Pancreatic function and extended mutation analysis in DeltaF508 heterozygous infants with an elevated immunoreactive trypsinogen but normal sweat electrolyte levels

BACKGROUND: Newborn screening for cystic fibrosis (CF) with immunoreactive trypsinogen (IRT) and DeltaF508 analysis followed by sweat testing misses some infants with CF and detects more DeltaF508 carriers than expected. Some of the apparent DeltaF508 carriers may be DeltaF508 compound heterozygotes with normal sweat electrolyte levels. METHODS: Infants identified by newborn screening with an elevated IRT level, one DeltaF508 allele, and a sweat chloride level <60 mmol/L underwent CF mutation analysis, pancreatic stimulation testing, and repeat IRT analysis followed by clinical review and repeat sweat test at 12 months. RESULTS: Over a 24-month period we identified 122 DeltaF508 heterozygotes and recruited 57; 4 had borderline sweat chloride levels (40 to 60 mmol/L), 5 (8.8%, 95% CI 1.4, 16.2) had a second CF mutation (R117H), and 11 (20%, 95% CI 10, 30) had the intron 8 5T allele. Three had clinical CF at 12 months (initial sweat chloride levels: 53, 51, and 32 mmol/L). Pancreatic electrolyte secretion in the subjects with a borderline sweat chloride level was similar to that in patients with known CF. CONCLUSION: The excess of DeltaF508 heterozygotes detected by IRT/DNA screening is associated with the presence of a second mutation or the 5T allele in some infants. Screened infants with borderline sweat chloride levels almost certainly have CF, but long-term follow-up of the infants with the genotype DeltaF508/R117H and DeltaF508/5T is required to determine their outcome. In the meantime, newborn screening should be confined to severe mutations associated with classic CF.     

Serum immunoreactive trypsin and pancreatic lipase in cystic fibrosis

Serum immunoreactive trypsin (IRT) and pancreatic lipase have been measured in 59 patients with cystic fibrosis (age 1 month-27 years). Follow-up values were obtained from 49 patients. Their serum enzyme levels were compared to those of 120 healthy children of all age groups. Faecal fat excretion was determined in selected patients (n=23) to elucidate the relationship between serum enzyme levels and pancreatic exocrine function.In cystic fibrosis IRT and lipase showed a very similar agecorrelated pattern: in infancy levels were markedly elevated. During the following years the concentrations of both enzymes decreased rapidly and were found to be far below the normal range after the 10th year of life. Elevated enzyme levels in infancy as well as low levels in all age groups coincided with steatorrhaea. Older patients (11–27 years) without severe pancreatic insufficiency however, had IRT and lipase levels in or above the normal range.In healthy children there was no age dependency of IRT levels, whereas in the first 12 months of life lipase levels were significantly lower than in later childhood.Abbreviations IRT Serum immunoreactive trypsin - CF Cystic fibrosis     

Failure to thrive: the earliest feature of cystic fibrosis in infants diagnosed by neonatal screening

The benefits of early treatment of nutritional and respiratory problems in the CF infant and of genetic counselling for the parents are widely recognized. However, clinical diagnosis of CF is often delayed despite early onset of symptoms and the usefulness of neonatal population screening as a preventive measure is still under debate. This study analyses the clinical history of CF patients diagnosed exclusively on the basis of positive neonatal screening tests with the aim of identifying the earliest markers of the disease. We studied 103 CF infants bom in north-east Italy, diagnosed following neonatal screening: assay of immunoreactive trypsin (IRT) from a heel-prick blood sample followed by a measurement of meconium lactase in cases with raised IRT. Diagnosis was confirmed by sweat test at an average age of 39 days. Eighty-one patients (79%) had symptoms strongly suggestive of CF at diagnosis, and signs and/or symptoms of pancreatic insufficiency were present in 16 of the remaining 22 cases. The most frequent symptom was growth failure (69% of infants) and of these. 44% weighed the same as at birth or less. Pancreatic insufficiency was confirmed by the low level of faecal chymotrypsin found in 85% of cases. IRT was elevated in all cases. CF had not been suspected in any symptomatic infant, although most of the infants had been monitored by a paediatrician. In conclusion, most infants with CF diagnosed by neonatal screening are already symptomatic in the first six weeks of life and the most frequent symptom is failure to thrive; pancreatic insufficiency was already present in most cases. In areas without CF neonatal screening programs, the disease should be excluded by differential diagnosis in all cases with growth failure notwithstanding adequate caloric intake in the first months of life. The high sensitivity, low cost and simple execution of IRT and fecal chymotrypsin tests make them an ideal first step in suspect cases before proceeding to the sweat test, often performed late because of limited availability.     

