Nutrition in patients with cystic fibrosis: a European Consensus

Journal of Cystic Fibrosis 1(2002) 51–75

1569-1993/02/$ - see front matter� 2002 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved.PII: S1569-1993Ž02.00032-2

Consensus Report

Nutrition in patients with cystic fibrosis: a European Consensus�

M. Sinaasappel *, M. Stern , J. Littlewood , S. Wolfe , G. Steinkamp , Harry G.M. Heijerman ,a, b c c d e

E. Robberecht , G. Doringf g¨

Department of Paediatric Gastroenterology, Erasmus Medical Centre, Rotterdam, The Netherlandsa

Department of Paediatrics, University of Tubingen, Tubingen, Germanyb ¨ ¨Regional Paediatric Cystic Fibrosis Unit, St James University Hospital, Leeds, UKc

Department of Paediatrics and Paediatric Pulmonology, Medizinische Hochschule, Hannover, Germanyd

Ziekenhuis Leyenburg, The Hague, The Netherlandse

Department of Paediatrics, University of Ghent, Ghent, Belgiumf

Hygiene-institut University of Tubingen, Tubingen, Germanyg ¨ ¨

Abstract

This document is the result of an European Consensus conference which took place in Artimino, Tuscany, Italy, in March 2001involving 33 experts on nutrition in patients with cystic fibrosis, organised by the European Cystic Fibrosis Society, and sponsoredby Axcan-Scandipharm, Baxter, Dr Falk Pharma, Fresenius, Nutricia, SHS International, Solvay Pharmaceuticals(major sponsor).The purpose of the conference was to develop a consensus document on nutrition in patients with cystic fibrosis based on currentevidence.� 2002 European Cystic Fibrosis Society. Published by Elsevier Science B.V. All rights reserved.

Keywords: European Consensus; Document; Cystic fibrosis

Table of Contents

1. Introduction2. Nutritional deficiencies in CF

2.1. Nutrition and growth of individuals with CF2.1.1. Growth during infancy2.1.2. Growth after infancy2.1.3. Delayed puberty and growth spurt

3. Malnutrition: definition and assessment3.1. Evaluation of nutrition and growth: anthropometry

3.1.1. Weight and height3.1.2. The body mass index(BMI)3.1.3. Other measurements3.1.4. Rate of weight gain and growth

� Consensus committee: Sanda Nousia Arvanitakis, Greece, Chris-tian Braegger, Switzerland, Wojciech Cichy, Poland, Armand Chris-tophe, Belgium, Carla Colombo, Italy, Diana Costantini, Italy, JohnDodge, UK, Stuart Elborn, UK, Pablo Ferrer, Spain, Natalia Kashir-skaya, Russia, Eitan Kerem, Israel, Christian Koch, Denmark, Bert-¨hold Koletzko, Germany, Sibylle Koletzko, Germany, AndersLindblad, Sweden, Javier Manzanares, Spain, Jean Navarro, France,Luca Romano, Italy, Birgitta Strandvik, Sweden, Jan Taminiau, TheNetherlands, Chris Taylor, UK, Dominique Turck, France, VeraVavrova, Czech Republic, Brigitte Winklhofer-Roob, Austria.*Corresponding author.

3.2. Laboratory investigations3.3. Definition of malnutrition

4. Factors contributing to malnutrition in CF4.1. Features of malabsorption in CF patients

4.1.1. Factors other than enzyme deficiency contrib-uting to malabsorption

4.1.2. Investigation and diagnosis of malabsorption4.2. Energy expenditure4.3. Inadequate energy intake4.4. Liver disease and bile salt loss4.5. Diabetes mellitus

5. Essential fatty acid(EFA) deficiency6. Vitamin deficiency

6.1. Vitamin A6.2. Vitamin D6.3. Vitamin E6.4. Vitamin K6.5. Water soluble vitamins

7. Mineral and trace element deficiency7.1. Minerals7.2. Trace elements

8. Antioxidant deficiency9. Prevention of malnutrition and treatment of pancreatic

insufficiency9.1. Infant feeding

52 M. Sinaasappel et al. / Journal of Cystic Fibrosis 1 (2002) 51–75

9.2. Control of malabsorption achieved with currentenzymes preparations

9.3. Failure to control gastrointestinal symptoms10. Side effects of pancreatic enzymes11. EFA treatment12. Vitamin supplementation

12.1. Vitamin A12.2. B-Carotene12.3. Vitamin D12.4. Vitamin E12.5. Vitamin K12.6. Water-soluble vitamins12.7. Conclusion

13. Mineral and trace element supplementation13.1. Minerals13.2. Trace elements

14. Supplementation with antioxidants15. Refeeding the malnourished child

15.1. Recommendations15.1.1. Oral feeding15.1.2. Supplements15.1.3. Tube feeding15.1.4. Total parenteral nutrition

16. Treatment of the malnourished adult17. The important questions and answers18 References

1. Introduction

Cystic fibrosis(CF) is a world-wide disease occurringin virtually all ethnic groups. In Caucasians it is themost common lethal hereditary disorder with autosomalrecessive inheritancew1x. Approximately 1 in 25 areheterozygous carriers, while the incidence of clinicaldisease is approximately 1 in 2500 live birthsw1x. Thecondition is caused by mutations in a single gene ofchromosome 7, which encodes the CF transmembraneconductance regulator(CFTR) w2x. The CFTR proteinis a membrane bound cAMP-regulated chloride channel,which is thought to regulate other cell membrane ionchannelsw3x. More than 1000 different mutations havebeen identified so far; however, a deletion of phenylal-anine in the amino acid position 508 is present inapproximately 66% of chromosomes of all patients withCF world-wide.CFTR mutations affect epithelial ion and water trans-

port mainly in cells in the respiratory, gastrointestinal,hepatobiliary, reproductive tracts and sweat glands. Thelack of chloride secretion in the pancreatic duct isresponsible for obstruction and autodigestion of thepancreas early in embryonic life leading to severeexocrine pancreatic insufficiency in approximately 85%of CF newborns. In addition, intestinal obstruction com-plicates the neonatal period in 10–15% of the infants.Both inadequately treated pancreatic insufficiency andintestinal obstruction were held responsible for a highmorbidity and mortality rate in patients with CF before

1970. As a result of various factors including betterneonatal care, surgery, antibiotic treatment of pulmonarycomplications and improved nutrition, the median sur-vival time of the patients has increased over the lastthree decades from 10 to 30 years. Nevertheless, it isstill not clear to what extent improved nutritional statuscontributes to increased survival. In a recent reportwasting was shown to be a significant predictor ofsurvival in patients with CF independent of lung func-tion, arterial blood oxygen and carbon dioxide tensionsw4x. The fact that there is a remarkably close relationshipbetween body weight and lung function and that terminalpatients with CF are almost always severely malnour-ished, suggests that good nutritional care is of benefitfor the patient with cystic fibrosis.

2. Nutritional deficiencies in CF

2.1. Nutrition and growth of individuals with CF

2.1.1. Growth during infancyThe mean birth weight of CF populations has been

reported as subnormal(CF males: 3.18 kg, females:3.04 kg; unaffected males: 3.37 kg, females: 3.25 kg)w5x. However, others have failed to confirm the findingof lower birth weights in CFw6,7x.Another study found children with CF to have a

reduced length(y1.24 standard deviation, S.D.) weight(y0.72 S.D.) and head circumferences(y1.82 S.D.)compared with controlsw8x. However, these data maynot be representative since 34.6% of the infants wereaffected by meconium ileus, which is associated withworse outcomesw8x.The early growth pattern of infants with CF is

dependent on both the age at diagnosis and the qualityof the subsequent treatment they receive. The majorityhave pancreatic insufficiency and experience early gas-trointestinal symptoms, which if not adequately treatedcan lead to subnormal weight gain. Even some infantsdiagnosed by neonatal screening have subnormal growththroughout the first year if the start of treatment isdelayed by more than a few weeks after birthw9x.

2.1.2. Growth after infancySubsequent growth velocity of CF infants is usually

normal if chest infections are prevented or effectivelytreated and the intestinal malabsorption is adequatelytreated w6,7x. Almost normal growth and weight gainwas maintained throughout childhood in Canadianpatients with CFw10x and in 51 Swedish children withCF height gain was normal between 5 and 8 yearsw11x.The authors conclude that subnormal growth in infancycan be compensated for by catch-up growth thereafter.In Australian patients growth, weight and respiratoryfunction were better at the age of 10 years in a group

53M. Sinaasappel et al. / Journal of Cystic Fibrosis 1 (2002) 51–75

of screened patients than in those born before screeningwas introducedw12x.As a consequence of patient registries, data from

larger numbers of patients with CF are available forepidemiological investigations. In 1998 the Cystic Fibro-sis Foundation(CFF) reported that 12.7% of childrenand 21.6% of adults were below 85% weight for heightw13x. Comparable median centile values for Canadianand American patients with CF were: for height 28 and21, respectively, weight 27 and 22, respectively, butboth were 103% of ideal weight for heightw14x. Datafrom the UK CF registry revealed that the mean weightS.D. scores of the males were betweeny0.25 andy0.5 until the age of 10 years after which they declinedas did the body mass index(BMI). The mean weightS.D. scores of females were approximatelyy0.5 butthey had a declining BMI after the age of 5 yearsw15,16x. After 10 years there was a progressive declinein SD scores for both height and weight. This deterio-ration in S.D. scores after the age of 10 years could beexplained by some delay in the onset of puberty.However, it is more likely to be a reflection of anoverall deterioration associated with an increase in theseverity of the pulmonary disease.It is increasingly apparent that the condition of the

patients is closely related to the treatment they receiveand that patients may be in a better nutritional state inclinics where regular attention is paid to nutrition andgrowth. It is encouraging that the nutritional state ofnew patients with CF has steadily improved over theyearsw17x.

2.1.3. Delayed puberty and growth spurtThere is delay in the onset of puberty and menarche

in patients with CF who have significant nutritionalproblemsw18–20x; even in well-nourished females somedelay has been reportedw19x. Surprisingly the delay inskeletal maturation is modest in most patients with CFand seems to increase with age, as pulmonary problemsbecome more severew5x.

3. Malnutrition: definition and assessment

3.1. Evaluation of nutrition and growth: anthropometry

3.1.1. Weight and heightThe patient should see an experienced doctor at every

visit and the specialist CF dietician at most clinic visitsand always if weight progress is unsatisfactoryw21,22x.Weight and height should be accurately measured ateach clinic attendance by trained clinic staffw23x; thesemeasurements should be charted to assess progress andcompared to reference valuesw24–27x. Caution shouldbe exercised when different anthropometric standardsare comparedw28x. Values are expressed either as(per)centiles, as percentage of the normal values for age or

as standard deviation(S.D.) or Z scores. Percentageweight for height, weight for age and height for age areoften used when expressing the nutritional status ofchildren and are preferred to body mass index(BMI).The measurements are calculated from the standardequation:

Ž .Current weight kg

Ž .Weight kg equivalent to current height percentile=100

When considering S.D. scores, for a population whosevalues are normally distributed, the relationship of per-centiles and S.D. scores are as follows:y2.0 S.D.(2.28th centile), 0 S.D. (50th centile), q2.0 S.D.(97.72nd centile) w24x.

3.1.2. The body mass index (BMI)The BMI (weight wkgxyheight wm x) shows a reason-2

able correlation to body fat mass in adults, but less soin children, and is in the first place used to quantifyobesity. Some adult CF clinics use BMI as a measureof nutritional state in their patients whose growth hasceased. Recently BMI categories for adults have beenredefined as underweight(-18.5), ideal (18.5–24.9),pre-obese(25.0–29.9) and obese(G30.0) w29x. Inchildren BMI values must be interpreted on the basis ofcomparison with age and gender specific referencecentilesw30x or S.D. scores. A low BMI without defi-cient fatness will be found in patients with proportion-ately long limbs and a short trunk, where there is poormusculature or in adolescents with delayed pubertyw24x.In children and adolescents, no advantage has beenshown of using BMI, rather than weight for height, fordocumenting malnutrition.

3.1.3. Other measurementsThe mid upper arm circumference and skinfold meas-

urementsw31x are held inappropriate for the detailedmonitoring required in CFw32x. Noting the stages ofbreast, pubic hair and genital development and recordingthe age of the menarche in girls are important as ameasure of the stage of developmentw25x for the correctinterpretation of changes in weight and height gainduring adolescence. Thus, after the age of 10 yearsknowledge of the puberty state is required to adequatelyassess growth and nutrition. More sophisticated methodsof measuring body composition, that are used primarilyfor research purposes, offer more accurate assessmentof nutritional status and growth response to nutritionaltherapy. These methods include total body potassiumw33,34x, total body electrical conductivity, bioelectricalimpedance analysisw35x, total body water by isotopedilution and dual energy X-ray absorptiometryw36x.Osteopenia and osteoporosis have been described inboth adults and children with CFw37,38x. Bone mineral


Table 1Guidelines for nutritional intervention. In case of malnutrition or weight loss there should be a full re-evaluation of all possible causes that affectnutritional state. If nutritional intervention is indicated the following guidelines can be used. First enhance nutritional densityyoptimal intakebefore starting supplements

-2 years 2–18 years )18 years

Normal nutritional state % wt.yht 90–110 % wt.yht 90–110 BMI 18.5–25 orPreventive counselling no recent wt. loss

Dietetic referral indicated Any degree of failure %wt.yht 85–89 or BMI-18.5 orConsider supplements to thrive wt. loss over 4-6 months or 5% wt. loss over-2 months

plateau in wt over 6 months

Invasive nutritional Failure to thrive despite Supplements tried and either: Supplements tried and either:support oral supplementation %wt.yht -85 or BMI-18.5 or

wt. falling 2 centile positions )5% wt. loss over-2 months

For all age categories pay special attention if stunting is evident as defined:(1) height centile-0.4th; (2) Htyage-90%.

density (BMD) is best determined by dual energy X-ray absorptiometry(DEXA). DEXA scans, which cansimultaneously assess fat mass and lean body mass, canbe carried out in most major CF units, and should beconsidered as part of the nutritional assessment in allpatients over the age of 10 years, but there is nodocumented evidence of the benefit of regular DEXAscans that are followed by targeted intervention.

3.1.4. Rate of weight gain and growthThe weight for height should remain above 90% and

ideally should be over 95%. Oral energy supplementsare usually advised if the weight for height is between85 and 90% in children or the BMI is less than 18.5 inadults and enteral tube feeding if weight for height fallsbelow 85% or BMI is less than 18.5, despite trying oralenergy supplements(see Table 1). Other causes ofabnormal nutrition and growth include either gastroin-testinal disorders such as food intolerance, coeliac dis-ease or inflammatory bowel diseasew39x or evenendocrine disordersw40x. Oral or long-term inhaledsteroid therapyw41x may cause a slowing of height gainin the presence of apparently normal or excessive weightgain.

3.2. Laboratory investigations

A variety of investigations may be helpful in theassessment of the patient’s nutritional statew42x, suchas haemoglobin, total white cell and neutrophil count,serum albumin andyor pre-albumin. Urea and electro-lytes should be checked whenever clinical progress isnot entirely satisfactory to identify salt depletion andpseudo-Bartter’s syndrome, which may cause significantgrowth failure w43x. Besides an ultrasound examinationof the liver and upper abdomen, plasma fat-solublevitamin A, D and E levels should be measured annually.

3.3. Definition of malnutrition

Malnutrition is defined as a weight for height valuebelow 90% in children or as BMI below 18.5 in adults.

4. Factors contributing to malnutrition in CF

4.1. Features of malabsorption in CF patients

Malabsorption is characterised by foul smelling loosepale stools. Infants identified through newborn screeningexhibit intestinal malabsorption which is of early onsetand severe and if left untreated leads to severe malnu-trition and growth failurew44x. Newly diagnosed chil-dren and adults may have untreated malabsorption andshould be evaluated. Due to the progressive nature ofthe pancreatic damage, pancreatic sufficient patientsw45xmay eventually develop pancreatic insufficiencyw46x.Malabsorption of fat and nitrogen is severe withoutenzyme treatment; nonetheless, some 40–50% of ingest-ed dietary fat is absorbed without treatment. This isprobably due to the action of lingual and gastric lipasew47x. Carbohydrate malabsorption is minimalw48x. Evenwhen clinical symptoms appear to be controlled bypancreatic enzyme supplementation, many patients stillhave a significant degree of fat malabsorption. Thus, thecontrol of gastrointestinal signs and symptoms is notalways indicative that malabsorption is controlled.Equally, persisting abdominal signs and symptoms inthe face of apparently reasonable doses of enzymes maynot be due to inadequate enzyme treatment but someother cause such as constipationw39x.

