Recommendations for pregnancies in patients with crigler-najjar syndrome.

During pregnancy, the developing foetus in mothers with Crigler-Najjar type 1 and 2 is exposed to raised levels of unconjugated bilirubin, with the risk of neurotoxicity. We describe two pregnancies in a patient with Crigler-Najjar type 2, who was carefully monitored prior to and during pregnancy and phototherapy adjusted to maintain serum bilirubin levels below 200 µmol/l and the bilirubin/albumin molar ratio below 50%. Both pregnancies resulted in normal delivery of healthy infants who had normal neurological development. A review of all reported pregnancies in Crigler-Najjar patients and a set of recommendations are presented.

Treatment of infants and toddlers with cystic fibrosis-related pancreatic insufficiency and fat malabsorption with pancrelipase MT.

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) improves nutritional status and growth in patients with cystic fibrosis (CF) with pancreatic insufficiency (PI). The current recommendation for infants and young children, who are not able to swallow the whole capsule, is to open the capsule and mix the beads in a spoon with some applesauce; however, the efficacy and safety data of this approach are currently lacking. The aim of this study was to assess the efficacy, palatability (ease of swallowing), and safety of 4 dose levels of pancrelipase microtablets (Pancrease MT) in infants and young children with CF-related PI. PATIENTS AND METHODS: This study was a phase II randomized, investigator-blinded, parallel-group pilot study in DNA-proven infants with CF and PI. The study design included a run-in period (days 1-5) and an experimental period (days 6-11). Pancrelipase microtablets (2-mm, enteric coated) were provided orally. Sixteen subjects, 6 to 30 months of age, were provided 500 U lipase/kg/meal for 5 days (baseline period). Subsequently, subjects were randomly assigned to 1 of 4 treatment groups (each n = 4), receiving 500, 1000, 1500, or 2000 U (Ph. EUR) of lipase/kg/meal, respectively, for 5 days (experimental period). The primary endpoint was medication efficacy assessed by the 72-hour fecal fat excretion, expressed as coefficient of fecal fat absorption (CFA), and 13C mixed triglyceride breath test. Secondary endpoints were safety and palatability. RESULTS: Overall compliance, defined as used study medication, was 89% to 99% for the entire study. None of the 4 dose regimens significantly influenced the CFA, relative to the baseline period (median range 83%-93%). During the run-in period the median cumulative % 13C was 11 (range -8 to 59). After randomization the median cumulative % 13C was 18 (range 14-23) in the 500-U, 14 (range -1 to 17) in the 1000-U, 10 (range 10-27) in the 1500-U, and 3 (range 1-49) in the 2000-U groups. Palatability was scored fair to good by the parents in each of the treatment groups. Gastrointestinal symptoms were reported in some patients, including common adverse events reported in clinical trials involving pancreatic enzyme therapy. No serious or other adverse events were reported. CONCLUSION: Treatment with Pancrease MT at a dosage of 500 U lipase/kg/meal resulted in a CFA of approximately 89% in pediatric subjects ages 6 to 30 months with PI resulting from CF. Pancrease MT doses were well tolerated and mean palatability was scored as fair to good. Present results do not indicate that a dosage higher than 500 U (Ph. EUR) lipase/kg/meal increases the coefficient of fat absorption in a cohort of infants 6 to 30 months of age.

Defining DIOS and constipation in cystic fibrosis with a multicentre study on the incidence, characteristics, and treatment of DIOS.

OBJECTIVES: Various definitions for distal intestinal obstruction syndrome (DIOS), meconium ileus equivalent, and constipation in patients with cystic fibrosis (CF) are used. However, an unequivocal definition for DIOS, meconium ileus equivalent, and constipation is preferred. The aims of this study were, therefore, to seek consensus on the definitions for DIOS and constipation in patients with CF and to determine the incidence, characteristics, and treatment of DIOS in a cohort of paediatric patients with CF. METHODS: During the 2005 European Society for Paediatric Gastroenterology, Hepatology, and Nutrition meeting in Porto a group of paediatric gastroenterologists discussed the definition of DIOS and constipation in CF. Subsequently, all patients younger than or equal to 18 years with complete DIOS according to the definition agreed upon and diagnosed during the years 2001 to 2005 in 8 CF centres were studied. RESULTS: Distal intestinal obstruction syndrome was defined as an acute complete or incomplete faecal obstruction in the ileocaecum, whereas constipation was defined as gradual faecal impaction of the total colon. Fifty-one episodes of DIOS in 39 patients were recorded, giving an overall incidence of 6.2 (95% confidence interval, 4.4-7.9) episodes per 1000 patient-years. Of the 39 patients with DIOS, 20% experienced a relapse, 92% were pancreatic insufficient, 44% had a history of meconium ileus at birth, and 82% had a severe genotype. Conservative treatment was effective in 49 of 51 DIOS episodes (96%). CONCLUSIONS: The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition CF Working Group definitions of DIOS and constipation in CF are specific and make a clear distinction between these 2 entities. The incidence of DIOS in the present study was considerably higher than reported previously.

