considerable number of patients will
be taking unnecessarily high doses of enzymes.58
Following the description of excessive PERT as a cause
of FC, dose reduction without deterioration in intestinal
absorption was reported,63,68 supporting the impression
The majority of people with CF treated with presently
available acid-resistant enzymes can tolerate a normal or
high-fat diet. The traditional low-fat diet is rarely required.
It is important that enzyme treatment is matched to the
approximate quantity of fat in each particular meal and
snack. This has received more attention following the need
to reduce enzyme doses, and is an aspect of treatment
where the dietitian’s expertise and guidance are essential.
It was suggested that the usual diet recommended for
people with CF is too low in fiber, and that increasing the
fiber intake will reduce any persisting abdominal symptoms,69 although this was not the experience of others.70
RECOMMENDATIONS FOR PANCREATIC
ENZYME REPLACEMENT THERAPY
Since the reports of FC, as part of the present-day
approach to the use of pancreatic enzymes, various
guidelines and reports of consensus groups have
appeared.46,59,71,72
For infants, it is suggested that minimicrospheres or
microsphere preparations be used (Creon Micro, Creon
10,000, or Pancrease). For every 120 ml of infant formula
or breast milk, an initial dose of half a scoop of Creon
Micro (2,500 IU Lipase) or one quarter to one third of a
capsule of Creon 10,000 (2,500–3,333 IU lipase) or one
third to one half a capsule Pancrease (1,666–2,500 IU
lipase) be given. These doses equate to approximately
400–800 IU lipase per gram of dietary fat.
The micro/minimicrospheres are mixed with a small
amount of formula, expressed breast milk, or fruit puree,
and given from a spoon. Ideally the dose should be divided
between the beginning, middle, and end of the feed. The
timing of administration can be adjusted according to the
infant’s symptoms and signs.
The dose is gradually increased according to clinical
symptoms and signs, e.g., the appearance and frequency of
stools, and objective assessment of weight gain, growth,
and fat absorption.
Once solid food is introduced, the enzyme dose is
individually titrated according to the fat intake. Regular
advice from a dietitian is mandatory to achieve the best
results. The aim is to keep the lipase intake below 10,000
IU per kg body weight per day.
For older children and adults, the suggested initial dose
is 2–4 scoops of Creon Micro (10,000–20,00 IU lipase),
1–2 capsules of Creon 10,000 (10,000–20,000 IU lipase)
or Pancrease (5,000–10,000 IU lipase) per meal, and 1–2
scoops of Creon Micro or a half to one capsule of Creon
Children 12.8
9 (5)
8 (4)
27
21 (13)
34 (19)
54 (51)
36 (34)
38 (36)
Brady et al., 1991116
Brady et al., 199264
Elliott et al., 1992117
Beker et al., 1994118
Sinaasappel et al., 1998119
Patchell et al., 2002120
Stern et al., 2000121
Konstan et al., 2004122
Adults 24.4
21 (10)
George et al., 1990115
8–36 years
7–36 years
26 (22)
31 (25)
10 (3–17)
12.2 (3–30)
(3–27)
(5–18)
8.8 (8–15)
(7–10)
8.9 (3–27)
Adults
23
12 (6–20)
(10–16)
Stead et al., 1987114