4.1.1. Factors other than enzyme deficiency contributingto malabsorptionDeficiency of pancreatic enzymes is the most impor-

tant, but not the only factor, responsible for malabsorp-tion in CF w49x. A further important consequence of thesevere pancreatic damage is deficiency of pancreaticbicarbonate resulting in diminished capacity to bufferinfluxes of gastric acid into the duodenumw50x. Thisresults in reduced efficacy of endogenous and exogenouspancreatic enzymes and precipitation of bile saltsw51,52x. Bile salt replacement contains a relative reduc-tion in taurine-conjugated and an increase in glycine-conjugated bile saltsw53x, the latter being less effective


at lipid solubilisation. Mucosal ion transport abnormal-ities resulting from deficiency of intestinal CFTR affectboth water and electrolyte transportw54x. In an acidmedium fatty acids, which are formed by fat digestionat the oilywater interphase, are not converted into soapsbut occur in the protonated form. In this form, they arenot transferred to the micellar phase but remain in theoil phase. This may further hamper fat digestion asunder these conditions pancreatic lipase may catalysethe formation of triglycerides out of their digestionproducts. There may also be impaired mucosal uptakeand transport of long chain fatty acidsw55x as well asaltered motility with an increase in small bowel transittime w56x. A variety of structural abnormalities mayresult from previous gastrointestinal surgery for meco-nium ileus including shortened bowel, strictures at thesite of previous intestinal anastomosis, malrotation andadhesions. In all patients there are histological abnor-malities of the bowel wall characteristic of CF and anexcess of mucus may also be relevantw57x.

4.1.2. Investigation and diagnosis of malabsorptionIt is important to obtain some objective evidence of

both intestinal malabsorption and pancreatic abnormalityin all patients with CF both to identify those who requireenzyme treatment, and to monitor the success of suchtreatment. If there is abdominal distension, abdominaldiscomfort, loose oily pale stools, and the patient ismalnourished it is most likely that there is intestinalmalabsorption w39,58x. Demonstrating that intestinalabsorption is controlled prevents unnecessary and poten-tially harmful increases in the enzyme dose and alsoprompts a search for another cause for the symptomsw22x. Poor weight gain and growth, particularly if theappetite is good, are suggestive of malabsorption. Indi-rect pancreatic function tests, which detect abnormalitiessecondary to loss of pancreatic function, such as mal-digestion and consequent malabsorption, are generallyemployed, because they are easier to perform and lessinvasive than direct assessment of the secretory capacityof the exocrine pancreasThe degree of fat malabsorption is usually taken as

the marker of intestinal malabsorption. The gold stan-dard for measuring fat absorption is an assessment ofthe fat excretion over 3 days and its relation to dietaryfat intake over the same time period. Normally theequivalent of less than 7% of the fat ingested is excretedi.e. there is over 93% fat absorption. The total faecal fatoutput is usually less than 7 g per day inhealthy adultsand less than 2 g in small childrenw59x. Measurementof faecal fat using near infrared spectroscopyw60xcompares favourably with the routine titrimetric methodw61x. As a minimum measurement of steatorrhoea, asemiquantitative estimate of faecal fat content should bemade by a method of faecal microscopy or acid steato-crit, which have been validated by comparison with

quantitative measurementsw62,63x. Other indirect pan-creatic function tests including the determination ofrelatively non-biodegradable pancreatic enzymes in fae-ces (chymotrypsinw64x and particularly, faecal pancre-atic elastase 1w65,66x) and tests which evaluate thecapacity of pancreatic enzymes to cleave specific syn-thetic substrates(e.g. PABA). The carbon mixed13

triglyceride breath test is a safe non-invasive way ofassessing fat digestion that can be used repeatedly inchildrenw67x. However, a large inter-individual variationunder condition of relatively mild fat malabsorption hasrecently been documented in a rat model, suggestingthat this test, as most other indirect tests of pancreaticfunction may be particularly useful for revealing severepancreatic insufficiencyw68x. The serum concentrationsof specific pancreatic enzymes(immunoreactive trypsinw69x and lipase) can be used to document residualpancreatic function.

4.2. Energy expenditure

The main factors leading to energy loss are malab-sorption due to pancreatic insufficiency and inflamma-tion. Glucosuria in diabetic patients and protein loss inlarge amounts of sputum may contribute to energylosses. As the energy intake is often lower than the120–150% of the recommended daily amount, a nega-tive energy balance is frequently seen in patients withCF. Energy requirements are determined by measuringenergy expenditure. Approximately 60–70% of totalenergy expenditure is determined by resting energyexpenditure(REE), 10–25% by physical activity, and10% for diet-induced thermogenesis.Energy expenditure can either be measured or calcu-

lated. Methods for quantifying energy expenditure are:(1) indirect calorimetry;(2) direct calorimetry;(3) 24-h energy expenditure with stable isotopes; and(4) the24-h monitoring of heart rate. Intra-individual variationof direct or indirect calorimetry is approximately 3%,while the 24-h techniques have much larger variances(10–15%). If techniques for measuring energy expen-diture are unavailable;(5) REE can be estimated frombody size. A direct comparison of these standards andmeasured values revealed differences of up to"20% inhealthy individuals. For patients with CF, a specificformula has been developed which is based on theFAOyWHOyUNO equation and supplemented with dis-ease and activity factorsw21x. However, when comparedwith results from indirect calorimetry, this equationunderestimated REE in children and infants with CFw70,71x.Many investigators report on increased REE in

patients with CFw72–78x. This increased REE is notalways associated with an increase in total energyexpenditure, especially in stable patients with moderatepulmonary diseasew79x. With few exceptions, mean


REE was reported to be increased by 7–35% in patientswith CF compared with predicted values. However, alarge range of values was obtained between differentindividuals. Impaired lung function causes a higherworkload for respiratory muscles, and increased oxygencost of breathing, causing in CF a REE twice that ofcontrols w72x. Chronic inflammation may also be asso-ciated with higher energy expenditure and correlationswith concentrations of TNFa have been reportedw77x.Acute respiratory exacerbations cause an increased REEin many patients, which reverts to lower values afterantibiotic therapyw74–77x. Similarly, after 2 weeks ofaerosolised dornase alpha, a decline of REE wasobservedw78x. Some authors reported correlations withimprovements of FEV , CRP, TNFa, or body weight,1

suggesting a parallel reduction in the host inflammatoryand catabolic responses after treatment.Patients homozygous forDF were reported in some508

studies to have higher mean REEw80–82x, whereasother authors did not find such a relationw83,84x.Therefore, if an energy-requiring defect is present in CF,its contribution to increased REE must be small. Thereis a paucity of data concerning longitudinal follow-upof individual patients. In the only long-term observa-tional trial REE was considered as an early indicator ofdisease severity independent of pulmonary functionw81x.Beta-agonists are bronchodilators that are frequently

administered in patients with CF. Salbutamol, a majordrug of this class, has been shown to increase restingenergy expenditure by 10% during the first hour afterinhalation w85x. When administering beta-agonists sev-eral times a day, an effect on energy requirements shouldbe considered.

4.3. Inadequate energy intake

The poor energy intake of many individuals with CFhas been well documented. Although intakes in excessof 120% of the estimated average requirement arecommonly advised, when the actual energy intake ismeasured it is often considerably less than thisw86x,particularly in male patientsw87x.Additionally, specific muscle stimulation with anabol-

ic medication appears to be an option. In patients withCF it has been shown that megestrol acetate, a proges-tagon, leads to an increased appetite, an increase inbodyweight with an increase in lean body mass andpulmonary function w88–90x. Disadvantages are thepossible development of diabetes, inhibition of growthand adrenal suppressionw89x. This is a subject whichneed further research, and because of the side effectsand the limited data available, patients should only betreated with anabolic medication in clinical trials.Growth hormone has also been shown to improvegrowth and clinical status in pre-pubertal patients withCF w91x. Growth hormone therapy is also associated

with a number of side effect e.g. glucose intolerance.Further research is required before its use can be widelyaccepted in the clinical situation.

4.4. Liver disease and bile salt loss

A significant percentage of individuals with CF even-tually have biochemical, ultrasound or clinical evidenceof liver disease. Prevalence estimates of liver involve-ment in CF remain highly variable; ranging between 2%and 37% among the studies based on the largest CFseries. On the other hand three prospective studiesrecently carried out indicate that liver disease is arelative frequent and early complication of CF. Preva-lence of cirrhosis is approximately 10%w92,93x. In onethird of these patients liver disease develops before theage of 5 years. Patients with CF who have overt clinicalliver disease commonly have serious nutritional prob-lems both generally and also relating to specific mac-ronutrients, fat-soluble vitamins and clotting factorsw94x. Many patients with CF have increased losses ofbile salts in the intestinew52x. Bile salt deficiencycompromises lipolysis leading to a reduction in fatabsorption of up to 50%. In one study lipolysis of thesubstrate was not affected in patients with CF relatedliver disease using the C-mixed triacylglycerol breath13

test w95x, but, bile salt concentration or intestinal losswas not studied. Ursodeoxycholic acid(URSO) isaccepted as a treatment for biochemical liver diseaseand has a beneficial effect on liver enzyme levels.Whether treatment with URSO leads to an improvementin nutritional state is unknown. Studies that show long-term effects on the prevention of fibrosis are lacking,and the observation that the nutritional state of patientswith CF and liver disease improved with URSOw96xwas not confirmed in a controlled trialw97x. Livertransplantation in such patients, however, has a benefi-cial effect on their nutritional statew98x.

4.5. Diabetes mellitus

Estimates of prevalence of CF related diabetes melli-tus(CFRD) vary from 2.5% to 12% of patients, increas-ing considerably with age. In Denmark, 32% of patientswith CF developed diabetes mellitus by the age of 25yearsw99x. This obviously has considerable nutritionalsignificance. CF related diabetes mellitus shares featuresof both type 1 and type 2 diabetes but is a distinctclinical entity. The primary cause is insulin deficiencybut it is also influenced by unique CF conditions.Undernutrition, chronic and acute infection, elevatedenergy expenditure, glucagon deficiency, malabsorption,abnormal intestinal transit time, bacterial overgrowth,and liver dysfunction all influence glucose tolerance.The diagnostic criteria of(CFRD) are reported in a

recent consensus report of the US CF Foundationw100x:


(i) 2-h plasma glucose(PG) )11 mmolyl during a 75-g OGTT; (ii) fasting PG(FPG) )7.0 mmolyl on twoor more occasions;(iii ) FPG)7.0 mmolyl plus casualglucose level)11.1 mmolyl regardless time or lastmeal; and(iv) casual glucose levels)11.1 mmolyl ontwo or more occasions with symptoms. The HbA1cscreening should not be used for detection of new casesof CF related diabetes mellitus but only for monitoringthe degree of control of blood glucose levels in patientswith established CFRD. The management of CFRD isbeyond the scope of the present consensus on nutrition.

5. Essential fatty acid (EFA) deficiency

Patients with CF carry a high risk of low essentialfatty acid levels, which have often been considered asessential fatty acid deficiency. Plasma and tissue lipidsof patients with CF tend to have low contents of theprecursor EFA, linoleic anda-linolenic acidsw101,102x.Several studies have also reported reduced levels ofomega-3 long-chain polyunsaturated fatty acids(LC-PUFA), such as eicosapentaenoic acid(EPA) and doco-sahexaenoic acid (DHA) w103x. In contrast,controversial data exist for omega-6 LC-PUFA, such asarachidonic acid(AA), which may be normal, reducedor even increasedw103x. A disturbed EFA and LC-PUFAstatus has been related to a variety of physiologicalimpairments and adverse effects, such as alteredmembrane and cellular functions, skin lesions, alterationof immune, renal, hepatic and pulmonary functionsw104,105x. Many of these symptoms are also observedin animals with experimental EFA deficiencyw106x.However, the question of possible causality in patientswith CF requires further clarification.Proposed mechanisms that can lead to polyunsaturated

fatty acid depletion in patients with CF include maldi-gestion and malabsorption of dietary lipids, as well asunderweight and negative energy balance with anincreased beta-oxidation of polyunsaturated fatty acids.Moreover, enhanced peroxidative destruction of poly-unsaturated fatty acids in patients with poor antioxidantstatus and high oxidative stress induced by infectionsmay contribute to low polyunsaturated fatty acid con-centrations. Alterations of EFA conversion to LC-PUFAwhich were proposed to be either causally linked to thebasic defect in CF or secondary to disease relatedphysiological alterations, an increased turnover of lino-leic acid w107x and an increased release of arachidonicacid(AA) from phospholipidsw108x have been proposedbut require further clarification. It is also of interest thatin a controlled trial, URSO therapy for 6 months led toan improvement of the EFA statusw109x.

6. Vitamin deficiency

6.1. Vitamin A

Low serum vitamin A concentrations are frequent inuntreated patients with CF, regardless of age, nutritionalstatus, meconium ileus, Shwachman score, genotype andexocrine pancreatic functionw110x. Pancreatic enzymereplacement to correct steatorrhoea apparently fails tonormalise serum vitamin A concentrations. The occur-rence of biochemical deficiency in patients withoutsteatorrhoea, suggests that other mechanisms, such as adisturbance in mobilisation of hepatic stores, areinvolved. A positive correlation between retinol bindingprotein (RBP) concentrations and zinc status has beendemonstratedw111x. Studies currently available tryingto clarify the interrelationship between vitamin A statusand liver disease are inconclusive. In a recent studyhepatic vitamin A stores in CF were found to be lowerthan normal, they decreased with age and showed nocorrelation to the severity of CF related liver diseasew112x.Many studies of vitamin A in CF underline the poor

correlation between biochemical and clinical findings.However, patients with CF with decreased serum retinolconcentrations were found to have disturbed dark adap-tation, which was reversed by supplementing vitamin Aw113x. Morphological changes of the eye like xerosis,have been reported recently but are exceptionalw114x.Low vitamin A levels are associated with poorer clinicalstatusw115x and impaired lung functionw116x. Whetherthis is related to the role of vitamin A in the immunesystem or any other specific function is unclear. Plasmalevels of b-carotene that acts as an antioxidant on itsown are low in practically all pancreatic insufficientpatients with CF.

6.2. Vitamin D

A quarter of infants with CF detected in a newbornscreening program were shown to have decreased serumconcentrations of 25-OH-cholecalciferol in the first 3months of life, before any treatment was startedw117x.This finding could be explained by the low serum levelsof the vitamin D-binding protein in CF homozygotes,suggesting that in CF hypovitaminosis D is mainly atransport problemw118x. Sunlight is the major determi-nant of the amount of vitamin D in the body, whichmainly depends on seasonal variation, geographicallocation and skin pigmentation. When there is sufficientskin exposure to ultraviolet light, dietary supplementa-tion is not essential. As result it is very difficult toestablish normal serum values and the frequency ofdeficiency in different studies varies accordinglyw119x.For vitamin D decreased biochemical concentrationshave also been found much more frequently than clinical


deficiency states such as rickets. In adolescents andadults osteopenia and osteoporosis are well documentedbut decreased vitamin D concentrations only play aminor partw119,120x.There are anecdotal reports of severe clinical defi-

ciency states in heavily pigmented adolescents living innorthern regions, after darker winter months.