Orlistat treatment of unconjugated hyperbilirubinemia in Crigler-Najjar disease: a randomized controlled trial.

Unconjugated hyperbilirubinemia in Crigler-Najjar (CN) disease is conventionally treated with phototherapy and phenobarbital. Orlistat treatment increases fecal fat excretion and decreases plasma unconjugated bilirubin (UCB) concentrations in Gunn rats, the animal model for CN disease. We determined in CN patients the effects of orlistat treatment on plasma UCB concentrations, and on fecal excretion of fat and UCB. A randomized, placebo-controlled, double-blind, cross-over trial was conducted in 16 patients, simultaneous with their regular treatment (phototherapy, n = 11, and/or phenobarbital, n = 6). Patients received orlistat or placebo, each for 4-6 wk. Compared with placebo, orlistat increased fecal fat excretion (+333%) and fecal UCB excretion (+43%). Orlistat treatment significantly decreased plasma UCB concentration (-9%). In 7 of 16 patients, the decrease in plasma UCB levels was clinically relevant (>10%, mean 21%). In patients with a clinically relevant response, plasma UCB concentrations during orlistat were strongly, negatively correlated with fecal fat excretion (r = -0.93). Clinically relevant response to orlistat treatment was not correlated with age, sex, CN type, BMI, or co-treatment with phototherapy or phenobarbital, but appeared correlated with a relatively lower dietary fat intake. In conclusion, orlistat treatment decreases plasma UCB concentrations, particularly in a subgroup of CN patients. Dietary fat intake may determine the responsiveness to orlistat treatment.

Novel kinetic insights into treatment of unconjugated hyperbilirubinemia: phototherapy and orlistat treatment in Gunn rats.

Treatment with phototherapy or with the lipase inhibitor orlistat decreases plasma unconjugated bilirubin (UCB) concentrations in hyperbilirubinemic Gunn rats. We investigated the mechanism(s) underlying the effects of orlistat, phototherapy, and combined treatment, using steady-state 3H-UCB kinetics. After three weeks of treatment with orlistat (200 mg/kg chow), phototherapy (19 microW/cm2/nm) or combined treatment, tracer 3H-UCB was administered IV to treated and untreated (control) Gunn rats. Plasma samples and feces were collected every 12h for 60h, and bile for 30 min at 60h. The following results were obtained: 1) each treatment decreased plasma bilirubin levels compared with controls: orlistat- 19%, phototherapy-32%, combined treatment-53%; 2) plasma bilirubin concentrations were strongly, negatively correlated with fractional bilirubin turnover; 3) orlistat treatment induced net transmucosal excretion of UCB into the intestinal lumen, whereas phototherapy increased biliary UCB excretion rate; 4) all treatments profoundly increased the enterohepatic circulation of UCB derivatives, indicating enhanced metabolism by intestinal bacteria. In conclusion, orlistat and phototherapy lower plasma bilirubin concentrations in Gunn rats by increasing (net) intestinal influx of UCB, either by transmucosal excretion (orlistat), or increased biliary secretion (phototherapy). The mechanism of phototherapy and orlistat treatment involves increasing the availability of UCB in the intestinal lumen for fecal excretion and for metabolism by intestinal bacteria.

Chemokine production by buccal epithelium as a distinctive feature of pediatric Crohn disease.