10 (10)
Age (yrs)
(range)
19 (19), but 6
patients unable to
tolerate Pancrex V
66
Number (finished)
Beverley et al., 198767
Mischler et al., 1982
Authors and year
Placebo
Creon 20
Placebo
Creon 20
Placebo
Ultrase MT 20
Placebo
Ultrase MT 20
Pancrex forte (5.6)
Pancreatin Merck (7.7)
Pancrex V Forte
Creon (8)
Pancrease (4)
Creon (8)
Pancrease (4)
Pancrease (4)
Pancrease (4)
Pancrease (4)
Pancrease (4)
Creon (8)
Pancrease MT 4, 12, 16
Pancrease MT 4, 12, 16
Creon 8 (8) microsphere
Creon 10 minimicrosphere (10)
Creon microspheres (8)
Creon minimicrosphere (10)
Creon (8)
Placebo
Cotazym
Pancrease
Pancrease (5)
Brand (1000 I.U. lipase)
TABLE 6— Selected Trials of ‘‘Standard’’ Pancreatic Enzyme Preparations
Usual
To deliver similar lipase dose
Dose required to achieve 80%
fat absorption
Nil
4,538 I.U. lipase/kg/day
Nil
7,856 I.U. lipase/kg/day
Nil
Not >2,500 I.U. lipase/kg/meal
Nil
Not >2,500 I.U. lipase/kg/meal
27.6/day
19/day
13/day (10–29)
9/day (7–18)
10/day
42/day
22/day premeals
22/day with meals
25/day
15/day
500 IU lipase/kg/meal
1,500 IU lipase/kg/ml
Doses to deliver similar lipase
Dose to deliver same lipase as in
Pancrease
18/day (6–40)
Nil
Both 2/meal and l/snack
Dose (caps/day)
50.9 7.3
87.2 1.7
52.15 5.6
84.1 2.2
46 35.8
79.4 12.5
58.7 16.5
87.3 10.2
74 (52–93)
81 (34–94)
70.6
83.4
81 2.7
81 3.1
86 (69–96)
91.3 (79–98.6)
92.7 1.4
91.6 1.4
89 (85–93)
90 (86–94)
86.2 (31–99)
91.2 (71–100)
85.7
83.2
93.5
91.3
85 (56–94)
45 29.6
73.7 15.4
84.1 6.9
87 (24–95)
% fat absorbed
‘‘Clearly establish
safety and efficacy
of Ultrase MT’’
6.7 g/24 hr
8.4 g/24 hr
(47/51 preferred
Creon 10,000)
6.2 g
7.2 g
27.7 g
15.2 g
22.4 3.4 g
24.4 g 4.7 g
67.9 1.3
29.9 22.2
17.3 9.3
Fecal fat g/24 hr
Intestinal Malabsorption in Cystic Fibrosis
41
84
83
85
55.6
76 (9–92)
91 (57–97)
96.1 (91–99.4)
95.8 (82–99.6)
Equivalent
control of
symptoms
90 (81–97)
90 (82–97)
<12
usual dose
2–8 on age
Nil
30 (15–100)
15 (8–80)
24
8
‘‘Usual dose’’
‘‘Usual dose’’
1
1
2 to 3 (55%) of usual dose
20 (12–30)
9 (6–11)
All improved when changed from Creon
25,000 to equivalent dose of Creon 40,000
Creon (8)
Pancrease HL (25)
Panzytrat 25,000 (25)
Placebo
Nutrizym GR (10)
Nutrizym 22 (22)
Creon (8)
Creon 25,000 (25)
Creon (8)
Pancrease (5)
Creon 25,000 (25)
Cotazym S Forte (10)
Creon Forte (25)
Creon 40,000
8.7 3.4
Adults
14 (14)
9 (no adverse
reactions)
Hartley et al., 200457
7.1
45 (44)
Robinson and Natoll 1988128
12.8 (6–21)
33 (31)
Taylor et al., 1996127
11.5 (4.9–14.1)
21 (18)
Friesen and Prestige, 1995126
12
15 (8)
Chazalette, 1993124
Bowler et al., 1993125
8 (1.25–27)
38 (27)
Morrison et al., 1992
Authors 2nd year
123
Age in years
(range)
Number
(finished)
1
3
% fat absorbed
Dose caps/day
Brand (1000 I.U. lipase)
Fecal fat g/day
26.1 (7.5–57.7)
8.7 (2.2–52.8)
3.1 (0.3–9.7)
3.4 (0.3–3.40)
Littlewood et al.
TABLE 7— Selected Trials of ‘‘High-Strength’’ Pancreatic Enzyme Preparations
42
10,000 or Pancrease with fat-containing snacks. Newly
diagnosed adult patients may be given Creon 25,000 at a
starting dose of 1–2 capsules per meal and 1 capsule per
fat-containing snack.
Enzymes should be given with all fat-containing foods.