6.3. Vitamin E

a-Tocopherol is a powerful antioxidant protectinglipoproteins and cellular membranes against destruction.Oxidative stress is enhanced in patients with CF due tochronic respiratory inflammationw121x. Almost all new-ly diagnosed patients with CF have low vitamin Eplasma concentrations irrespective of exocrine pancreaticfunction w110x. This and the fact that administration ofpancreatic enzymes does not correct an existing bio-chemical vitamin E deficiency suggests that exocrinepancreatic insufficiency is not the only underlying path-ogenetic mechanism. Impaired intestinal availability ofbile acids plays an equal or even more important rolein vitamin E uptake from the gutw122,123x. CF relatedliver disease with only mild cholestasis does not seemto play a significant role in this contextw124x. VitaminE absorption is also improved by URSOw124xAlthough biochemical vitamin E deficiency is a fre-

quent finding in patients with CF, clinical symptoms area rare event. However, long-standing severe biochemicaldeficiency will eventually result in irreversible neurolog-ical damage. Therefore, routine testing for biochemicalvitamin E deficiency is recommended. A consequenceof biochemical vitamin E deficiency is an impairmentof the resistance of plasma lipids to oxidationw125x. Ininfants with CF, clinical deficiency mainly presents ashaemolytic anaemia while in older patients symptomsare related to the nervous systemw126,127x. In onestudy abnormal brainstem evoked auditory potentialswere detected and proposed as useful in the evaluationw128x. No abnormalities, however, were detected innerve conductionw129x. Whether vitamin E supplemen-tation protects against oxidative lung damage in patientswith CF is still speculative. A positive correlationbetween percent FEV and plasma vitamin E levels in1

patients with CF was recently reportedw130x.

6.4. Vitamin K

As long as vitamin K was only supposed to beimportant in coagulation, a diagnosis of deficiency wasexceptional and supplements were restricted to patientswith haemoptysis, uncontrollable malabsorption frompancreatic disease, liver disease, intestinal resections orlong-term use of antibioticsw131x. Recent studies indi-cate vitamin K acts as a cofactor in the carboxylation,not only of prothrombin involved in coagulation, but

also of osteocalcin in bone formationw132x. Determi-nation of proteins induced in vitamin K absence(PIV-KA), a new sensitive method for the measurement ofthis vitamin, demonstrates that deficiency is common inCF especially in unsupplemented pancreatic insufficien-cy w133x. Based on the carboxylation state of theseproteins in patients with CF, 5 mg vitamin K wassupplemented weekly without reaching normal levels inthese patientsw134x. But in a recent study from Torontounsuspected biochemical vitamin K deficiency was part-ly corrected by an oral supplementw135x. A water-soluble, oral vitamin K preparation is often given topatients with CF, even though adequate comparativedata on the bioavailability of vitamin K from thestandard preparation and the water-soluble micellar prep-aration are unavailable. The parenteral route should onlybe chosen to correct an acute symptomatic deficiency,in severe liver disease or malabsorption. Further studiesare needed in patients with CF with liver disease, severemalabsorption, small bowel resections and long-termantibiotic use before the optimal dose of vitamin K isdetermined.

6.5. Water soluble vitamins

Water-soluble vitamins usually do not pose an appre-ciable problem in CF. Many patients with CF withexocrine pancreatic insufficiency have a disturbed Schil-ling test indicating an abnormal vitamin B12 absorption,but pancreatic enzyme preparations promote absorptionof vitamin B12. Patients who underwent extensive resec-tions of the terminal ileum need lifelong treatment witha parenteral administration of 100mg vitamin B12 permonth. In contrast, vitamin B12 deficiency in pancreaticsufficient patients with CF not taking pancreatic enzymesupplements is exceptionalw136x. Plasma vitamin Cconcentrations are inversely related to age and differentindices of inflammationw137x. The antioxidant role ofvitamin C is currently under investigation.

7. Mineral and trace element deficiency

In the daily diet, macronutrients are needed for thebody in relative large amounts and are important for thecell or the extracellular compartment. Micronutrients ascofactors are essential for enzymatic reactions or asstructural elements of proteins.

7.1. Minerals

Sodium and chloride are the most important ions inthe extracellular fluidw138x. The mean daily intake ofsodium is between 6 and9 g a day for adults, which isin excess of the daily minimal requirement(-3.5 gyday). Newborns need more sodium and chloride inrelation to their bodyweight for the increase of extra


Table 2Minimal daily requirements for sodium, chloride and potassium innormal individuals

Age Sodium Chloride Potassium(mg) (mg) (mg)

-1 year 120–200 180–300 500–700)1 year 225–500 350–750 1000–2000

Source: National Research Council, 1989. In CF more loss throughsweat and stool can be anticipated, and has to be supplemented on anindividual basis.

cellular volume. The minimal need is based on theconcentration of breast milk(sodium 160 mgyl, chloride385 mgyl, and potassium 500 mgyl). In the first 6months the population reference intake(PRI) for sodiumis 23 mgykg per day, the recommended intake is 23–46 mgykg per day. For newborn babies the acceptableintake for chloride is 35–71 mgykg per day. The dailysodium loss in sweat is approximately 500 mg in adults.The loss may increase 10 times in CF during exercisein the sun, sometimes accompanied by hyponatraemiaand alkalosis. In moderate climates the excess of sodiumintake in food compensates this extra loss. The serumsodium concentration is regulated by the renin-angioten-sin-aldosterone axis that diminishes the sodium excretionin the urine during activation. In most patients thisbalance is maintained. Since human milk is low insodium, breast fed babies may need supplementationduring fever or hot summer months.Potassium is the most important intracellular cation,

involved in nerve conductance, muscle contraction andblood pressure. Potassium loss with sweat is low. Themean potassium intake for adults is between 2 and 3.5g daily. Rapidly growing young children need duringincreased growth velocity approximately 78 mgy100kcal (recommended intake) or 35–78 mgykg per day(acceptable intake) (Table 2).Calcium is important for the mineralisation of the

skeleton, muscle contractions and signal transmission inthe nervous systemw139x. Fat malabsorption and vitaminD deficiency are the main causes of low calcium uptakein the intestinew140x. Calcium intake in non-CF indi-viduals is dependent on age and growth velocity. Chil-dren need 400 to 800 mg calcium and adolescents 800–1200 mg calcium daily. In CF, tetany, rickets or clottingabnormalities are rare. Plasma calcium levels and calci-um excretion in the urine are normal. In young childrenwith CF bone mineralisation is thought to be normal,but in adolescent and adult patients with CF bonemineral density and bone content is often diminishedand spontaneous fractures are describedw141x. Alsophosphate homeostasis is strongly related to calciumand regulated by vitamin Dw142x. Most food productsare rich in phosphate and a deficient intake is excep-tionally rare. Only young infants with low body weight

are at risk for nutritional deficiency of phosphate. Theideal ratio of calcium to phosphate intake is 2:1.Only 1% of the body store of magnesium(adult: 25

g) is in the extracellular fluid. Magnesium is importantin the skeleton(60% of the magnesium pool) andmuscles and in many biochemical processes. Normalserum levels are 0.7–1.0 mmolyl. Based on the concen-tration in human milk the recommended dose for infantsand young children is 7 mgykg per day and for adults3.5 mgykg per day. Hypomagnesaemia is characterisedby tremor, tetany, neuromuscular irritability and seizures.Magnesium absorption is disturbed in pancreatic insuf-ficiency and is closely associated with calcium andphosphorus. Urinary magnesium excretion is increasedby aminoglycosides probably causing renal tubular dam-age w143x. Serum levels do not always correlate withthe severity of symptoms.

7.2. Trace elements

The iron store in the body is 3–4 g of which 70% isin the red blood cells and 25% in ferritin and haemosi-derin in liver, spleen and bone marrow. The transportprotein in plasma is transferrin. Children need 5–10 mgof iron daily. Iron deficiency is frequent in CF andcaused by multiple factors: inadequate dietary intake,malabsorption, chronic infection, and blood loss. Pan-creatic enzymes may be responsible for impaired oraliron absorption and iron should not be supplemented inclose proximity to pancreatic enzyme supplementsw144x.It is unclear whether iron supplementation will improvethe iron status, which is monitored by measuring serumferritin levels in patients with CF. Ferritin levels can beincreased during infection.The total body zinc content is 2 g and most of it is

intracellularly deposited in the skeleton, muscles, liverand skin. Red blood cells contain 0.9–1.5 mg zinc per100 ml. Zinc has an important function in manyenzymes. Deficiency is characterised by growth retar-dation, acrodermatitis, and disturbed immune function.Children need 5–10 mgyday and adults up to 15 mg. Itis suspected that subclinical zinc deficiency due to fatmalabsorption is wide spread in CF and is caused byzinc forming complexes with fat and phosphorusw145x.Pancreatic enzyme supplements improve zinc absorptionw146x.Like zinc, copper is part of many enzymes and found

mostly intracellularly in liver, muscle and bone. In theplasma copper is bound by caeruloplasmin. Copperdeficiency results in anaemia, neutropenia, heart disor-ders, muscle weakness, immune disorders, pancreaticatrophy, and connective tissue impairment. Copper defi-ciency is only partially represented by plasma copperlevels because caeruloplasmin is an acute phase protein.There is insufficient information to support supplemen-


tation of copper more than the age appropriate recom-mended daily allowance(RDA) w147x.Selenium is an essential part of the antioxidant glu-

tathione peroxidase. Deficiency of selenium causes car-diomyopathy and muscle weakness. Glutathioneperoxidase activity in red blood cells is a better indicatorof selenium status than plasma values. In CF there is anindication that the selenium status is disturbedw148x,however, at present, it cannot be recommended tosupplement selenium in patients with CF. Pancreaticenzyme preparations contain 0.5–1.6mgyg of seleniumand this amount is sufficient to affect glutathione per-oxidase activityw149x.Iodine is incorporated in hormones of the thyroid

gland. Iodine deficiency does not occur in CF, sinceiodine is easily absorbed from food. Iodine requirementsincrease with age: 40mg during the first 6 months to150 mg at 10 years. Manganese is necessary for theantioxidant superoxide dismutase. The total body poolis 10–20 mg and supplementation for patients with CFis not needed. Similarly, molybdenum deficiency isextremely rare and does not need supplementation.Chromium plays a role in carbohydrate and lipid metab-olism and protein synthesis and is important for growth.Patients with CF had normal plasma levels duringsupplementation of 0.5–0.75mgykg per dayw150x. It isquestionable if supplementation is necessary. Fluorine isfound in tooth and bone and supplements are notrequired.

8. Antioxidant deficiency

In patients with CF, the antioxidant protective screenis markedly disturbed as a result of impaired status ofglutathione, vitamin E and carotenoids such asb-carotene and lycopene. Occasionally low plasma con-centrations of albumin, vitamin C and selenium arefound. Glutathione deficiency has been described tooccur both locally in the CF airways and systemicallyw151x. Glutathione is transported via the CFTR, sug-gesting that glutathione deficiency is intrinsically relatedto CF w152x. The glutathione status is also associatedwith nutritional statusw153x. Carotenoids are highlylipophilic compounds not considered to be vitamins, ofwhich the plasma and lipoprotein concentrations arevery low in CF patients with exocrine pancreatic insuf-ficiency. In addition to its provitamin A function,b-carotene acts as an antioxidant. Correction of poorvitamin E andb-carotene status to normal enhances theresistance against oxidation of plasma lipoproteinsw125,154x, decreases plasma lipid peroxidationw154–156x and reduces inflammationw157x. For counterbal-ancing the enhanced reactive oxygen species productiondue to chronic inflammation, full correction of theantioxidant screen is warranted. Future studies shouldaddress the question as to whether the final goal of

antioxidant supplementation is to achieve plasma con-centrations in CF higher than those in healthy subjects.

9. Prevention of malnutrition and treatment of pan-creatic insufficiency

Prevention of malnutrition requires early intervention.Therefore early diagnosis is of importance and may beachieved by neonatal screeningw9x. Following diagnosis,frequent reviews by a specialist CF dietician are man-datory; during the first 12 months after diagnosis atleast once every month, thereafter at least every 3months. The frequency of clinical reviews depends onthe clinical state, control of the malabsorption andweight gain. Patients on a special diet(e.g. vegetarian)should be monitored more closely.The majority of individuals with CF can tolerate a

normal to high fat diet if treated with pancreatic enzymesin doses(Tables 3 and 4) matched to fat intakew158x.A 3-day faecal fat study and dietary assessment is thebest measure of fat absorption. The diet is quite oftenlow in fibre but for some who experience recurrentabdominal pain, an increase in fibre intake to 30 g perday with additional water may reduce abdominal symp-toms w159x and may lead to an improved appetite andenergy intake in some patients. In children with CF andwell-controlled absorption and only mild chest infec-tions, a normal energy intake may be sufficient. How-ever, if the nutritional state andyor growth are abnormal,the diet should provide in excess of 20% of the recom-mended daily amount and high-energy dietary supple-ments or even enteral tube feeding may be required. Asenergy requirements vary so widely it is important thatan assessment of each individual’s needs is undertaken.

9.1. Infant feeding

Infants with CF fed on breast milkw5x achieve normalweight gain and growth by the age of 1 year as doinfants on normal formulaew6x and those fed on apredigested medium chain triglyceride containing for-mula w160x. For the first year of life the ESPGHANrecommendation of exclusive breast feeding for the first4–6 months of life is appropriate for the infant with CF.w5x. If breast-feeding is not possible or there is insuffi-cient milk, cows’ milk-based infant formulae can beused w6,160x. Whole cows’ milk should not be givenduring the first year of life. Infants who receive a feedcontaining adequate energy and who are also given anappropriate dose of supplemental pancreatic enzymesshould thrive satisfactorily irrespective of the type ofmilk w6,161x. Extensively hydrolysed protein formulaeshould be considered for infants who have undergoneextensive gut resection for meconium ileus and for thosewith milk intolerance(e.g. cows’ milk allergy or lactoseintolerance) w162x. A feed containing medium chain


Table 3Minimum enzyme content of pancreatic enzyme preparations

Name Maker Lipase Protease Amylase

Enteric-coated microspheresCotazym Thiemann10 000 10 000 Ph Eur u 375 Ph Eur u 6250 Ph Eur u20 000 20 000 Ph Eur u 750 Ph Eur u 12 500 Ph Eur u30 000 30 000 Ph Eur u 1125 Ph Eur u 18 750 Ph Eur u40 000 40 000 Ph Eur u 1500 Ph Eur u 25 000 Ph Eur u

Nutrizym GRa Merck 10 000 BP u 650 BP u 10 000 BP uPancrease Janssen-Cilag 5000 BP u 330 BP u 2900 BP u

Enteric-coated minimicrospheresCreon Solvay10 000 10 000 Ph Eur u 600 Ph Eur u 8000 Ph Eur u25 000 25 000 Ph Eur u 1000 Ph Eur u 18 000 Ph Eur u40 000 40 000 Ph Eur u 2000 Ph Eur u 30 000 Ph Eur uFor children 5000 Ph Eur u 200 Ph Eur u 3600 Ph Eur u

Enteric-coated minitabletsNutrizyma Merck10 10 000 BP u 500 BP u 9000 BP u22 22 000 BP u 1100 BP u 19 800 BP u

Panzytrata Knoll10 000 10 000 Ph Eur u 500 Ph Eur u 9000 Ph Eur u25 000 25 000 Ph Eur u 1250 Ph Eur u 22 500 Ph Eur u

Pancrease HLa Janssen-Cilag 25 000 BP u 1250 BP u 22 500 BP u

Note: For amylase and lipase 1 BP units1 Ph Eur unit; for protease there is no direct equivalence between BP and Ph Eur units because ofthe use of different assay methods.

Eudragit-coated.a

triglycerides should be considered in patients with cho-lestasis or uncontrolled steatorrhoea. If weight gain ispoor, additional energy supplements may be added toformulae or a high-energy infant formula used. A normalto high fat weaning diet is recommended depending onthe infant’s growth. The first 2 years are a period ofvery rapid growth; therefore close monitoring of thegeneral condition, the nutritional state and the growthrate of the infant with CF is needed. If poor weight gainis related to an increase in frequency of chest infections,vigorous treatment of the latter will both improve thenutritional state and reduce the amount of pulmonarydamage.Treatment of acute and chronic lung infection nor-

mally results in an increase in bodyweight, which isrelated to a reduction in systemic inflammationw163–166x.