OBJECTIVES: Inflammatory bowel diseases (IBD) represent an aberrant immune response by the mucosal immune system to luminal bacteria. Because the oral mucosa harbors the first epithelial cells that interact with microorganisms, we assessed the immunologic activity of buccal epithelium in children with IBD and adults with Crohn disease. METHODS: Buccal epithelial cells were obtained from 17 children and 14 adults with Crohn disease, 18 children with ulcerative colitis, and 40 controls. Cells were cultured with and without microbial stimulation. Chemokine levels were determined in culture supernatants by cytometric bead array and enzyme-linked immunoabsorbent assay. CXCL-8 production was studied by immunohistochemical analysis of these cells. CXCL-8 production by lipopolysaccharide stimulated monocyte-derived dendritic cells from these patients was determined. RESULTS: Compared with controls, pediatric ulcerative colitis patients, and adult Crohn disease patients, only in children with Crohn disease did buccal epithelial cells exhibit enhanced production of CXCL-8, CXCL-9, and CXCL-10. In vitro stimulation with lipopolysaccharide or zymosan resulted in a further increase of chemokine levels only in cells from pediatric Crohn disease patients. CXCL-8 production by stimulated monocyte-derived dendritic cells from children with Crohn disease was equal to that of children with ulcerative colitis. CONCLUSIONS: Buccal epithelium of children with Crohn disease is immunologically active, even in the absence of oral lesions. The enhanced chemokine production is associated with pediatric Crohn disease and appears restricted to cells derived from the epithelial barrier. Assessment of chemokine production by buccal epithelial cells may become a new, rapid, noninvasive test for screening and classification of IBD in children.

Successful treatment of UGT1A1 deficiency in a rat model of Crigler-Najjar disease by intravenous administration of a liver-specific lentiviral vector.

Treatment of congenital and acquired liver disease is one of the main issues in the field of gene therapy. Self-inactivating lentiviral vectors have several potential advantages over alternative systems. We have constructed a self-inactivating lentiviral vector (LV-ALBUGT) that expresses the human bilirubin UDP-glucuronosyltransferase (UGT1A1) from a liver-specific promoter. UGT1A1 is involved in the clearance of heme metabolites in the liver. This enzyme is deficient in Crigler-Najjar disease, a recessive inherited disorder in humans characterized by chronic severe jaundice, i.e., high plasma bilirubin levels. Gunn rats suffer from the same defect and are used as an animal model of this disease. We have treated juvenile Gunn rats by single intravenous injection with the LV-ALBUGT vector. Over 1 year after treatment with the highest dose (5 x 10(8) transducing units), we observed a stable reduction of bilirubin levels to near normal levels and normal secretion of bilirubin conjugates in the bile, in contrast to untreated animals. In situ hybridization showed expression of the therapeutic gene in more than 30% of liver parenchymal cells. Thus, we demonstrate stable and complete clinical remission of a congenital metabolic liver disease in an animal model, after systemic administration of a therapeutic lentiviral vector.

Birth prevalence and survival in cystic fibrosis: a national cohort study in the Netherlands.

BACKGROUND: Birth prevalence and survival in patients with cystic fibrosis (CF) in the Netherlands were last investigated > 30 years ago. However, since then the birth prevalence may have decreased because of genetic counseling and an increased number of newborns of non-European descent. Although survival of CF patients has increased worldwide, a significantly lower median age at death was recently reported in the Netherlands compared with data from the United States. OBJECTIVES: To analyze birth prevalence and survival in CF patients in the Netherlands, and to compare this survival data with US CF data. DESIGN: Survey of all CF patients living in the Netherlands, and analysis of Dutch CF mortality statistics using data from the Dutch central statistics office, Statistics Netherlands (Voorburg, the Netherlands), and a comparison with Cystic Fibrosis Foundation (Bethesda, MD) patient registry data. SETTING: All CF centers in the Netherlands and the United States. PARTICIPANTS: All CF patients treated in the Netherlands on January 1, 2001, and all persons who died of CF between 1974 and 2000, and an equivalent US population. MEASUREMENTS: Birth prevalence and birth cohort-specific survival. RESULTS: The overall birth prevalence of CF for 1974 to 1994 was 1 in 4,750 live births, which is a considerable decrease compared with 1961 to 1965 (1 in 3,600 live births). Estimated survival to 30 years increased from 6% in the 1950-to-1954 cohort, to 36% in the 1970-to-1973 cohort. Exact survival could be calculated from 1974 onwards. Survival to 15 years increased from 72% from the 1974-to-1979 cohort, to 91% in the 1985-to-1989 cohort. Survival in the United States in the 1980-to-1984 cohort was better compared to the Netherlands, but this difference has disappeared over subsequent cohorts. CONCLUSIONS: The actual birth prevalence of CF in the Netherlands is clearly lower than it was 30 years ago. Survival in CF has dramatically improved. The difference in survival between the Netherlands and the United States, as observed in the cohorts born > 20 years ago, has disappeared.