The dose should be worked out individually, with the help
of a dietitian, and varied according to fat intake. Because
of multiple factors affecting enzyme efficacy, dose
requirements can vary widely between 500–4,000 IU
lipase per gram of fat.
The capsules should be swallowed whole as early as
possible; many will manage this by 3 or 4 years of age. If
removed from the capsules, the microspheres should not
be sprinkled on or mixed with the whole meal, but should
be mixed with a little fluid or food and immediately given
from a spoon in one swallow. They should not be crushed
or chewed in the mouth.
The dose is gradually increased until the symptoms
are controlled. Evidence is then sought that fat absorption has been controlled, either by fecal fat microscopy
or acid steatocrit, or by measuring the 3-day fecal fat
output.
Patients and parents should be encouraged to openly
discuss any problems with enzyme adherence that they
may have. Advice should be given to help overcome these
relatively common problems.
USE OF PANCREATIC ENZYMES IN
PATIENTS RECEIVING ENTERAL FEEDS
Pancreatic enzymes should be taken with all fatcontaining enteral feeds, whether elemental or polymeric.
The dose is worked out on an individual basis, taking the
fat content and rate of administration of the feed into
consideration. It is usual practice to administer enzymes
either at the beginning of the feed and before going to
bed,73 or at the beginning and end of the feed.74 If the
infusion is over a long period, it was observed that only
small doses of enzyme are required, e.g., 2 Creon 10,000 at
the beginning and end of the feed. This may be related to
the presence of gastric lipase activity.75
PANCREATIC ENZYME THERAPY
IN THE VENTILATED PATIENT
Enteric-coated enzymes cannot be put down standard
nasogastric and gastrostomy tubes. If the patient is
unconscious and is unable to take enzymes orally, it is
possible to give a powdered enzyme preparation, e.g.,
Pancrex V. These enzymes (approximately 0.5 g) should
be mixed with fluid and flushed down the tube with each
bolus feed, or every 3–4 hr if the patient is fed
continuously. The enzymatic activity of powdered
enzymes is largely destroyed in the acid environment of
the stomach. Therefore, an acid-blocking agent (e.g.,
Intestinal Malabsorption in Cystic Fibrosis
omeprazole) should be given to try to preserve some of the
enzymatic activity.
LONG-TERM MONITORING OF SYMPTOMS,
SIGNS, NUTRITION, GROWTH, AND ABSORPTION
At all clinic visits and the annual review, it is important to ensure that the goals of nutritional therapy are
being achieved, i.e., are weight, height, and growth rate
normal?
ASSESSING DEGREE OF
CONTROL OF MALABSORPTION
The patient should tolerate a normal to high-fat diet
without abdominal pain, distension, or abnormal or
excessively frequent fatty stools.
In some children with well-controlled absorption and
little or no chest infection, a normal energy intake may
be adequate to achieve good weight gain and growth.
However, if the nutritional state and/or growth are
abnormal, the diet should provide in excess of 120%
of the energy recommended for age. In such patients, a
full dietary assessment is indicated by a dietitian
experienced in cystic fibrosis. High-energy dietary
supplements or even enteral feeding may be required
for some.
Weight should be recorded at every clinic visit, and
in children, height should also be recorded. In adults,
height should be recorded at every clinic visit until
growth has ceased, and then it should be recorded
annually. The head circumference of infants should be
measured periodically. Weight and height should be
plotted on a growth chart appropriate for the local
population. After age 10 years, the stage of puberty
should be noted, as the stage of development affects the
rate of growth, both being influenced by the nutritional
state.