9.2. Control of malabsorption achieved with currentenzymes preparations

Enzyme preparations may differ in their enzymecontent, which often varies with batches, in their disso-lution characteristics in relation to the pH and to otherconstituents of the duodenal fluidw167x and in the sizeof the particles and their rate of exit from the stomachin relation to the meal. The practical details of admin-istration, including adjusting the enzyme dose to the fatintake and the timing in relation to the meal will have

a significant effect. Future studies are needed in thiscontext.Coefficients of fat absorption of between 85% and

95% of intake should be possible with presently avail-able enzyme preparationsw168–173x. Nevertheless, asubstantial number of patients with CF do not achievenormal absorptionw174x. Based on reports of fibrosingcolonopathy, various guidelines for the use of pancreaticenzymes in CF have appearedw58,175–177x. Recom-mendations are summarised in Table 4.

9.3. Failure to control gastrointestinal symptoms

Sometimes, control of symptoms is not achieved evenwith a dose of enzyme equivalent to the recommended10 000 IU lipaseykg per day w175x is given in anappropriate manner. The degree of residual malabsorp-tion should be estimated and other gastrointestinal dis-orders should be considered. A progressive increase inenzyme dose without further investigations is not rec-ommendedw178x. Distal intestinal obstruction syndrome(DIOS) is characterised by recurrent attacks of abdom-inal pain with variable symptoms of obstruction and isrelatively common in patients with CFw179x. Anincrease in pancreatic enzyme dose in patients withDIOS is likely to worsen the abdominal pain andconstipationw22x. Other possible gastrointestinal prob-lems include gastro-oesophageal reflux, which seems tobe common both in infantsw180,181x and older patients


Table 4Recommendations for pancreatic enzyme supplementation therapy in CF

Infants• Use a microsphere or minimicrosphere preparation• For every 120 ml infant formula or breast milk give as the initial dose of

one-quarter to one-third of a capsule of standard strength pancreatin(asCreon 10 000s2500–3333 IU lipase; as Pancreases1666–2500 IU lipase).These doses equate to approximately 400–800 IU lipase per g of dietary fat.

• Mix the enzyme microspheres or minimicrospheres with a small amount ofinfant formula or expressed breast milk or fruit puree and give from a spoondirectly before the feed.

• Increase the dose gradually according to clinical symptoms, appearance ofthe stools and objective assessment of weight gain, growth and absorption.

• Once solid food is introduced, individually titrate enzyme dose according tothe fat intake. Regular advice from a dietician is mandatory for best results.

• Aim to keep the lipase intake below 10 000 IU per kg body weight per day.

Older children and adults• Initial dose of 1–2 capsules of standard pancreatin preparation(as Creon

10 000s10 000-20 000 IU lipase; as Pancreases5000–10 000 IU lipase)per meal and a half to one capsule with fat containing snacks.

• One paediatric unit has continued to use high strength microsphere capsules(Creon 25 000) without problems.

• Enzymes should be given with all fat containing foods and supplements.The dose should be worked out individually, initially with the help of adietician, and varied according to the fat intake. Dose requirements canvary widely between 500 and 4000 IU lipase per gram of dietary fat.

• The capsules should be swallowed whole at as early an age as possible andmany children will manage this by 3 or 4 years, some very much earlier. Ifremoved from the capsules, the microspheres shouldnot be sprinkled on ormixed with the whole meal but should be mixed with a little fluid or foodand immediately given from a spoon in one swallow. They should not becrushed or chewed.

• Enzymes are best given at the beginning or early in the meal, e.g. half thedose at the beginning and half in the middle of the meal.

• The dose is gradually increased until the symptoms are controlled whenevidence is sought that absorption has been controlled.

• Patients and parents should be encouraged to discuss any problems theymay have with adherence to enzyme treatment.

• In tube or gastrostomy fed patients pancreatic enzymes should be givenbefore and after the feed.

From: Littlewood JM, Wolfe SP. Control of malabsorption in cystic fibrosis. Paediatr Drugs 2000;2:205–222.

w182x, inflammatory bowel diseasew183x, pancreatitis inpancreatic sufficient patientsw184x, short bowel withbacterial overgrowth and adhesions after intestinal sur-gery, liver and gall bladder diseasew185x, cows’ milkprotein allergy or lactose maldigestionw162x and evenintolerance to the porcine enzyme preparationsw186x.Patient adherence to treatment provides another prob-

lem in the control of gastrointestinal symptoms and therole of an experienced dietician to discuss the practicaldetails of treatment in such circumstances cannot beover emphasised.Reduction of gastric acid has improved absorption in

patients with CF where control was poor even withenteric-coated acid resistant enzymes. Treatments haveincluded cimetidinew187x; ranitidine w188x omeprazolew189x and lansoprazolew190x Long-term side effects ofthis group of drugs have not been investigated. Taurine-conjugated bile acids are in relatively short supply dueto the gastrointestinal losses, which occur in CF. There

is a relatively greater compensatory production of gly-cine-conjugated bile acidsw52x. Therefore, in CF taurine-conjugated bile acids, which are more efficient at lipidsolubilisation, are deficient in plasma and bilew53x.There is still controversy as to whether or not oraltaurine corrects the deficiency and improves the malab-sorption. Further studies are neededw191x.

10. Side effects of pancreatic enzymes

Hyperuricaemia and hyperuricosuria, which occurredwith the older less pure pancreatic extracts, are nolonger a problem with the modern microsphere prepa-rations w192x. Soreness of the mouth may occur withpowdered preparations or if acid resistant microspheresare chewed or held in the mouth and dissolve with apH of greater than 5.5. If older powdered preparationsare used in breast-fed infants, soreness both of theinfant’s mouth and of the mother’s nipples may occur.


Perianal irritation may result from the passage of signif-icant enzyme activity in the stools if intestinal transit israpid or the enzyme dose excessive. The porcine originof the pancreatic enzymes causes apparently insignifi-cant immunological response in most patientsw193x,however, this has been suggested a possible aetiologicalfactor in fibrosing colonopathy(FC) w194x. Severe acuteand chronic gastrointestinal allergic reactionsw186x andgeneral allergic reactions may occur in people adminis-tering powdered enzymes to infants with CFw195,196x.In patients who have had chronic significant fat malab-sorption a too rapid increase in enzyme dose may causesevere constipation.Fibrosing colonopathy(FC) was first reported in 1994

w197,198x. The exact pathophysiology is still uncertain,however, the progressive increase in pancreatin doseprescribed for persisting intestinal symptoms appears tohave been a major factor in reaching the very high dosesimplicated in FC w198,199x. Toxicity from the co-polymer Eudragit L30 D55, an acrylic resin based onpolymethacrylic acid and polyacrylic acid esters, usedas an enteric coating by some pancreatin preparations,has also been proposedw198,200,201x. However, acrylicresin is widely used in many different preparations andtoxicity the role in the causation of FC is not generallyacceptedw202–204x. A list of co-polymer coated prep-arations is given in Table 3, together with phthalate-coated alternatives.With the increased awareness of FC, pancreatin dos-

ing has become more conservative with the recommen-dation not exceeding 10 000 USP lipaseykg per day;this and restriction of high strength preparations()25 000 IU lipaseycapsule) to adult populations hasresulted in a dramatic fall in the incidence of FC inEurope.

11. EFA treatment

Dietary treatment of patients with CF should aim atavoiding clearly subnormal levels of EFA and LC-PUFA.Strategies to achieve that goal include an adequatesupply of energy, polyunsaturated fatty acids of both then-6 and the n-3 series in balanced proportions, as wellas antioxidants. Several studies have failed to demon-strate any general improvement by supplementation ofEFA w205,206x but physiological improvement in liversteatosis, kidney function and sodium transport havebeen reportedw207,208x. However, excessive intakes ofEFA and LC-PUFA carry the risk of adverse effects,such as enhanced lipid peroxidation and unbalancedsynthesis of specific eicosanoids, with clinicalconsequences.Beneficial effects of supplying increased intakes of

specific fatty acids, or groups of fatty acids, have beenproposed. High supplies of fish oil rich in the omega-3fatty acid EPA reduce the liberation of proinflammatory

leukotrienes from granulocytes of patients with CF invitro w209x and in vivo w210x and were reported toimprove pulmonary function in some preliminary studiesw211,212x, this observation deserves further evaluation.Very high intakes of the omega-3 fatty acid DHA havebeen reported to reduce organ damage in a mouse modelof CF. Whether or not comparable clinical benefits canbe achieved in patients with CF supplemented with highdoses of DHA should be evaluated. Based on theavailable evidence it is recommended that patients withCF should receive an adequate dietary intake of omega-3 fatty acids as is recommended for the general popu-lation, it is considered premature to recommend highpharmacological doses of specific omega-3 fatty acidsprior to further characterisation of the efficacy of suchintervention. In a controlled trial, URSO therapy for 6months led to an improvement in EFA statusw109x.

12. Vitamin supplementation

Clinical evidence of vitamin deficiency is rare andthere is no uniformity on the goals of supplementation.Relevant questions are how to prevent isolated biochem-ical deficiencies and subclinical abnormalities. The pres-ent consensus favours prophylactic substitution of thosevitamins for which low blood levels or deficiencies haveever been described. The initial dose proposed usuallyis adequate to normalise blood concentrations in mostpatients with CF without causing hypervitaminosis. It isprudent to measure vitamin blood levels after a fewmonths and after any change in the treatment of themalabsorption because this can influence vitaminabsorption. Subsequent supplementation should beadjusted according to the patient’s blood levels; after-wards annual monitoring is sufficientw117x.

12.1. Vitamin A

The vitamin A intake should be high enough toachieve serum concentrations in the normal range with-out provoking side effects. This can be achieved withdaily doses between 4000 and 10 000 IU of a fat-solublepreparationw114x. Water-soluble or water-miscible formsof vitamin A preparations have not been studied in CF.As absorption and metabolism of vitamin A differbetween individuals, serum concentrations should beestimated at least once a year and 3–6 months after anychange in dose. If plasma levels are low despite supple-mentation to the above levels consideration should begiven to patient compliance and the RBP and the zinclevel should be checked. In view of the potential toxicityof vitamin A, supplementation should never exceed20 000 IU if the RBP is low. Special consideration mustbe given to vitamin A supplementation during pregnan-cy. A relationship has been suggested between theincidence of birth defects and high vitamin A intake


()10 000 IUyday). In CF serum levels should bechecked at the start of pregnancy. If plasma levels arehigh it is recommended the dose is reduced. If levelsare low or normal supplementation should continue at alevel less than 10 000 IUyday.

12.2. B-Carotene

In patients with CF with pancreatic insufficiency adaily dose of 0.5–1 mgykg b-carotene corrected verylow plasma and lipoprotein concentrations to normalw156–158x. However, plasma concentrations need to bemonitored to make sure that above normal concentra-tions will not be achieved in the individual patient,given the fact that in smokers, a group of subjects alsoexhibiting oxidative stress, higher than normal plasmab-carotene concentrations were associated with seriousside effects.

12.3. Vitamin D

As sunlight is the major source of vitamin D for thebody, serum concentrations will depend largely onendogenous production in the skin and this will differbetween individualsw213x.Decreased serum concentrations of 25-OH-CC have

been described in patients with CF receiving daily oralsupplementation of up to 2000 IU of vitamin Dw214x.No cases of hypervitaminosis D were reported with thisconcentration in patients with CF. No studies are avail-able on the effect of intermittent large doses. To keepblood levels within a normal range, a daily dose ofbetween 400 and 2000 IU is required. Recent evidencesuggests that the serum level should be maintainedwithin the upper part of the normal range to ensureoptimal bone healthw214x. In severe hepatocellulardisease 25-hydroxylation is impaired and therefore 25-OH-vitamin D is preferred for supplementationw214x.

12.4. Vitamin E

Clinical deficiency states are exceptional in patientswith CF w130x, but enhanced susceptibility to lipidperoxidation has been demonstrated to occur in patientswith low vitamin E statusw126x. Therefore regularvitamin E supplementation is recommended. As vitaminE is non-toxic there is no objection to using up to 400IU daily (s400 mg all-rac-a-tocopheryl acetates450mg dl-a-tocopheryl acetate or 268 mg RRR-a-tocoph-erol) w124x. In animals and humans side effects wereonly seen when excessively high amounts were given.The more expensive water-soluble form has no advan-tage over the fat-soluble form, provided the latter istaken with pancreatic enzymesw124,215x. RRR-a-tocopherol and all-rac-a-tocopheryl acetate were shownto be equally effective, when given at a dose of 400 mg

IUyday w124x. With that dose a normal resistance tooxidation of lipoprotein could be achievedw126x. It hasbeen recommended to use for the interpretation ofadequate levels of the plasma, tocopherolytotal lipid orcholesterol ratio as an index of vitamin E status partic-ularly when levels are low, because the vitamin E levelsrise with lipids.

12.5. Vitamin K

Routine supplementation with vitamin K has alwaysbeen controversial. But recent studies have revealedunsuspected biochemical deficiency, which may be animportant factor in the osteoporosis in CFw134x. Patientswith demonstrated or suspected deficiency should begiven 10 mg daily. However, the dose required to correctPIVKA levels is still controversial. A recent randomisedprospective study found better biochemical parameterswith a supplementation of 5 mg weeklyw134x. Eventhen normal levels were not achieved in all patientsw135x. Probably better results are achieved with a dailysupplementw136x. For systemic substitution, an oralwater-soluble form should be given; parenteral admin-istration should be reserved for correction of acutesymptomatic deficiency, in severe hepatocellular diseaseor uncorrectable malabsorption.

12.6. Water-soluble vitamins

Patients who underwent extensive resections of theterminal ileum need lifelong treatment with parenteraladministration of 100mg vitamin B per month. A12

supplement of at least 100 mg vitamin C per day shouldbe prescribed for patients with an unbalanced diet,deficient in vitamin C. No other water-soluble vitaminsupplements are needed.

12.7. Conclusion

The doses proposed in Table 5 are those reported toachieve normal plasma concentrations in patients withCF without liver disease that will not cause toxicity.The availability of a preparation that combines thevitamins at the required doses could help improvecompliance and make life of patients with CF moreconvenient. Fat-soluble vitamins need to be taken at thesame time as a meal for which pancreatic enzymes arerequired.

13. Mineral and trace element supplementation

13.1. Minerals

Sodium and chloride supplementation is usually notnecessary except during exercise in hot climates whenextra salt is recommended(for minimal need see Table


Table 5Recommendations for vitamin supplements in CF

Fat soluble CF patients Starting dosevitamins needing supplements

A EPI 4000–10 000 IUydaya

D EPI, northern countries 400–800 IUydayb

depending on serum levelE All 100–400 IUydayc

K EPI, cholestasis 1 mgyday to 10 mgyweekB12 Schilling test-45% 100m i.m.ymonth

after ileal resectionOther water soluble None if dietary intake is normalvitamins

EPI, exocrine pancreatic insufficiency. Conversion factors: IU to mg: vitamin A: IU=0.3sm; vitamin D: IUy40sm; vitamin E: all-rac-a-a b c

tocopheryl acetate: IUsmg; RRR-a-tocopherol: IUy1.49smg.The need for vitamin supplementation in pancreatic sufficient patients should be assessed on an individual basis according to plasma levels.

2). Moreover, breast fed infants are not always able tomeet their sodium chloride needs and may requiresupplementation, particularly when exposed to highambient temperatures or at high water losses due tofever, sweating or tachypnoea. Children and adults withCF need oral calcium supplementation if their diet isfound to be deficient.During long-term treatment with aminoglycosides and

severe malabsorption patients with CF may need extrasubstitution of magnesium.

13.2. Trace elements

The need for iron supplementation should be deter-mined by the plasma transferrin saturation and not givensimultaneously with pancreatic enzymes. In growthretardation and severe steatorrhoea zinc should be sup-plemented. Selenium supplements may be needed inspecial areas(e.g. in Switzerland, Austria). However,these should be used with caution, as there is a narrowrange between supplementary and toxic doses.

14. Supplementation with antioxidants

Vitamin E is the most important fat-soluble antioxi-dant and the doses recommended for supplementationare presented above. However, higher doses will berequired if the intake of polyunsaturated fatty acids(such as DHA) is increased above the average dietaryintake. Supplementation with vitamin C and selenium,which represents an integral constituent of the antioxi-dant enzyme glutathione peroxidase, and glutathioneprecursors or derivatives need to prove to be beneficialbut randomised controlled studies are required beforetheir use can be recommended.