Activation of CFTR by ASBT-mediated bile salt absorption.

In cholangiocytes, bile salt (BS) uptake via the apical sodium-dependent bile acid transporter (ASBT) may evoke ductular flow by enhancing cAMP-mediated signaling to the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. We considered that ASBT-mediated BS uptake in the distal ileum might also modulate intestinal fluid secretion. Taurocholate (TC) induced a biphasic rise in the short circuit current across ileal tissue, reflecting transepithelial electrogenic ion transport. This response was sensitive to bumetanide and largely abrogated in Cftr-null mice, indicating that it predominantly reflects CFTR-mediated Cl- secretion. The residual response in Cftr-null mice could be attributed to electrogenic ASBT activity, as it matched the TC-coupled absorptive Na+ flux. TC-evoked Cl- secretion required ASBT-mediated TC uptake, because it was blocked by a selective ASBT inhibitor and was restricted to the distal ileum. Suppression of neurotransmitter or prostaglandin release, blocking of the histamine H1 receptor, or pretreatment with 5-hydroxytryptamine did not abrogate the TC response, suggesting that neurocrine or immune mediators of Cl- secretion are not involved. Responses to TC were retained after carbachol treatment and after permeabilization of the basolateral membrane with nystatin, indicating that BS modulate CFTR channel gating rather than the driving force for Cl- exit. TC-induced Cl- secretion was maintained in cGMP-dependent protein kinase II-deficient mice and only partially inhibited by the cAMP-dependent protein kinase inhibitor H89, suggesting a mechanism of CFTR activation different from cAMP or cGMP signaling. We conclude that active BS absorption in the ileum triggers CFTR activation and, consequently, local salt and water secretion, which may serve to prevent intestinal obstruction in the postprandial state.

Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats.

We sought to develop an oral treatment for unconjugated hyperbilirubinemia. In the Gunn rat model of unconjugated hyperbilirubinemia, dietary supplementation with the lipase inhibitor orlistat (Orl) or with calcium phosphate (CaP) decreases plasma unconjugated bilirubin (UCB) levels. We determined whether Orl, CaP, or their combination is superior to phototherapy, the conventional treatment, and whether the effects of Orl and CaP are influenced by dietary fat content. Gunn rats were treated with Orl (200 mg/kg chow), CaP (20 g/kg chow), Orl + CaP, or continuous phototherapy (19 muW/cm(2)/nm) during a low-fat (LF) diet (13 energy%) or high-fat (HF) diet (35 energy%). Plasma UCB and fecal fat excretion were measured before, during, and/or at the end of treatment. Orl treatment for 2 weeks (HF diet) reduced plasma UCB concentrations similar to phototherapy (-34% and -28%, respectively); the combination of both was more effective than either treatment alone (-48%; P < .001). After 3 weeks of a HF diet, plasma UCB was 46% lower compared with the LF diet (P < .001). Plasma UCB concentrations were negatively correlated with fecal fat excretion (r = -0.96; P < .001). Irrespective of dietary fat content, 3 weeks of combined treatment (Orl + CaP) decreased plasma UCB by approximately 50% (P < .01) and was more effective than phototherapy (P < .05) at the intensity provided. In conclusion, plasma UCB concentrations in Gunn rats are negatively related to fecal fat excretion and dietary fat content. Orlistat is equally effective as phototherapy for the treatment of unconjugated hyperbilirubinemia in Gunn rats, and combined oral treatment with Orl + CaP is more effective than phototherapy. The present results support the feasibility of an efficient oral treatment of unconjugated hyperbilirubinemia.

Fat absorption in cystic fibrosis mice is impeded by defective lipolysis and post-lipolytic events.

Cystic fibrosis (CF) is frequently associated with progressive loss of exocrine pancreas function, leading to incomplete digestion and absorption of dietary fat. Supplementing patients with pancreatic lipase reduces fat excretion, but it does not completely correct fat malabsorption, indicating that additional pathological processes affect lipolysis and/or uptake of lipolytic products. To delineate the role of such (post) lipolytic processes in CF-related fat malabsorption, we assessed fat absorption, lipolysis, and fatty acid uptake in two murine CF models by measuring fecal fat excretion and uptake of oleate- and triolein-derived lipid. Pancreatic and biliary function was investigated by determining lipase secretion and biliary bile salt (BS) secretion, respectively. A marked increase in fecal fat excretion was observed in cftr null mice but not in homozygous DeltaF508 mice. Fecal BS loss was enhanced in both CF models, but biliary BS secretion rates were similar. Uptake of free fatty acid was delayed in both CF models, but only in null mice was a specific reduction in lipolytic activity apparent, characterized by strongly reduced triglyceride absorption. Impaired lipolysis was not due to reduced pancreatic lipase secretion. Suppression of gastric acid secretion partially restored lipolytic activity and lipid uptake, indicating that incomplete neutralization of gastric acid impedes fat absorption. We conclude that fat malabsorption in cftr null mice is caused by impairment of lipolysis, which may result from aberrant duodenal pH regulation.