At the annual review, measurements should also be
converted to standard deviation scores (Z scores) or
percent weight for height, percent weight for age,
percent height for age, and body mass index (BMI),
to allow for greater accuracy in the determination of
nutritional status and changes over time.22,23 It is
important that, for children, BMI is plotted on the
appropriate centile charts or converted to Z scores for the
data to be meaningful.76
Fecal chymotrypsin values should be normal. Coefficients of fat absorption of between 85–95% of intake
should be achievable in most patients with presently
available enzyme preparations. In patients whose absorption has been a problem or who have abdominal
symptoms, a formal measurement of fat absorption is
advisable. In others, fecal fat microscopy should show
43
TABLE 8— Assessing Degree of Control of Malabsorption
Gastrointestinal symptoms and signs
Dietary and enzyme assessment by dietitian experienced in CF
Measurement and assessment of nutritional state and growth
Fecal chymotrypsin
Fecal fat output
Fecal microscopy for fat or steatocrit
Plasma fat-soluble vitamins A, D, and E
Serum albumin (or prealbumin)
little or no neutral fat and only þ or þþ split fat in 2 or 3
small, randomly collected fecal specimens.37 A repeated
excess of neutral fat suggests significant maldigestion and
malabsorption. Normal plasma levels of fat-soluble
vitamins A, D, and E should be achieved in the majority
of patients receiving regular vitamin supplements of
vitamin A 4,000–10,000 IU, vitamin D 400–2,000 IU,
and vitamin E 50–200 mg daily. Albumin levels are
usually normal and low values are very unusual,
except in people with CF who have significant liver
disease. Low albumin levels should prompt further
investigation.
FAILURE TO CONTROL
GASTROINTESTINAL SYMPTOMS
If control of symptoms is not achieved with a dose of
enzyme equivalent to 10,000 IU lipase per kg per day
given in an appropriate manner, some estimation of the
degree of residual malabsorption is mandatory. Also, it is
important to consider other gastrointestinal disorders as a
cause of persisting gastrointestinal symptoms, as the
symptoms may not be due to fat malabsorption. It is likely
that the larger doses of enzymes that UK patients are
continuing to take are due to their dose being determined
by symptoms and not by firm evidence of persisting fat
malabsorption.58
Doses slightly in excess of 10,000 IU lipase per kg per
day are used in some CF centers, including our own, for a
minority of patients, but only after investigations have
demonstrated the presence and severity of persisting
intestinal malabsorption (Fig. 1). These patients usually
have very high fat intakes.
Persisting and recurrent abdominal symptoms in
patients on PERT whose malabsorption is adequately
controlled (coefficient of fat absorption >85%) (Table 10),
require further investigation.
The whole range of causes of recurrent abdominal pain
and other gastrointestinal symptoms was reported in
people with CF (Table 9), and these were reviewed
extensively elsewhere.20,34
Distal intestinal obstruction syndrome (DIOS) is
characterized by recurrent attacks of abdominal pain with
44
Littlewood et al.
TABLE 9— Other Causes of Abdominal Pain
Distal intestinal obstruction syndrome
Chronic constipation and acquired megacolon
Gastrointestinal reflux
Cows’ milk intolerance
Inflammatory bowel disease
Pancreatitis
Helicobacter pylori infection
Celiac disease
Liver and gall bladder disease
Intolerance to porcine enzyme preparations
variable symptoms of obstruction, and is relatively
common in people with cystic fibrosis.77 Inadequate
PERT was suggested as a contributory factor in some
patients.78 However, in some people, DIOS may result
from excessive enzyme intakes, and it is important that
PERT is not progressively increased unless significant fat
malabsorption is confirmed by fecal fat studies. An
increase in enzyme dose in patients with abdominal pain,
whose symptoms are due to constipation, may worsen
their symptoms. In these patients, treatment to clear the
bowel contents may be more appropriate, followed by a
period of laxative therapy.79,80
A plain abdominal x-ray is invaluable in identifying the
frequent gross fecal overloading of the colon, which may
not be detected from the history or by abdominal palpation
(Fig. 2).20 Pancreatic enzyme therapy should be reviewed,
and treatment with laxatives may be indicated. Inconsistent or excessive enzyme-dosing may cause chronic
constipation.
Gastro-esophageal reflux seems particularly common
in both infants81,82 and older patients,83 and may cause
significant upper abdominal or lower chest pain not
obviously of esophageal origin.