15. Refeeding the malnourished child

In many CF studies a relationship has been shownbetween body weight and lung functionw216x, but it is

unclear what is cause and what is effectw217x. Reasonsfor a decrease in energy intake include anorexia, feedingdisorders(neonatal tube feeding), depression, interac-tions with parents, oesophagitis, DIOS, iatrogenic fatrestriction, decreased appetite by concomitant drugs orpulmonary inflammation and lack of general well being.In most cases early intervention is extremely importantto prevent negative long-term effects. Intervention isoften complicated because the multifactorial nature ofthe problem.Interventions include behavioural treatment, psycho-

logical support, dietetic advice, oral supplementation,nasogastric tube feeding, gastrostomy feeding and par-enteral feeding. Although there are reports that eating isa problem for patients with CFw218x, a positive effectof any form of nutritional intervention with oral supple-ments is still unprovenw219,220x possibly due to smalland uncontrolled studies which differ in design, para-meters and outcome measures. It is important to startinterventions earlyw217x (Table 1).

15.1. Recommendations

15.1.1. Oral feeding0–1 year: Breast feeding is the preferred way of

feeding infants and also should be recommended forthose with CF. Mothers of breast-fed infants may needto be encouraged to feed more frequently to increasemilk formation and thus meet their infant’s energy needs.Some breast fed infants may benefit from sodiumchloride supplementation, particularly at high ambienttemperatures or with increased water losses due to fever,diarrhoea, tachypnoea or increased sweating.Formula fed infants will usually receive regular for-

mula that can be supplemented with up to a totalcarbohydrate content of 10–12 gy100 ml and a total fatcontent of 5 gy100 ml which will achieve an energydensity of approximately 1 kcalyml. Supplementationshould be gradually increased up to these levels. Aspecial dietetic product for infants with a high energy


content could also be used but may be less flexible andmore expensive. The volume of feed should be adaptedto achieve normal weight gain and growth velocity,which often means that higher volumes will need to befed than in healthy babies. Solids should be introducedat the normal age of 4–6 months. Most infants with CFwill thrive satisfactorily on a normal weaning diet. Ifthe infant is failing to thrive, higher fat foods may beused, with appropriate adjustment of the pancreaticenzymes.2–5 years: A normal to high fat diet should be

advised depending on growth and nutritional status. Inthe past oral supplements were often unpalatable, how-ever, recent studies show that some supplements arewell accepted by this age group. A compromise mustbe found between palatability, volume and the optimalcomposition to obtain maximal compliance. For childrenin this age range specific commercially products areavailable now.5 years: Standard adult supplements can be used and

the choice is often directed by the taste of the patientand long-term acceptance. Preferably, high energy den-sity formulae should be used.

15.1.2. SupplementsThere are many types of nutritional supplements

available. Palatability, volume and the optimal compo-sition determine the choice. For children of approxi-mately 1–5 years age specific commercially availableproducts can be used. Standard adult supplements aresuitable for children over 5 years. The choice of thesupplement is often determined by the taste preferenceof the patient to obtain maximal compliance. High-energy dense preparations should be used whereverpossible.Supplements should be given before or after meals or

before bedtime to ensure that the appetite for normalfood is maintained. At the present time there is a lackof evidence to support the use of dietary supplementsw219x. A large multicentre trial is currently addressingthis issue in the UK.

15.1.3. Tube feedingTube feeding can be administered by naso-gastric tube

or by gastrostomy, patient’s preference determining thechoice of the route. Preferably, tube feeding should begiven overnight with the aim to maintain normal dietaryintake during the day. Gastro-oesophageal reflux(GER)may be a problem in some patients and should bemonitored closely before feeding is recommended. IfGER is documented, a Nissen’s fundoplication may beindicated prior to gastrostomy insertion. In patients withborderline glucose intolerance nocturnal hyperglycaemiashould be monitored and if necessary treated withinsulin. Normally, a high calorie non-elemental formulacan be used. If this is not tolerated, and in rare instances,

individual patients may benefit from elemental or medi-um chain triglyceride (MCT) containing formulae.Because of the slow flow of fat infusion absorption isgenerally adequately controlled by taking a small doseof enzymes at the start and during the feed. If patientsawake spontaneously they can also take extra enzymesduring night.

15.1.4. Total parenteral nutritionTotal parenteral nutrition is not recommended for

long-term treatment, but may be useful for short termsupport in infants and children after major(GI) surgeryand in the severely ill patient waiting for a lung or livertransplant. Several studies have shown an improvementin nutritional status with supplementary parenteral feed-ing w221,222x.

16. Treatment of the malnourished adult

The goal of treating the malnourished adult is toincrease lean body massw21x. Initially a high fat andhigh calorie diet may be used, but oral supplements areoften needed. Oral supplements should be highly palat-able and provide a large amount of calories in a smallvolume, preferably by having a high content of fat. Themain disadvantage of oral supplements is their influenceon normal appetite, thereby adversely affecting theenergy intake. However, the use of palatable high calorieoral supplements showed an overall increase in dailyenergy intake. If dietary interventions, including oralsupplementation, fail to increase bodyweight, one shouldconsider nasogastric tube or gastrostomy feeding(PEG).Percutaneous sonographic gastrostomy(PSG) can beperformed under local anaesthesia by an experiencedradiologist guided by ultrasoundw223x or by a gastro-enterologist using fluoroscopic guidance. Enteral feedingoffers the possibility of feeding overnight, thereby notinfluencing the patients’ appetite during the dayw224,225x. The formula used for tube feeding may benon-elemental provided that enzymes are taken at thestart and preferably during the nocturnal feedingw226x(see Section 15.1). Parenteral nutrition is generally notrecommended since it is limited by volume, immobilisesthe patient and increases the risk of sepsisw227x. Forthese reasons the use of parenteral nutrition is usuallyrestricted to when the GI tract is non-functional or inseverely malnourished patients awaiting transplantation.When hyperalimentation is given as the sole interven-

tion in malnourished adult patients with CF, body weightwill increase but lean body mass may remain unchangedw228x. Since increase of muscle mass is an importanttarget, the combination of nutritional support with spe-cific muscle stimulation appears a relevant option. Com-bining nutritional support with an exercise programmemay result in an increase in lean body mass, maximal


ventilatory capacity, oxygen uptake and maximal exer-cise capacityw229–231x.

17. The important questions and answers

Q1. Does a nutritional deficit exist in CF patientsand, if so, what impact does it have on disease progres-sion and survival?

A1. Many patients with CF present with below normalweight andyor height. Even with treatment, malnutritionmay occur leading to reduced weight gain and growthand nutritional deficiencies, which are associated with amore rapid progression, the disease and shortened sur-vival. Nutritional deficits may be responsible for thedelay in the onset of puberty and menarche in teenagerswith CF. The nutritional state of patients has steadilyimproved over the years and is likely to be one of themajor factors contributing to the increased survival inrecent years. Provided the chest infection and associatedinflammation are treated effectively, prevention andearly treatment of nutritional deficits are associated withimproved growth and respiratory function and are likelyto improve prognosis.

Q2. How does malnutrition present in CF and howdo we measure it?

A2. Malnutrition may present as underweight, sub-normal longitudinal growth, or deficiencies in one ormore single nutrients. Underweight is defined as aweight for height of less than 90% using appropriatenormal values for the population or in adults, body massindex of less than 18.5 kgym . In children, BMI values2

should be interpreted on the basis of gender-specificcentile charts orZ scores. Standard deviation scores givesimilar information and are more convenient for statis-tical calculations. In the absence of normal values thelongitudinal assessment of nutrition and growth is par-ticularly important. Knowledge of the puberty state isnecessary for the adequate assessment of growth overthe age of 10 years. Assessment of diet, clinical andlaboratory indicators of nutritional status should beperformed at least annually. A longitudinal assessmentis important.

Q3. What are the causes of malnutrition in CF?A3. Malnutrition in CF has several causes including

intestinal malabsorption, inadequate intake and increasedenergy requirements. Maldigestion and malabsorption,particularly of fat and protein, are early and severe inmost patients. The most important cause is pancreaticinsufficiency with inadequate secretion of enzymes andbicarbonate; other factors include impaired mucosaluptake, altered motility, liver disease and bile salt abnor-malities and structural abnormalities due to previousbowel surgery. Energy intake may be inadequate due topoor appetite secondary to chronic pulmonary and gas-trointestinal disease, acute infection or psychosocialproblems causing abnormal eating behaviour. Energy

requirements are increased due to chronic infection andinflammation, the excessive work of breathing andpossibly secondary to the primary genetic defect.

Q4. Are essential fatty acids reduced in plasma andtissues of CF patients, and which mechanisms areresponsible?

A4. Many CF patients have low plasma and tissuecontents of linoleic acid and of omega-3 long-chainpolyunsaturated fatty acids, such as eicosapentaenoicacid and docosahexaenoic acid. Omega-6 long-chainpolyunsaturated fatty acids such as arachidonic acid aremore variable. These changes have been related to avariety of physiological impairments and adverse effectsand are considered as essential fatty acid deficiency.Possible mechanisms that lead to polyunsaturated fattyacid depletion include fat malabsorption, underweightand negative energy balance with an increased beta-oxidation of polyunsaturated fatty acids, and enhancedperoxidative destruction of polyunsaturated fatty acidsdue to poor antioxidant status and high oxidative stress.Moreover, the conversion of essential fatty acids tolong-chain polyunsaturated fatty acids may be altered,and linoleic acid turnover and arachidonic acid releasefrom phospholipids may be increased.

Q5. Is there evidence for vitamin deficiency?A5. Blood levels of fat-soluble vitamins are frequently

low in patients with CF. Biochemical evidence of vita-min A, vitamin D, vitamin E and vitamin K deficiencyis frequently found even in the absence of clinicalsymptoms. Deficiencies of water-soluble vitamins arerare.

Q6. Is there evidence for mineral and trace elementdeficiency?

A6. Patients with CF are at risk of salt depletion andmetabolic alkalosis in particular during fever, hot weath-er and exercise. They may suffer from mineral and traceelement deficiency, including chloride, sodium, calcium,magnesium, zinc, iron and selenium.

Q7. What is the strategy to prevent malnutrition?A7. Early diagnosis of CF by neonatal screening and

early recognition of CF specific complications and non-CF related disorders, followed by appropriate treatmentsin specialised CF centres including optimal treatment ofpulmonary infection, is recommended. There should befrequent and regular surveillance of the patients includ-ing expert dietary advice. For dietary intake in the firstyear of life the ESPGAN recommendations should befollowed including exclusive breast-feeding in the first4–6 months of life but if necessary a normal infantformula can be used. If the child fails to thrive, earlyintervention is mandatory. If children are gaining weightnormally on a normal diet this can be continued. No fatlimitations and no advice to increase fibre intake shouldbe given. At all ages there should be close attention tobehavioural factors, which may compromise adherenceto medical treatment and food intake. Patients on special


diets(e.g. vegetarians) should be monitored particularlyclosely.

Q8. Does aggressive treatment of pulmonary diseasein CF influence nutritional state?

A8. Malnutrition, infection, inflammation and dis-turbed immune function create a vicious cycle in whicheach factor in turn may exacerbate the other. Effectivetreatment of lung infection has been demonstrated toimprove the nutritional status.

Q9. Does treatment of the nutritional status influencelung disease?

A9. Nutritional interventions have been shown toinhibit the decrease in lung function, thereby improvingsurvival in patients with CF.

Q10. How do we treat pancreatic insufficiency?A10. All patients with CF who have evidence of

malabsorption due to pancreatic insufficiency should betreated with pancreatic enzymes using standard prepa-rations. Special attention has to be paid to other condi-tions if fat malabsorption, poor growth or underweightpersist in spite of adequate dosing. Recommendationsare summarised in Tables 3 and 4.

Q11. What is the significance of fibrosing colonopa-thy (FC)?

A11. Although the exact pathophysiology of FC isstill unknown, the progressive increase in enzyme dosein response to persisting symptoms was a major factorin reaching the very high doses implicated in the causeof fibrosing colonopathy. Enzyme doses in excess of10 000 IU lipaseykg per day should only be used withcaution and after excluding other causes of malabsorp-tion and persisting gastrointestinal symptoms.

Q12. Is there an influence of ursodeoxycholic acid(URSO) on nutritional status in CF patients with CFrelated liver disease?

A12. URSO may enhance biliary bicarbonate secre-tion and bile flow. Some studies have provided indica-tions for positive effects of URSO on biochemicalparameters indicating liver disease, the bioavailabilityof dietary lipids and lipid soluble vitamins, and onweight gain which deserve further evaluation.

Q13. Is there a role for treatment strategies targetingessential fatty acid status in CF patients?

A13. Dietary treatment of CF patients should aim atavoiding subnormal levels of essential fatty acids andlong-chain polyunsaturated fatty acids. Energy, antioxi-dants and polyunsaturated fatty acids of both the omega-6 and the omega-3 series should be adequately suppliedin balanced proportions. Fish oil preparations have ananti-inflammatory effect. Their effect on pulmonaryfunction deserves further evaluation. Similarly, benefi-cial effects of high amounts of DHA in CF mice needto be substantiated in CF patients. CF patients shouldconsume omega-3 fatty acids in amounts as recom-mended for the general population.

Q14. What vitamins need to be supplemented, inwhich doses and how?

A14. In general fat-soluble vitamins should be givento patients with CF. Recommended doses are given inTable 5. Vitamins should be given with a fat containingmeal and pancreatic enzymes. The dose of the vitaminsshould be sufficient to achieve and maintain normalblood concentrations. While there is little risk of over-dosing with vitamins E and K, caution is necessary forvitamins A and D.

Q15. What minerals and trace elements need to besubstituted?

A15. During exercise, in hot environments and duringfever, sodium and chloride supplementation is recom-mended. During long-term treatment with aminoglyco-sides patients with CF may need additional magnesium.Iron and zinc deficiency should be corrected and resultscontrolled biochemically.

Q16. How should we re-feed the malnourished child?A16. In case of malnutrition or weight loss there

should be a full re-evaluation of all the possible causesthat may affect the nutritional state. If nutritional inter-vention is indicated, guidelines can be used. The firstapproach should be to ensure maximal energy intakeusing normal or energy-dense foods. Recommendationsare given in the table. Supplements should be givenbetween or after meals or before bedtime to ensure thatthe appetite for normal food is maintained. Tube feedingcan be administered by naso-gastric tube or by gastros-tomy, patients’ preference determining the choice of theroute. Preferably, tube feeding should be given overnightwith the aim to maintain normal dietary intake. Totalparenteral nutrition is only recommended for specialindications.

Q17. How do we re-feed the malnourished adult?A17. The indication for supplemental feeding either

by oral supplements or tube feeding is the same inadults as in older children and adolescents. Monitoringfor impaired glucose tolerance is needed. Psychosocialissues including body image should be addressed. Anexercise-training program with the aim to increase leanbody weight should accompany re-feeding in adoles-cents and adults.

Q18. Should anabolic steroids be used in re-feedingthe malnourished CF patient?

A18. In a very limited number of CF patients it hasbeen shown that megestrol acetate, a progestagon, maytemporarily lead to an increased appetite, an increase inbody weight with an increase in lean body mass andpulmonary function. Disadvantages are the possibledevelopment of diabetes, inhibition of growth, adrenalsuppression, cardiomyopathy and behavioural problemsincluding depression. Because of the side effects andthe limited data available, anabolic medication shouldnot be used in routine clinical practice.


Q19. Which future studies should be carried out tofind more evidence for optimal nutrition in CF?

1. Long-term studies concerning the effect of antioxi-dants, particularly studies involving vitamin E, C,b-carotene and selenium, on clinical progress, res-piratory function and nutritional status.

2. Long-term supplementation studies measuring vita-min K status and bone mineral density. The relation-ship between antibiotic therapy, gut flora and vitaminK status should be studied. In general drug-nutrientinteractions should be determined and studied.