Ex vivo CF diagnosis by intestinal current measurements (ICM) in small aperture, circulating Ussing chambers.

Intestinal current measurements (ICM) on rectal suction biopsies are a tool for the ex vivo diagnosis of classical and atypical cystic fibrosis (CF). We present the basic ICM protocol, typical tracings and their interpretation. The ICM technique allows the registration of CF-induced changes in electrogenic transepithelial ion transport (Cl-, HCO3-, K+) in a Cl- secretory epithelium, and on the basis of pharmacological criteria, is able to discriminate between CFTR-mediated Cl- secretion and secretion through alternative anion channels. ICM is particularly useful for the classification of individuals with CF-like clinical features with equivocal sweat test values and/or no or one identifiable CFTR mutation.

Gastrointestinal and other clinical manifestations in 17 children with congenital disorders of glycosylation type Ia, Ib, and Ic.

OBJECTIVES: The typical signs and symptoms of congenital disorders of glycosylation (CDG) include dysmorphy, failure to thrive, and neurologic abnormalities. However, more and more children diagnosed at a young age are not dysmorphic and do not have neurologic involvement. The authors studied the gastrointestinal and other clinical manifestations of CDG type Ia, Ib, and Ic. METHODS: As of January 2003, 17 children were identified with CDG at the authors' institution. The medical records of the patients were reviewed. RESULTS: Five children had CDG Ia, three children CDG Ib, and nine children CDG Ic. Age at diagnosis ranged from 2 months to 15 years. Failure to thrive was present in 80% of patients with CDG Ia, in 66% of those with CDG Ib, and in 11% of those with CDG Ic. Five children had protein-losing enteropathy (two CDG Ia, two CDG Ib, and one CDG Ic). Hepatomegaly was present in 40% of patients with CDG Ia, in 66% of those with CDG Ib, and in 11% of those with CDG Ic. In CDG Ic, hepatomegaly was transient. In CDG Ia, histologic analysis of the liver showed swollen hepatocytes, steatosis, and fibrosis. In CDG Ib, hamartomatous collections of bile ducts were seen. In one patient with CDG Ib, the clinical picture was restricted to congenital hepatic fibrosis for more than a decade. CONCLUSIONS: The study confirms the heterogeneity of the clinical picture in children with CDG type Ia, Ib, and Ic. Children with protein-losing enteropathy should be tested for CDG. Protein-losing enteropathy can be caused, not only by CDG Ia and Ib, but also by type Ic. Children with congenital hepatic fibrosis should be tested for CDG, even in the absence of other symptoms. In CDG Ib, histologic analysis of the liver showed hamartomatous collections of bile ducts (Meyenburg complex).

Plasmodium falciparum-activated chloride channels are defective in erythrocytes from cystic fibrosis patients.

An inwardly rectifying anion channel in malaria-infected red blood cells has been proposed to function as the "new permeation pathway" for parasite nutrient acquisition. As the channel shares several properties with the cystic fibrosis transmembrane conductance regulator (CFTR), we tested their interrelationship by whole-cell current measurements in Plasmodium falciparum-infected and uninfected red blood cells from control and cystic fibrosis (CF) patients. A CFTR-like linear chloride conductance as well as a malaria parasite-induced and a shrinkage-activated endogenous inwardly rectifying chloride conductance with properties identical to the malaria-induced channel were all found to be defective in CF erythrocytes. Surprisingly, the absence of the inwardly rectifying chloride conductance in CF erythrocytes had no gross effect on in vitro parasite growth or new permeation pathway activity, supporting an argument against a close association between the Plasmodium-activated chloride channel and the new permeation pathway. The functional expression of CFTR in red blood cells opens new perspectives to exploit the erythrocyte as a readily available cell type in electrophysiological, diagnostic, and therapeutic studies of CF.