Other conditions that may cause confusion include
cows’ milk intolerance,84 inflammatory bowel disease,85,86 pancreatitis87–89 (in PS patients), Helicobacter
pylori infection,90 celiac disease,30,91 liver and gall
bladder disease,92 and intolerance of porcine enzyme
preparations.93
TABLE 10— Inadequate Control on 10,000 IU Lipase Per kg
Equivalent Per Day
Review enzyme dose, method, and timing of enzyme intake
Confirm there is persisting malabsorption by fecal fat output,
microscopy, or steatocrit
Review by experienced dietitian, particularly considering patient
adherence
Endeavor to tailor enzyme dose more closely to dietary fat intake
Check expiration date on enzyme packet
Changing to different enzyme preparation
Reduction in gastric acid by adding proton pump inhibitor, e.g.,
omeprazole
Addition of taurine supplements
Fig. 2. Chronic constipation and acquired megacolon are
common findings when investigating chronic abdominal pain
in people with CF who may not complain of constipation or any
disturbance in bowel habits. Overloaded colon is outlined.
Persisting abdominal symptoms in patients on PERT in
doses equivalent 10,000 IU lipase per kg per day whose
malabsorption is not adequately controlled (coefficient of
fat absorption <85%), requires consideration of patient
adherance.
Consideration of the patient’s adherence to the dose and
method of taking enzymes is important, as poor adherence
is a common problem. Schoolchildren and adolescents
may be reluctant to take enzymes when with their friends
or at school. Persistently low fecal chymotrypsin suggests
that poor adherence may be an important factor in the poor
control of malabsorption. Failure to take other treatments
will also make nonadherence a likely cause for the persisting malabsorption, e.g., a low plasma vitamin E level
despite apparently taking an adequate supplemental dose
of the vitamin. The importance of the role of an experienced dietitian to discuss the practical details of treatment
in such circumstances cannot be overemphasized.
Adjusting the enzyme intake to match the fat content of
the foods eaten can make a major contribution to
improving the degree of fat absorption. A refinement of
this is to adjust the enzyme intake to each gram of fat.94
Intestinal Malabsorption in Cystic Fibrosis
Matching the enzyme dose to the fat content of a meal has
enabled significant reduction in dose to be made without
compromising nutrition or growth.68
Consideration should be given to changing to another
brand of enzyme that, in the same dose, may result in a
quite dramatic improvement in symptoms and absorption.
Presumably the many differences in pharmacological
characteristics may be relevant to their differing performance in practice, including their quantitative and
qualitative enzyme content,95 dissolution characteristics,60 and size of the particles.61,62 The individual
differences in dose requirements, even in patients with
little or no residual pancreatic function, are presumably
due, in part, to these brand differences.
The variable mixing of enzymes with the meal in the
stomach and rate of leaving the stomach suggest that a trial
of varying the timing of taking the enzymes through the
meal may improve absorption in individual patients, e.g.,
give more at the start or more near the end, or give
regularly during the meal. Dividing the dose will also
reduce the chance of overdosing if the meal is refused
halfway through.
Reduction of gastric acid as a means of improving
enzyme function was the subject of considerable research
before the introduction of acid-resistant preparations in
the early 1980s,96–100 but interest waned as more effective
enzymes became generally available. However, the report
of FC in 1994,45 and the subsequent recommendation not
to exceed the equivalent of 10,000 IU lipase per kg per day,
renewed interest in acid suppression for the minority of
patients who require more than this dose. Sodium
bicarbonate is being revisited in an effort to reduce
duodenal acidity and improve enzyme function. Although
combining sodium bicarbonate with an acid-resistant
enzyme (Pancrecarb) does not appear to improve absorption,101 the addition of sodium bicarbonate (5.2 g/m2
surface area) improved fat absorption in patients whose
control was poor.97 In present-day practice, additional
bicarbonate is rarely used, as it represents yet another
medication to take before every meal, and there are more
effective means of reducing gastric acid.