3. Quality vs. quantity in nutritional support.4. Eating disorders and behaviour—categorisation, pre-

vention, treatment and intervention studies.5. Factors affecting adherence to enzyme therapy.6. Reasons for failure to correct levels of nutrients.7. Optimal levels of various nutrients for people with

CF.8. Evaluation of appetite stimulants.9. Value of new prokinetic drugs.10. Benefit of specific anti-inflammatory treatment, e.g.

anti-TNF.11. Role of leptins in cystic fibrosis.12. Value of high-energy oral supplements.13. Ideal feeds for enteral feeding.14. Best enzyme regimen for overnight feeds.15. Possibility of delaying pancreatic insufficiency.16. Role of acid suppression in improving steatorrhoea.17. Optimal prevention and management of

osteoporosis.18. Confirmation and study of reduced head circumfer-

ence brain development and fatty acid status duringinfancy.

19. Early intervention in the development of diabetesmellitus. At what stage do we intervene?

20. Use of anabolic steroids.21. Treatment with DHA or fish oil.22. Role of probiotics in nutrition and infection.23. Effect on nutritional status of continuous antimicro-

bial treatment, started soon after diagnosis followingneonatal screening.

24. Optimisation of oral supplements.25. Further knowledge of the homeostasis of calcium,

the lipid peroxidation and role of selenium and zincdeficiency in young children.

26. The potential effects of URSO on nutritional status,in subgroups of patients with CF who have differentdisease states and conditions.

27. The effects of supplying increased intakes of specificfatty acids, and of groups of fatty acids such aslong-chain omega-3 fatty acids, should be evaluated.

28. Relationship of fatty acids and immune functionsand neurological development.

References

w1x Lewis PA. The epidemiology of cystic fibrosis. In: HodsonME, Geddes D, editors. 2nd ed. Cystic fibrosis. London:Arnold; 2000.

w2x Santis G. Basic molecular biology. In: Hodson ME, GeddesD, editors. 2nd ed. Cystic fibrosis. London: Arnold; 2000.

w3x Sheppard MN. The pathology of cystic fibrosis. In: HodsonME, Geddes D, editors. 2nd ed. Cystic fibrosis. London:Arnold; 2000.

w4x Sharma R, Florea VG, Bolger AP, et al. Wasting as anindependent predictor of mortality in patients with cysticfibrosis. Thorax 2001;56:746–50.

w5x Mearns MB. Growth and development. In: Hodson ME, Nor-man AP, Batten JC, editors. Cystic fibrosis. London: BailliereTindall; 1983. p. 183–96.

w6x Holliday KE, Allen JR, Waters DL, Gruca MA, ThompsonSM, Gaskin KJ. Growth of human milk-fed and formula-fedinfants with cystic fibrosis. J Pediatr 1991;118:77–9.

w7x Simmonds EJ, Wall CR, Wolfe SP, Littlewood JM. A reviewof infant feeding practices at a regional cystic fibrosis unit. JHum Nutr Diet 1994;7:31–8.

w8x Ghosal S, Taylor CJ, Pickering M, et al. Disproportionate headgrowth retardation in cystic fibrosis. Arch Dis Child1995;72:150–2.

w9x Farrell PM, Kosorok MR, Rock MJ, et al. Early diagnosis ofcystic fibrosis through neonatal screening prevents severemalnutrition and improves long-term growth. Wisconsin CysticFibrosis Neonatal Screening Study Group. Pediatrics2001;107:1–13.

w10x Corey M, McLaughlin FJ, Williams M, Levison H. A compar-ison of survival, growth and pulmonary function in patientswith cystic fibrosis in Boston and Toronto. J Clin Epidemiol1988;41:583–91.

w11x Karlberg J, Kjellmer I, Kristianssson B. Linear growth inchildren with cystic fibrosis. Acta Paediatr Scand1991;80:508–14.

w12x Waters DL, Wilcken B, Irwig L, et al. Clinical outcomes ofnewborn screening for cystic fibrosis. Arch Dis Child1999;80:F1–F7.

w13x Cystic Fibrosis Foundation. Patient Registry 1998 Annual DataReport. Bethesda, MD: Cystic Fibrosis Foundation, 1999.

w14x Hui-Chuan L, Kosorok MR, Sondel SA, et al. Growth statusin children with cystic fibrosis based on the National CysticFibrosis Patient Registry data: evaluation of various criteriaused to identify malnutrition. J Pediatr 1998;132:478–85.

w15x Cole TJ, Freeman JV, Preece MA. Body mass index referencecurves for the UK, 1990. Arch Dis Child 1995;73:25–9.

w16x Morison S, Dodge JA, Cole TJ, et al. Height and weight incystic fibrosis: a cross sectional study. UK Cystic FibrosisSurvey Management Committee. Arch Dis Child 1997;77:497–500.

w17x Littlewood JM, Wolfe SP. Growth, development and nutrition.In: Hodson ME, Geddes DM, editors. 2nd ed. Cystic fibrosis.London: Arnold; 2000.

w18x Weltman EA, Stern RC, Doershuk CF, Moir RN, Palmer K,Jaffe AC. Weight and menstrual function in patients witheating disorders and cystic fibrosis. Pediatrics 1990;85:282–7.

w19x Johannesson M, Gottlieb C, Hjelte L. Delayed puberty in girlswith cystic fibrosis despite good clinical status. Pediatrics1997;99:29–34.

w20x Byard PJ. The adolescent growth spurt in cystic fibrosis. AnnHum Biol 1994;21:229–40.

w21x Ramsey BW, Farrell PM, Pencharz P. Nutritional assessmentand management in cystic fibrosis: a consensus report. TheConsensus Committee. Am J Clin Nutr 1992;55:108–16.


w22x Littlewood JM. Gastrointestinal complications of cystic fibro-sis. J R Soc Med 1992;85(Suppl 19):13–9.

w23x Poustie VJ, Watling RM, Ashby D, Smyth RL. Reliability ofpercentage ideal weight for height. Arch Dis Child2000;88:183–4.

w24x Buckler JMH. A Reference Manual of Growth and Develop-ment. 2nd ed. Oxford: Blackwell Science, 1997.

w25x Tanner JM, Whitehouse RH. Clinical longitudinal standardsfor height, weight, height velocity, weight velocity and thestages of puberty. Arch Dis Child 1976;51:1170–9.

w26x Freeman JV, Cole TJ, Chinn S, Jones PRM, White EM, PreeceMA. Cross-sectional stature and weight reference curves forthe UK, 1990. Arch Dis Child 1995;73:17–24.

w27x Van’t Hof MA, Haschke F. Euro-Growth references for bodymass index and weight for length. J Pediatr Gastroenterol Nutr2000;31(Suppl 1):S48–S59 (and the Euro-growth study group).

w28x Shin J, Corey M, Kalnins D, Pencharz P. A comparison ofanthropomorphic standards for evaluation of CF patients.Pediatr Pulmonol 1997;14(Suppl):312.

w29x International Obesity Task Force. Obesity; preventing andmanaging the global epidemic. Report of the WHO consultationon obesity, Geneva, 3–5th June 1998. Geneva: WHO, 1998.

w30x Cole TJ, Belizzi MC, Flegal KM, Dietz WH. Establishing astandard definition for child overweight and obesity worldwide:international survey. Br Med J 2000;320:1240–3.

w31x Johnston JL, Leong MS, Checkland EG, Zuberbuhler PC,Conger PR. Body fat assessed from body density and estimatedfrom skinfold thickness in normal children and children withcystic fibrosis. Am J Clin Nutr 1988;48:1362–6.

w32x Newby MJ, Kiem NL, Brown DL. Body composition of adultcystic fibrosis patients and control subjects as determined bydensitometry, bioelectrical impedance, total electrical bodyconductivity, skinfold measurements and deuterium oxide dilu-tion. Am J Clin Nutr 1990;52:209–13.

w33x Shepherd RW, Holt TL, Greer R, Cleghorn GJ, Thomas BJ.Total body potassium in cystic fibrosis. J Pediatr GastroenterolNutr 1989;9:200–5.

w34x Greer R, Shepherd R, Cleghorn G, Bowling FG, Holt T.Evaluation of growth and changes in body composition follow-ing neonatal diagnosis of cystic fibrosis. J Pediatr GastroenterolNutr 1991;13:52–8.

w35x Azcue M, Fried M, Pencharz PB. Use of bioelectrical impe-dance analysis to measure total body water in patients withcystic fibrosis. J Pediatr Gastroenterol Nutr 1993;16:440–5.

w36x Slosman DO, Casez JP, Pichard C, et al. Assessment of wholebody composition with dual-energy X-ray absorptiometry.Radiology 1992;185:593–8.

w37x Henderson RC, Madsen CD. Bone mineral density in childrenand adults with cystic fibrosis. J Pediatr 1996;128:28–34.

w38x Haworth CS, Selby PL, Webb AK, et al. Low bone mineraldensity in adults with cystic fibrosis. Thorax 1999;54:961–7.

w39x Littlewood JM. Abdominal pain in cystic fibrosis. J R SocMed 1995;88(Suppl. 25):9–17.

w40x Mullins PE, Liechti-Gallati S, Di Silvio L, Brook CG, Paes-Alves AF. Short stature in a patient with cystic fibrosis causedby a 6.7-kb human growth hormone deletion. Horm Res1991;36:4–8.

w41x Shaw NJ, Fraser NC, Weller PH. Asthma treatment and growth.Arch Dis Child 1997;77:284–6.

w42x Littlewood JM. Value of comprehensive assessment and inves-tigation in the management of cystic fibrosis. In: Escobar H,Basquero L, Suarez L, editors. Clinical ecology of cysticfibrosis.Elsevier; 1993. p. 181–7.

w43x Kennedy JD, Dinwiddie R, Daman-Williams C, Dillon MJ,Matthew DJ. Pseudo Bartter’s syndrome in cystic fibrosis.Arch Dis Child 1990;65:786–7.

w44x Bronstein MN, Sokol RJ, Abman SH, et al. Pancreatic insuf-ficiency, growth, and nutrition in infants identified by newbornscreening as having cystic fibrosis. J Pediatr 1992;120:533–40.

w45x Kristidis P, Bozon D, Corey M, et al. Genetic determinationof exocrine pancreatic function in cystic fibrosis. Am J HumGenet 1992;50:1178–84.

w46x Couper R, Corey M, Durie PR, et al. Longitudinal evaluationof serum trypsinogen measurement in pancreatic-insufficientand pancreatic sufficient patients with cystic fibrosis. J Pediatr1995;127:408–13.

w47x Balasubramanian K, Zenther-Munro P, Batten JC, et al.Increased intragastric acid-resistant activity and lipolysis inpancreatic steatorrhoea due to cystic fibrosis. Pancreas1992;7:305–10.

w48x Hoffman R, Isenberg JN, Powell GK. Carbohydrate malabsorp-tion is normal in school age cystic fibrosis children. Dig DisSci 1987;32:1071–4.

w49x Zentler-Munro PL. Pancreatic exocrine insufficiency and cysticfibrosis. Curr Opin Gastroenterol 1989;5:706–10.

w50x Robinson PJ, Smith AL, Sly PD. Duodenal pH in cysticfibrosis and its relationship to fat malabsorption. Dig Dis Sci1990;35:1299–304.

w51x Zentler-Munro PL, Fitzpatrick JWF, Batten JC, et al. Effect ofintraduodenal acidity on aqueous phase bile acid and lipidconcentrations in pancreatic steatorrhoea due to cystic fibrosis.Gut 1984;25:500–7.

w52x Walters MP, Littlewood JM. Faecal bile acid and dietary residueexcretion in cystic fibrosis: age group variations. J PediatrGastroenterol Nutr 1998;27:296–300.

w53x Roy CC, Weber AM, Morin CL, et al. Abnormal biliarycomposition in cystic fibrosis. Effect of pancreatic enzymes. NEngl J Med 1977;292:1301–5.

w54x Sinaasappel M. Relationship between intestinal function andchloride secretion in patients with cystic fibrosis. NetherlandsJ Med 1992;41:110–4.

w55x Kalivianakis M, Minich DM, Bijleveld CMA, et al. Fatmalabsorption in cystic fibrosis patients receiving enzymereplacement therapy is due to impaired intestinal uptake oflong chain fatty acids. Am J Clin Nutr 1999;69:127–34.

w56x Dalzell AM, Freestone NS, Billington D, et al. Small intestinalpermeability and oro-caecal transit time in cystic fibrosis. ArchDis Child 1990;65:585–8.

w57x Oppenheimer EH, Esterly JR. Pathology of cystic fibrosis.Review of the literature and comparison with 146 autopsiedcases. Perspect Pediatr Pathol 1975;2:241–78.

w58x Borowitz DS, Grand RJ, Durie PR. Fibrosing colonopathy inpatients with cystic fibrosis. J Pediatr 1995;127:681–4.

w59x Gilbert J, Kelleher J, Walters MP, Littlewood JM. Markers forfaecal fat estimation in monitoring steatorrhoea in cysticfibrosis. Gut 1988;29:1286–8.

w60x Bekers O, Postma C, Lombarts AJ. Determination of faecal fatby near-infrared spectroscopy. Eur J Clin Chem Clin Biochem1995;33:83–6.

w61x Van de Kamer JH, ten Bokkel Huinink H, Weyers HA. Rapidmethod for the determination of fat in faeces. J Biol Chem1949;177:347–55.

w62x Walters MP, Kelleher J, Gilbert J, Littlewood JM. Clinicalmonitoring of steatorrhoea in cystic fibrosis. Arch Dis Child1990;63:99–102.

w63x Van der Neucker A, Pestel A, Tran TM, et al. Clinical use ofacid steatocrit. Acta Paediatr 1997;86:466–9.

w64x Brown GA, Sule D, Williams J, et al. Faecal chymotrypsin: areliable index of exocrine pancreatic function. Arch Dis Child1988;63:785–9.


w65x Soldan W, Henker J, Sprossig C. Sensitivity and specificity ofquantitative determination of pancreatic elastase 1 in feces ofchildren. J Pediatr Gastroenterol Nutr 1997;24:53–5.

w66x Cade A, Walters MP, McGinley N, et al. Evaluation of fecalelastase-1 as a measure of pancreatic exocrine function inchildren with cystic fibrosis. Pediatr Pulmonol 2000;29:172–6.

w67x Amarri S, Harding M, Coward WA, et al. 13 carbon mixedtriglyceride breath test and pancreatic supplementation in cysticfibrosis. Arch Dis Child 1997;76:349–51.

w68x Kalivianakis M, Elstrodt J, Havinga R, et al. Validation in ananimal model of the carbon 13-labeled mixed triglyceridebreath test for the detection of intestinal fat malabsorption. JPediatr 1999;135:444–50.

w69x Brown RC, Chalmers DM, Rowe VL, Kelleher J, LittlewoodJM, Losowsky MS. Comparison of the diagnostic value ofserum pancreatic isoamylase and immunoreactive trypsin meas-urement in patients with cystic fibrosis. J Clin Pathol1982;35:547–9.

w70x Reilly JJ, Evans TJ, Wilkinson J, Paton JY. Adequacy ofclinical formulae for estimation of energy requirements inchildren with cystic fibrosis. Arch Dis Child 1999;81:120–4.

w71x Thomson MA, Bucolo S, Quirk P, Shepherd RW. Measuredversus predicted resting energy expenditure in infants: a needfor reappraisal. J Pediatr 1995;126:21–7.

w72x Bell SC, Saunders MJ, Elborn JS, Shale DJ. Resting energyexpenditure and oxygen cost of breathing in patients withcystic fibrosis. Thorax 1996;51:126–31.

w73x Burdet L, Hugli O, Aubert JD, Schutz Y, Roulet M, FittingJW. Effect of elective antibiotic therapy on resting energyexpenditure and inflammation in cystic fibrosis. Eur J Pediatr1999;158:711–6.

w74x Stallings VA, Fung EB, Hofley PM, Scanlin TF. Acute pul-monary exacerbation is not associated with increased energyexpenditure in children with cystic fibrosis. J Pediatr1998;132:493–9.

w75x Steinkamp G, Drommer A, von der H. Resting energy expen-diture before and after treatment for Pseudomonas aeruginosainfection in patients with cystic fibrosis. Am J Clin Nutr1993;57:685–689.