Changes in globus pallidus with (pre)term kernicterus.

OBJECTIVE: We report serial magnetic resonance (MR) and sonographic behavior of globus pallidus in 5 preterm and 3 term infants with kernicterus and describe the clinical context in very low birth weight preterm infants. On the basis of this information, we suggest means of diagnosis and prevention. METHODS: Charts and MR and ultrasound images of 5 preterm infants and 3 term infants with suspected bilirubin-associated brain damage were reviewed. Included were preterm infants with severe hearing loss, quadriplegic hypertonia, and abnormal hypersignal of globus pallidus on T2-weighted MR imaging (MRI). In 1 infant who died on day 150, the diagnosis was confirmed during the neonatal period. The others were picked up as outpatients and scanned at 12 or 22 months' corrected age. Three instances of term kernicterus were included for comparison of serial MRI in the neonatal period and early infancy: they were caused by glucose-6-phosphate dehydrogenase deficiency, urosepsis, and dehydration plus fructose 1-6 biphosphatase deficiency. RESULTS: Five preterm infants of 25 to 29 weeks' gestational age presented with total serum bilirubin (TSB) levels below exchange transfusion thresholds commonly advised. Mixed acidosis was present in 3 infants around the TSB peak. The bilirubin/albumin molar ratio was >0.5 in all, in the absence of displacing drugs. All failed to pass bedside hearing screen tests and had severe hearing loss on auditory brain response testing. Symmetrical homogeneous hyperechogenicity of globus pallidus was the alerting feature in 1 infant. Globus pallidus was hyperintense on T1-weighted MR images in this child. The other infants presented with severe developmental delay as a result of dyskinetic quadriplegia and hearing loss. Globus pallidus was normal on T1- but hyperintense on T2-weighted MR images at 12 or 22 months' corrected age. Subthalamic involvement was documented in coronal fluid attenuated inversion recovery MRI in 2 infants. The term infants with classical clinical presentation in the neonatal period had MR behavior similar to the preterms, but pallidal injury was not recognized with targeted sonographic examination. Their neonatal MR images demonstrated pallidal T1 hyperintensity and mild T2 hyperintensity. CONCLUSION: Acidotic very low birth weight preterm infants with low serum albumin levels develop MR-confirmed pallidal injury and hearing loss facing "accepted" TSB levels. Serial MRI documents a shift from acute mainly T1 hypersignal to permanent T2 hypersignal in globus pallidus within the late neonatal period. Subthalamic and not thalamic involvement helps to differentiate from ischemic or metabolic disorder. As newborns, these infants are rigid and have severe apnea, before developing hypertonic quadriplegia in infancy.

Assessment of nutritional status in children with cystic fibrosis: conventional anthropometry and bioelectrical impedance analysis. A cross-sectional study in Dutch patients.

BACKGROUND: Assessment of nutritional status in children with cystic fibrosis (CF) is clinically relevant. Methods to measure nutritional status should be reliable and non-invasive, and reference values should be available. AIM: To compare weight and height measurements and measurements of specific body compartments in children with CF. METHODS: In a cross-sectional survey of 58 children with CF (28 females), we compared height and weight (expressed as: weight-for-height, body mass index (BMI), height-for-age and weight-for-age) with fat mass (skinfold sum (SFS)), muscle mass (upper arm circumference (UAC)) and bioelectrical impedance analysis (BIA). Results were expressed as Z-scores, using Dutch reference values. RESULTS: BMI and weight-for-height were within the normal range (mean Z-score (range): -0.13 (-1.5, 2.7) and -0.02 (-1.7, 2.8)). Weight and height corrected for age were below normal (mean Z-score (range): -0.79 (-2.4, -0.05) and -1.2 (-2.8, 1.4) (P<0.01)). Lean body mass by skinfold sum (LBM(sfs)), UAC and BIA were also significantly below reference values (mean Z-score (range): -0.9 (-2.2, 1.8), -0.95 (-2.4, 1.8) and -1.1 (-3.6, 1.0) (P<0.01)). Lean body mass (LBM) by BIA correlated with LBM(sfs). BIA systematically underestimated LBM in both CF patients and in control subjects. CONCLUSION: Nutritional status of children with CF must be evaluated, using age-corrected weight and height expressed in Z-score. LBM estimated by SFS, UAC and by BIA appear to be useful, although longitudinal studies in CF children should be performed to evaluate their clinical significance in detecting changes in nutritional status.