Acid suppression using a variety of agents to reduce
gastric acid has improved absorption in some of those
patients where control was poor even with acid-resistant
enzymes. A recent Cochrane review concluded there was
limited evidence that agents that reduce gastric acidity in
people with CF are associated with improvement in
gastrointestinal symptoms and fat absorption, and there
was insufficient evidence to indicate whether they
improved nutritional status or lung function.102 Treatments have included cimetidine, both with conventional
enzymes96,99,100 and with enteric-coated, acid-resistant
microspheres.98 Ranitidine 4 mg/kg/day in two divided
doses, maximum 300 mg b.d.,103 omeprazole 20 mg daily
in adults and 0.7–1.4 mg/kg/day in children,104,105 and
45
lansoprazole 15 mg daily will improve absorption in many
patients whose absorption is poorly controlled on 10,000
IU lipase per kg doses of enzymes.106
Finally, taurine-conjugated bile acids are in relatively
short supply due to the gastrointestinal losses that occur in
CF and the relatively greater compensatory production of
glycine-conjugated bile acids.9 In CF, taurine-conjugated
bile acids are deficient in plasma and bile.10 There is some
evidence that oral taurine (30 mg/kg/day) will correct the
deficiency and improve malabsorption.107
SIDE EFFECTS OF PANCREATIC ENZYMES
Fibrosing colonopathy is the most serious side effect,
and was reviewed elsewhere (see Table 11).53,55,59
Hyperuricemia and hyperuricosuria, which occurred with
the older, less pure pancreatic extracts,108 are no longer
a problem with modern microsphere preparations.109
Soreness of the mouth may occur with powdered preparations or if acid-resistant microspheres are crunched or
held in the mouth and dissolved with a pH of greater than
5.5. Perianal irritation may result from the passage of
significant proteolytic enzyme activity in the stools if
intestinal transit is rapid or the enzyme dose excessive,
with the latter also being suggested by a high fecal
chymotrypsin level.
Immune reactions related to the porcine origin of
pancreatic enzymes usually cause an insignificant immunological response in most patients,110 although this was
suggested as a possible etiological factor in fibrosing
colonopathy.111 However, severe acute and chronic
gastrointestinal allergic reactions may occur and should
be considered when control of symptoms proves difficult.93 General allergic reactions may occur in people
administering powdered enzymes.112,113
In patients who have had chronic uncontrolled severe
fat malabsorption, a too rapid increase in enzyme dose
may cause severe constipation and abdominal pain, which
presents similar problems to distal intestinal obstruction
syndrome.
CONCLUSIONS
The aims and practical details of management of
malabsorption in people with cystic fibrosis have been
reviewed in the light of the recent developments and
recommendations. This is timely, as many people with CF
TABLE 11— Side Effects of Pancreatic Enzymes
Fibrosing colonopathy
Hyperuricemia and hyperuricosuria
Soreness of mouth
Perianal irritation
Immune reactions
Abdominal pain and constipation
Distal intestinal obstruction
46
Littlewood et al.
in the UK are still taking more PERT than is necessary58
and considerably more than recommended by the
Committee on Safety of Medicines.59
The fine details of enzyme administration and the need
to avoid excessive doses are important, as is the need to
identify other correctable causes of persisting abdominal
symptoms.
It is particularly important to investigate people with
CF who have chronic abdominal symptoms rather than
always attributing their symptoms to CF and merely
increasing the dose of enzymes.
Fibrosing colonopathy was undoubtedly a new condition which developed in a few people with CF within 6–24
months of starting certain high-strength enzyme preparations. Although opinions are clearly divided as to whether
the copolymer covering is an important contributory
cause, all are agreed that the very high doses of pancreatic
enzymes achieved were an important factor in the
pathogenesis of the condition.
It is important that regular gastrointestinal surveillance
of all patients taking PERT should be routine practice in
specialist CF centers and CF clinics. Clinicians must
convince laboratories of the importance of fecal fat
estimations in certain patients and of routine monitoring of
fecal fat by semiquantitative methods, such as fecal
microscopy, in all patients. Also, patients and their
families should be persuaded of the importance of
collecting occasional small fecal specimens for analysis
by microscopy.
Using the pancreatic enzyme preparations available at
present, it should be possible to achieve control of
abdominal symptoms, near-normal intestinal absorption,
and normal nutrition and growth in the majority of people
who have cystic fibrosis.
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