w76x Bell SC, Bowerman AM, Nixon LE, Macdonald IA, ElbornJS, Shale DJ. Metabolic and inflammatory responses to pul-monary exacerbation in adults with cystic fibrosis. Eur J ClinInvest 2000;30:553–9.

w77x Wilmott RW, Frenzke M, Kociela V, Peng L. Plasma interleu-kin-1 alpha and beta, tumor necrosis factor-alpha, and lipopo-lysaccharide concentrations during pulmonary exacerbations ofcystic fibrosis. Pediatr Pulmonol 1994;18:21–7.

w78x Amin N, Dozor AJ. Effects of administration of aerosolizedrecombinant human deoxyribonuclease on resting energyexpenditure in patients with cystic fibrosis. Pediatr Pulmonol1994;18:150–4.

w79x McCloskey M, Redmond AO, Pyper S, et al. Total energyexpenditure in stable patients with cystic fibrosis. Clin Nutr2001;20:235–41.

w80x O’Rawe A, McIntosh I, Dodge JA, et al. Increased energyexpenditure in cystic fibrosis is associated with specific muta-tions. Clin Sci 1992;82:71–6.

w81x Zemel BS, Kawchak DA, Cnaan A, Zhao H, Scanlin TF,Stallings VA. Prospective evaluation of resting energy expen-diture, nutritional status, pulmonary function, and genotype inchildren with cystic fibrosis. Pediatr Res 1996;40:578–86.

w82x Thomson MA, Wilmott RW, Wainwright C, Masters B, FrancisPJ, Shepherd RW. Resting energy expenditure, pulmonaryinflammation, and genotype in the early course of cysticfibrosis. J Pediatr 1996;129:367–73.

w83x Fried MD, Durie PR, Tsui LC, Corey M, Levison H, PencharzPB. The cystic fibrosis gene and resting energy expenditure. JPediatr 1991;119:913–6.

w84x Tomezsko JL, Stallings VA, Kawchak DA, Goin JE, DiamondG, Scanlin TF. Energy expenditure and genotype of childrenwith cystic fibrosis. Pediatr Res 1994;35:451–60.

w85x Vaisman N, Levy LD, Pencharz PB, et al. Effect of salbutamolon resting energy expenditure in patients with cystic fibrosis.J Pediatr 1987;111:137–9.

w86x Morrison JM, O’Rawe A, McCracken KJ, Redmond AOB,Dodge JA. Energy intakes and losses in cystic fibrosis. J HumNutr Diet 1994;7:39–46.

w87x Collins CE, O’Loughlin EV, Henry R. Discrepancies betweenmales and females with cystic fibrosis in dietary intake andpancreatic enzyme use. J Pediatr Gastroenterol Nutr1998;26:258–62.

w88x Nasr SZ, Hurwitz ME, Brown RW, Elghoroury M, Rosen D.Treatment of anorexia and weight loss with megestrol acetatein patients with cystic fibrosis. Pediatr Pulmonol 2000;29:244.

w89x Marcand V, Baker SS, Stark TJ, Baker RD. Randomized,double blind, placebo-controlled pilot trial of megestrol acetatein malnourished children with cystic fibrosis. J Pediatr Gas-troenter Nutr 2000;31:264–9.

w90x Eubanks V, Atchinson J, Arani R, et al. Effects of megestrolacetate on energy intake, weight gain, body composition, andresting energy expenditure in cystic fibrosis patients. PediatrPulmonol 2000;20(Suppl):A518.

w91x Hardin DS, Ellis KJ, Dyson M, et al. Growth hormoneimproves clinical status in prepubertal children with cysticfibrosis: results of a randomized controlled trial. J Pediatr2001;139(5):636–42.

w92x Colombo C, Crosignani A, Battezzati M. Liver involvement incystic fibrosis. J Hepatol 1999;31:946–54.

w93x Linblad A, Glaumann H, Strandvik B. Natural history of liverdisease in cystic fibrosis. Hepatology 1999;30:1151–8.

w94x Sokol RJ, Durie PR. J Pediatr Gastroenterol Nutr 1999;28:S1–S13 (for the Cystic Fibrosis Foundation Hepatobiliary DiseaseConsensus Group).

w95x Ling SC, Amarri S, Slater C, Hollman AS, Preston T, WeaverLT. Liver disease does not affect lipolysis as measured withthe C-mixed triacylglycerol breath test in children with cystic13

fibrosis. J Pediatric Gastroenterol Nutr 2000;30:368–72.w96x Cotting J, Lentze MJ, Reichen J. Effects of ursodeoxycholic

acid treatment on nutrition and liver function in patients withcystic fibrosis and long-standing cholestasis. Gut 1990;31:918–21.

w97x Merli M, Bertasi S, Servi R, et al. Effect of a medium dose ofursodeoxycholic acid with or without taurine supplementationon the nutritional status of patients with cystic fibrosis: arandomized, placebo controlled, crossover trial. J Pediatr Gas-troenterol Nutr 1994;19:198–203.

w98x Noble-Jamieson G, Barnes N, Jamieson N, Friend P, Calne R.Liver transplantation for hepatic cirrhosis in cystic fibrosis. JR Soc Med 1996;89(Suppl 27):31–7.

w99x Lanng S, Thorsteinsson B, Nerup J, Koch C. Glucose tolerancein cystic fibrosis. Arch Dis Child 1991;66:612–6.

w100x Moran A, Hardin D, Rodman D, et al. Diagnosis, screeningand management of cystic fibrosis related diabetes mellitus. Aconsensus conference report. Diabetes Res Clin Pract1999;45:61–73.

w101x Strandvik B, Brobbegard M, Gilljam H, Carlstedt-Duke J.¨Relation between defective regulation of arachidonic acidrelease and symptoms in cystic fibrosis. Scand J GastroenterolSuppl 1988;143:1–4.


w102x Strandvik B. Relation between essential fatty acid metabolismand gastrointestinal symptoms in cystic fibrosis. Acta PaediatrScand Suppl 1989;363:58–65.

w103x Strandvik B, Gronowitz E, Enlund F, Martinsson T, WahlstromJ. Essential fatty acid deficiency in relation to genotype inpatients with cystic fibrosis. J Pediatr 2001;139:650–5.

w104x Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY,Alvarez JG. A membrane lipid imbalance plays a role in thephenotypic expression of cystic fibrosis in cftryyy mice.Proc Natl Acad Sci USA 1999;96:13995–4000.

w105x Steinkamp G, Demmelmair H, Ruhl-Bagheri I, von der HardtH, Koletzko B. Energy supplements rich in linoleic acidimprove body weight and essential fatty acid status of cysticfibrosis patients. J Pediatr Gastroenterol Nutr 2000;31:418–23.

w106x Korotkova M, Strandvik B. Essential fatty acid deficiencyaffects the fatty acid composition of the rat small intestinaland colonic mucosa differently. Biochim Biophys Acta2000;1487:319–25.

w107x Roulet M, Franscarolo P, Rappaz I, Pilet M. Essential fattyacid deficiency in well nourished young cystic fibrosis patients.Eur J Pediatr 1997;156:952–6.

w108x Carlstedt-Duke J, Bronnegard M, Strandvik B. Pathologicalregulation of arachidonic acid release in cystic fibrosis: theputative basis defect. Proc Natl Acad Sci USA1986;83(23):9202–6.

w109x Lepage G, Paradis K, Lacaille F, et al. Ursodeoxycholic acidimproves the hepatic metabolism of essential fatty acids andretinol in children with cystic fibrosis. J Pediatr 1997;130:52–8.

w110x Lancellotti L, D’Orazio C, Mastella G, Mazzi G, Lippi U.Deficiency of vitamins E and A in cystic fibrosis is independentof pancreatic function and current enzyme and vitamin supple-mentation. Eur J Pediatr 1996;155:281–5.

w111x Navarro J, Desquilbet N. Depressed vitamin A and Retinolbinding protein in cystic fibrosis. Effects of zinc supplemen-tation. Am J Clin Nutr 1998;34:1439–40.

w112x Lindblad A, Diczfalusy U, Hultcrantz R, Thorell A, StrandvikB. Vitamin A concentration in the liver decreases with age inpatients with cystic fibrosis. J Pediatr Gastroenterol Nutr1997;24:264–70.

w113x Huet F, Semama D, Maingueneau C, Charavel A, Nivelon JL.Vitamin A deficiency and nocturnal vision in teenagers withcystic fibrosis. Eur J Pediatr 1997;156:949–51.

w114x Brooks HL, Driebe WT, Schemmer GG. Xerophthalmia andcystic fibrosis. Arch Ophthalmol 1990;108:354–7.

w115x Raybner RJ, Tyrrell JC, Hiller EJ, et al. Night blindness andconjunctival xerosis caused by vitamin A deficiency in patientswith cystic fibrosis. Arch Dis Child 1989;641:151–6.

w116x Carr SB, Dinwiddie R. Annual review or continuous assess-ment? J R Soc Med 1996;89(Suppl 27):3–7.

w117x Feranchak AP, Sontag MK, Wagener JS, Hammond KB,Accurso FJ, Sokol RJ. Prospective, long-term study of fat-soluble vitamin status in children with cystic fibrosis. J Pediatr1999;135:601–10.

w118x Coppenhaver D, Kneppers F, Schidlow D, et al. Serum con-centrations of vitamin D-binding protein(group-specific com-ponent) in cystic fibrosis. Hum Genet 1981;57:399–403.

w119x Henderson RC, Madsen CD. Bone mineral content and bodycomposition in children and young adults with cystic fibrosis.Pediatr Pulmonol 1999;27:80–4.

w120x Donovan DS, Papadopoulos A, Staron RB, et al. Bone massand vitamin D deficiency in adults with advanced cysticfibrosis lung disease. Am J Respir Crit Care Med1998;157:1892–9.

w121x Brown RK, Wyatt H, Price JF, Kelly FJ. Pulmonary dysfunctionin cystic fibrosis is associated with oxidative stress. Eur RespirJ 1996;9:334–9.

w122x Winklhofer-Roob BM, Shmerling DH, Schimek MG, Tuchs-chmid PE. Short-term changes in erythrocytea-tocopherolcontent of vitamin E-deficient patients with cystic fibrosis. AmJ Clin Nutr 1992;55:100–3.

w123x Skopnik H, Kusenbach G, Bergt U, et al. Taurine supplemen-tation in cystic fibrosis(CF): effect on vitamin E absorptionkinetics. Klin Pediatr 1991;203:28–32.

w124x Thomas PS, Bellamie M, Geddes D. Malabsorption of vitaminE in cystic fibrosis improved after ursodeoxycholic acid. Lancet1995;346:1230–1.

w125x Winklhofer-Roob BM, Ziouzenkova O, Puhl H, et al. Impairedresistance to oxidation of low density lipoprotein in cysticfibrosis: improvement during vitamin E supplementation. FreeRadic Biol Med 1995;19:725–33.

w126x Swann IL, Kendra JR. Anemia, vitamin E deficiency andfailure to thrive in an infant. Clin Lab Haematol 1998;20:61–3.

w127x Bye AME, Muller DPR, Wilson J, Wright VM, Mearns MB.Symptomatic vitamin E deficiency in cystic fibrosis. Arch DisChild 1985;60:163–4.

w128x Vaisman N, Tabachnik E, Shahar E, Gilai A. Impaired brain-stem auditory evoked potentials in patients with cystic fibrosis.Dev Med Child Neurol 1996;38:59–64.

w129x De Schepper J, Hachimi Idrissi S, Dab I, Schmedding E. Nerveconduction in vitamin E deficient cystic fibrosis patients. EurJ Pediatr 1997;156:251–2.

w130x De Vriese S, Robberecht E, De Gussem J, Christophe A.FEV correlates with plasma vitamin E in young cystic fibrosis1

(CF) patients: an argument for early administration? Nether-lands J Med 54:S61,A144.

w131x Durie PR. Vitamin K and the management of patients withcystic fibrosis. Can Med Assoc J 1994;151:933–6.

w132x Weber P. Management of osteoporosis: is there a role forvitamin K? Int J Vitam Nutr Res 1997;67:350–6.

w133x Rashid M, Durie P, Andrew M, et al. Prevalance of vitamin Kdeficiency in cystic fibrosis. Acta Pediatr 1999;70:378–82.

w134x Beker LT, Ahrens RA, Fink RJ, et al. Effect of vitamin K1supplementation on vitamin K status in cystic fibrosis patients.J Pediatr Gastroenterol Nutr 1997;24:512–7.

w135x Wilson DS, Ahrens RA, Fink RJ, et al. Treatment of vitaminK deficiency in cystic fibrosis: effectiveness of a daily fat-soluble vitamin combination. J Pediatr 2001;138:851–5.

w136x Gueant JL, Champigneulle B, Gaucher P, Nicolas JP. Malab-sorption of vitamin B12 in pancreatic insufficiency of the adultand of the child. Pancreas 1990;5:559–67.

w137x Winklhofer-Roob BM, Ellemunter H, Fruhwirth M, et al.Plasma vitamin C concentrations in patients with cystic fibro-sis: evidence of association with lung inflammation. Am J ClinNutr 1997;65:1858–66.

w138x Legris GJ, Dearborn D, Stern RC, et al. Sodium space andintravascular volume: dietary sodium effects in Cystic Fibrosisand healthy adolescent subjects. Pediatrics 1998;101:48–56.

w139x Laursen EM, Mølgaard C, Michaelsen KF, Koch C, Muller J.¨Bone mineral status in 134 patients with cystic fibrosis. ArchDis Child 1999;81:235–40.

w140x Salamoni F, Roulet M, Gudinchet F, Pilet M, Thiebaud D,Burckhardt D. Bone mineral content in cystic fibrosis patients:correlation with fat-free mass. Arch Dis Child 1996;74:314–8.

w141x Haworth CS, Webb AK, Egan JJ, et al. Bone histomorphometryin adult patients with cystic fibrosis. Chest 2000;118:434–9.

w142x Aris RM, Lester GE, Dingman S, Ontjes DA. Altered calciumhomeostatis in adults with cystic fibrosis. Osteoporos Int1999;10:102–8.


w143x Akbar A, Rees JH, Nyamugunduru G, English MW, SpencerDA, Weller PH. Aminoglycoside-associated hypomagnesaemiain children with cystic fibrosis. Acta Paediatr 1999;7:783–5.

w144x Zempsky WT, Rosenstein BJ, Carroll JA, Oski FA. Effect ofpancreatic enzyme supplements in iron absorption. Am J DisChild 1989;143(8):969–72.

w145x Krebs NF, Sontag M, Accurso FJ, Hambidge KM. Low plasmazinc concentrations in young infants with cystic fibrosis. JPediatr 1998;12:761–4.

w146x Easley D, Krebs N, Jefferson M, et al. Effect of pancreaticenzymes on zinc absorption in cystic fibrosis. J Pediatr Gas-troenterol Nutr 1998;26:136–9.

w147x Percival SS, Bowser E, Wagner M. Reduced copper enzymeactivities in blood cells of children with cystic fibrosis. Am JClin Nutr 1995;62:633–8.

w148x Portal BC, Richard MJ, Faure HS, Hadjian AJ, Favier AE.Altered antioxidant status and increased lipid peroxidation inchildren with cystic fibrosis. Am J Clin Nutr 1995;61:843–7.

w149x Winklhofer-Roob BM, Tiran B, Tuchschmid PE, van ‘t HofMA, Shmerling DH. Effects of pancreatic enzyme preparationson erythrocyte glutathione peroxidase activities and plasmaselenium concentrations in cystic fibrosis. Free Radic BiolMed 1998;25:242–9.

w150x Bougle D, Bureau F, Voirin J, Neuville D, Drosdowsky M,Duhamel JF. Plasma chromium concentrations in normal infantsand cystic fibrosis patients. Biol Trace Element Res1992;32:53–5.

w151x Roum JH, Buhl R, McElvaney NG, Borok Z, Crystal RG.Systemic deficiency of glutathione in cystic fibrosis. J ApplPhysiol 1993;75:2419–24.

w152x Linsdell P, Hanrahan JW. Glutathione permeability of CFTR.Am J Physiol 1998;275:C323–C326.

w153x Lands LC, Grey V, Smountas AA, Kramer VG, McKenna D.Lymphocyte glutathione levels in children with cystic fibrosis.Chest 1999;116:201–5.

w154x Winklhofer-Roob BM, Puhl H, Khoschsorur G, van ‘t HofMA, Esterbauer H, Shmerling DH. Enhanced resistance tooxidation of low density lipoproteins and decreased lipidperoxide formation duringb-carotene supplementation in cysticfibrosis. Free Radic Biol Med 1995;18:849–59.

w155x Lepage G, Champagne J, Ronco N, et al. Supplementationwith carotenoids corrects increased lipid peroxidation in chil-dren with cystic fibrosis. Am J Clin Nutr 1996;65:87–93.

w156x Rust P, Eichler I, Renner S, Elmadfa I. Effects of long-termoral b-carotene supplementation on lipid peroxidation inpatients with cystic fibrosis. Int J Vitam Nutr Res 1998;68:83–7.

w157x Winklhofer-Roob BM, Schlegel-Haueter SE, Khoschsorur G,van ‘t Hof MA, Suter S, Shmerling DH. Neutrophil elastaseya 1-proteinase inhibitor complex levels decrease in plasma ofcystic fibrosis patients during long-term oralb-carotene sup-plementation. Pediatr Res 1996;40:130–4.

w158x Collins CE, O’Loughlin EV, Henry RL. Fat gram target toachieve high energy intake in cystic fibrosis. J Pediatr ChildHealth 1997;31:142–7.

w159x Gavin J, Ellis J, Dewar AL, et al. Dietary fibre and theoccurrence of gut symptoms in cystic fibrosis. Arch Dis Child1997;76:35–7.

w160x Farrell P, Mischler EH, Sondel S, et al. Predigested formulafor infants with cystic fibrosis. J Am Diet Assoc1987;93:1353–6.

w161x Ellis L, Kalnins D, Corey M, Brennan J, Pencharz P, Durie P.Do infants with cystic fibrosis need a protein hydrolysateformula? A prospective, randomized, comparative study. JPediatr 1998;132:270–6.

w162x Hill SM, Phillips AD, Mearns M, Walker-Smith JA. Cows’milk sensitive enteropathy in cystic fibrosis. Arch Dis Child1989;64:1251–5.

w163x Vic P, Ategbo S, Gottrand F, et al. Nutritional impact ofantipseudomonas intravenous antibiotic courses in cystic fibro-sis. Arch Dis Child 1997;76:437–40.

w164x Reilly JJ, Ralston JM, Paton JY, et al. Energy balance duringacute exacerbations in children with cystic fibrosis. Eur RespirJ 1999;13:804–9.

w165x Burdet L, Huglo O, Aubert JD, Schutz Y, Roulet M, FittingJW. Effect of elective antibiotic therapy on resting energyexpenditure and inflammation in cystic fibrosis. Eur J Pediatr1999;158:71–6.

w166x Doring G, Conway SP, Heijerman HGM, et al. Antibiotictherapy againstPseudomonas aeruginosa in cystic fibrosis: aEuropean consensus. Eur Respir J 2000;16:749–67.

w167x Atkinson SN. A comparative study of enzyme activity acidresistance and dissolution characteristics of four enteric coatedmicrosphere preparations of pancreatic enzymes. Eur J ClinRes 1991;1:37–45.

w168x Brady MS, Rickard KA, Yu PL, et al. Effectiveness and safetyof small vs. large doses of enteric coated pancreatic enzymesin reducing steatorrhoea in children with cystic fibrosis: arandomized prospective study. Pediatr Pulmonol 1991;10:79–85.

w169x Beker LT, Fink RJ, Shamas FH, et al. Comparison of weightbased dosages of enteric-coated microtablet enzyme prepara-tions in patients with cystic fibrosis. J Pediatr GastroenterolNutr 1994;19:191–7.

w170x Sinaasappel M, Swart GR, Hoekstra JH, et al. Double blind,cross over study to prove the equivalence of Creon 10,000minimicrospheres versus Creon 8000 microspheres in patientswith cystic fibrosis. Pediatr Pulmonol ; Suppl :358, P1998;17:536.

w171x Chazalette JP. A double blind placebo controlled trial of apancreatic enzyme formulation(Panzytrat 25,000) in the treat-ment of impaired lipid digestion in patients with cystic fibrosis.Drug Invest 1993;5:274–80.

w172x Bowler IM, Wolfe SP, Owens HM, Sheldon TA, LittlewoodJM, Walters MP. A double blind lipase for lipase comparisonof a high and standard pancreatic enzyme preparation in cysticfibrosis. Arch Dis Child 1993;68:227–30.

w173x Taylor CJ, McGaw J, Ghosal S, et al. Evaluation of Creon25,000 compared to standard lipase pancreatic enzyme supple-mentation in cystic fibrosis patients. Israel J Med Sci1996;32:S220.

w174x Durie PR, Kalnins D, Ellis L. Uses and abuses of enzymetherapy in cystic fibrosis. J Roy Soc Med 1998;91(Suppl34):2–13.

w175x Committee on Safety of Medicines. Report of the PancreaticEnzymes Working Party, London. 1995.

w176x Littlewood JM. Implications of the Committee on Safety ofMedicines 10,000 IU lipaseykgyday recommendation for useof pancreatic enzymes in cystic fibrosis. Arch Dis Child1996;74:466–8.

w177x Anthony H, Collins CE, Davidson G, et al. Pancreatic replace-ment therapy in cystic Fibrosis: Australian Guidelines. JPaediatr Child Health 1999;35:125–9.

w178x Littlewood JM. Update on intestinal strictures. J R Soc Med1999;92(Suppl.37):41–9.

w179x Rubinstein S, Moss R, Lewiston N. Constipation and meconi-um ileus equivalent in patients with cystic fibrosis. Pediatrics1986;78:473–9.

w180x Malfroot A, Dab I. New insights into gastrointestinal reflux incystic fibrosis by longitudinal follow-up. Arch Dis Child1991;66:1339–45.


w181x Heine RG, Button BM, Olinsky A, et al. Gastro-oesophagealreflux in infants under 6 months with cystic fibrosis. Arch DisChild 1998;78:44–8.

w182x Ledson MJ, Tran J, Walshaw MJ. Prevalence and mechanisms of gastro-oesophageal reflux in adult cystic fibrosis patients.J Roy Soc Med 1998;91(Suppl):7–9.

w183x Lloyd-Still JD. Cystic Fibrosis, Crohn’s disease, biliary abnor-malities and cancer. J Pediatr Gastroenterol Nutr 1990;11:434–7.

w184x Gross V, Schoelmerich J, Denzel K, et al. Relapsing pancreatitisas an initial manifestation of cystic fibrosis in young man withcystic fibrosis. Int J Pancreatol 1989;4:221–8.

w185x Colombo C, Battezzati PM, Strazzabosco M, et al. Liver andbiliary problems in cystic fibrosis. Semin Liver Dis1998;18:227–35.

w186x Chamarthy LM, Reinstein LJ, Schnapf B, et al. Desensitisationto pancreatic enzyme intolerance in a child with cystic fibrosis.Pediatrics 1998;102:e13.

w187x Gow R, Bradbear R, Francis P, et al. Comparative study ofvarying regimens to improve steatorrhoea and creatorrhoea incystic fibrosis: effectiveness of an enteral coated preparationwith and without antacids and cimetidine. Lancet1981;11:1071–4.

w188x Heijerman HG, Lamers CB, Dijkman JH, et al. Ranitidinecompared with the dimethylprostaglandin E2 analogue enprostilas adjunct to pancreatic enzyme replacement in adult cysticfibrosis. Scand J Gastrenterol Suppl 1990;178:26–31.

w189x Heijerman RG, Lamers CB, Bakker W, et al. Improvement offecal fat excretion after addition of omeprazole to pancrease incystic fibrosis is related to residual exocrine function of thepancreas. Dig Dis Sci 1993;38:1–6.

w190x Hendriks JJE, Wesseling GJ, et al. Lansoprazole therapy inyoung CF patients improved fat absorption, bone mineralcontent and hyperinflation. Nether J Med 1999;54(Suppl):S68.

w191x Smith LJ, Lacaille F, Lepage G, et al. Taurine decreases fecalfatty acid and sterol excretion in cystic fibrosis. A randomizeddouble blind trial. Am J Dis Child 1991;145:1401–4.

w192x Wiersbitzky S, Ballke EH, Wolf E, et al. Uric acid serumconcentrations in CF children after pancreatic enzyme supple-mentation. Paediatrie Grenzgebiete 1989;28:171–3.

w193x Couper R, Lichtman S, Cleghorn G, et al. Serum immunoglob-ulin G directed against porcine trypsin in pancreatic insufficientcystic fibrosis patients receiving pancreatic enzyme supple-ments. Pancreas 1991;6:558–63.

w194x Lee J, Ip W, Durie P. Is fibrosing colonopathy an immunemediated disease? Arch Dis Child 1997;77:66–70.

w195x Lipkin GW, Vickers DW. Allergy in cystic fibrosis nurses topancreatic extract. Lancet 1987;i:392.

w196x Twarog FJ, Weinstein SF, Khaw K-T, et al. Hypersensitivity topancreatic extracts in parents of patients with cystic fibrosis. JAllergy Clin Immunol 1997;59:35–40.

w197x Smyth RL, van Veltzen D, Smyth AR, et al. Strictures of theascending colon in cystic fibrosis and high strength pancreaticenzymes. Lancet 1994;343:85–6.

w198x Smyth RL, Ashby D, O’Hea U, et al. Fibrosing colonopathyin cystic fibrosis: results of a case-controlled study. Lancet1995;346:1247–51.

w199x FitzSimmons SC, Burkhart GA, Borowitz D, et al. High dosepancreatic enzyme supplements and fibrosing colonopathy inchildren with cystic fibrosis. N Engl J Med 1997;336:1283–9.

w200x Jones R, Franklin K, Spicer R, Berry J. Colonic strictures inchildren with cystic fibrosis on low strength pancreaticenzymes. Lancet 1995;346:1230.

w201x Ramsden WH, Moya EF, Littlewood JM. Colonic wall thick-ness, pancreatic enzyme dose and type of preparation in cysticfibrosis. Arch Dis Child 1998;79:339–43.

w202x Powell CJ. Colonic toxicity from pancreatins: a contemporarysafety issue. Lancet 1999;353:911–5.

w203x Lloyd-Still JD, Beno DWA, Uhing MR, et al. Pancreaticenzymes and fibrosing colonopathy. Lancet 1999;354:251.

w204x Dodge JA. Colonic wall thickness and pancreatic enzymes incystic fibrosis. Arch Dis Child 1999;81:97.

w205x van Egmond A, Kosorok MR, Koscik R, Laxova A, FarrellPM. Effect of linoleic acid intake on growth of infants withcystic fibrosis. Am J Clin Nutr 1996;63:5–52.

w206x Mischler EH, Parrell SW, Farrell PM, Raynor WJ, Lemen RJ.Correction of linoleic acid deficiency in cystic fibrosis. PediatrRes 1986;20:36–41.

w207x Strandvik B, Hultcrantz R. Liver function and morphologyduring long-term fatty acid supplementation in cystic fibrosis.Liver 1994;14:1–6.

w208x Sigstrom L, Strandvik B. Erythrocyte sodium-potassium trans-port in cystic fibrosis. Pediatr Res 1992;31:5–7.

w209x Keicher U, Koletzko B, Reinhardt D. Omega-3 fatty acidssuppress the enhanced production of 5-lipoxygenase productsfrom polymorph neutrophil granulocytes in cystic fibrosis. EurJ Clin Invest 1995;25:915–9.

w210x Kurlandsky LE. The absorption and effect of dietary supple-mentation with omega-3-fatty acids on serum leukotriene B4in patients with cystic fibrosis. Pediatr Pulmonol 1994;18:211.

w211x Lawrence R, Sorrell T. Eicosapentaenoic acid in cystic fibrosis:evidence of a pathogenetic role for leukotriene B4. Lancet1993;342:465–9.

w212x Katz DP, Manner T, Guida L, et al. The use of an intravenousfish oil emulsion enriched with omega-3-fatty acids in patientswith CF. Nutrition 1996;12:334–9.

w213x Pasco JA, Henry MJ, Nicholson GC, et al. Vitamin D statusof women in the Geelong Osteoporosis Study: association withdiet and casual exposure to sunlight. Med J Aust2001;175:401–5.

w214x Vieth R. Problems with direct 25-hydroxyvitamin D assays,and the target amount of vitamin D nutrition desirable forpatients with osteoporosis. Osteoporos Int 2000;11(7):553–5.

w215x Soltanini-Frisk S, Gronowitz E, Andersson H, Strandvik B.Water-miscible tocopherol is not superior to fat-soluble prepa-ration for vitamin E absorption in cystic fibrosis. Acta Paediatr2001;90:1112–5.

w216x Steinkamp G, von der Hardt H. Improvement of nutritionalstatus and lung function after long-term nocturnal gastrostomyfeedings in cystic fibrosis. J Pediatr 1994;124:244–9.

w217x Walker SA, Gozal D. Pulmonary function correlates in theprediction of long-term weight gain in cystic fibrosis patientswith gastrostomy tube feedings. J Pediatr Gastroenterol Nutr1998;27:53–6.

w218x Stark LJ, Jelalian E, Mulvihill MM, et al. Eating in preschoolchildren with cystic fibrosis and healthy peers: behavioralanalysis. Pediatrics 1995;95:210–5.

w219x Smyth R, Walters S. Oral calorie supplements for cystic fibrosis(Cochrane Review). The Cochrane Library Issue 1, Oxford.2000.

w220x Jelalian E, Stark LJ, Reynolds L, Seifer R. Nutrition interven-tion for weight gain in cystic fibrosis: a meta analysis. J Pediatr1998;132:486–92.

w221x Lester LA, Rothberg RM, Dawson G, et al. Supplementalparenteral nutrition in cystic fibrosis. J Parenter Enteral Nutr1986;102:89–95.

w222x Skeie B, Askanazi J, Rothkopf MM, et al. Improved exercisetolerance with long-term parenteral nutrition in cystic fibrosis.Crit Care Med 1987;15:960–2.

w223x Gebel M, Wagner S, Strassburg CP, et al. Percutaneous sono-


graphic gastrostomy: method, indications, and problems. Am JGastroenterol 1998;93:941–5.

w224x Williams SG, Ashworth F, McAlweenie A, Poole S, HodsonME, Westaby D. Percutaneous endoscopic gastrostomy feedingin patients with cystic fibrosis. Gut 1999;44:87–90.

w225x Rosenfeld M, Casey S, Pepe M, Ramsey BW. Nutritionaleffects of long-term gastrostomy feedings in children withcystic fibrosis. J Am Diet Assoc 1999;99:191–4.

w226x Erskine JM, Lingard CD, Sontag MK, Accurso FJ. Enteralnutrition for patients with cystic fibrosis: comparison of asemi-elemental and non-elemental formula. J Pediatr1998;132:265–9.

w227x Allen ED, Mick AB, Nicol J, McCoy KS. Prolonged parenteralnutrition for cystic fibrosis patients. Nutr Clin Pract1995;10:73–9.

w228x Pencharz P, Hill R, Archibald E, Levy L, Newth C. Energyneeds and nutritional rehabilitation in undernourished adoles-cents and young adult patients with CF. J Pediatr GastroenterolNutr 1984;3(Suppl 1):147–53.

w229x Alison JA, Donnelly PM, Lennon M, et al. The effect of acomprehensive, intensive inpatient treatment program on lungfunction and exercise capacity in patients with cystic fibrosis.Phys Ther 1994;74:583–91.

w230x Heijerman HGM, Bakker W, Sterk PJ, Dijkman JH. Oxygen-assisted exercise training in adult cystic fibrosis with pulmo-nary limitation to exercise. Int J Rehab Res 1991;14:101–15.

w231x Heijerman HGM. Chronic obstructive lung disease and respi-ratory muscle function: the role of nutrition and exercisetraining in cystic fibrosis. Respir Med 1993;87(Suppl B):49–51.

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Nutrition in patients with cystic fibrosis: a European Consensus