Genetic and clinical features of false-negative infants in a neonatal screening programme for cystic fibrosis

A study was performed on the delayed diagnosis of cystic fibrosis (CF) in infants who had false-negative results in a neonatal screening programme. The genetic and clinical features of false-negative infants in this screening programme were assessed together with the efficiency of the screening procedure in the Lombardia region. In total, 774 687 newborns were screened using a two-step immunoreactive trypsinogen (IRT) (in the years 1990-1992), IRT/IRT + delF508 (1993-1998) or IRT/IRT + polymerase chain reaction (PCR) and oligonucleotide ligation assay (OLA) protocol (1998-1999). Out of 196 CF children born in the 10 y period 15 were false negative on screening (7.6%) and molecular analysis showed a high variability in the genotypes. The cystic fibrosis transmembrane regulator (CFTR) gene mutations identified were delF508, D1152H, R1066C, R334W, G542X, N1303K, F1052V, A120T, 3849 + 10kbC →T, 2789 + 5G →A, 5T-12TG and the novel mutation D110E. In three patients no mutation was identified after denaturing gradient gel electrophoresis of the majority of CFTR gene exons.

Conclusion: The clinical phenotypes of CF children diagnosed by their symptoms at different ages were very mild. None of them presented with a severe lung disease. The majority of them did not seem to have been damaged by the delayed diagnosis. The combination of IRT assay plus genotype analysis (1998-1999) appears to be a more reliable method of detecting CF than IRT measurement alone or combined with only the delF508 mutation.     

Deletion allele of angiotensin-converting enzyme is associated with increased risk and severity of bronchopulmonary dysplasia

OBJECTIVE: To explore whether the deletion (D) allele of angiotensin-converting enzyme (ACE) is associated with the risk or severity of bronchopulmonary dysplasia (BPD) among very low birth weight (BW) infants. STUDY DESIGN: Infants with a BW < or = 1250 g were prospectively recruited. The D and I (insertion) alleles of ACE were determined using a polymerase chain reaction followed by restriction fragment length polymorphism analysis. RESULTS: Infants with DD/DI genotype of ACE had a (mean +/- SD) birth weight (938 +/- 204 g vs 925 +/- 196 g) and gestational age (28 +/- 3 weeks vs 28 +/- 2 weeks), similar to infants with II genotype of ACE (P > .05). Infants with DD/DI genotype of ACE were more likely to have BPD than infants with II genotype (47% vs 22%, P = .025). Among infants with BPD, ACE DD/DI genotype was more common among infants with moderate or severe BPD compared with infants with mild BPD (74% vs 26%, P = .012). The number of D alleles of ACE correlated directly and positively with the severity of BPD (R = 0.23, P = .045). CONCLUSION: The D allele of ACE is associated with an increased risk and severity of BPD among preterm infants.     

Immunoreactive trypsin levels in neonates with meconium ileus

Serum immunoreactive trypsin (IRT) is used as a screening test for cystic fibrosis (CF) in neonates in many countries. Variations in IRT levels are observed in healthy and cystic neonates within the first few weeks of life. Fifteen percentage of CF neonates present with meconium ileus (MI). We hypothesised that there may be differences in serum IRT levels in cystic babies with simple and complicated MI. The aim of this study was to investigate the serum levels of IRT in neonates with CF presenting with MI. IRT levels were sequentially measured in neonates (n=29) with CF with intestinal obstruction due to simple or complicated MI. These were compared to levels obtained from non-cystic neonates/controls admitted with a variety of other intra-abdominal pathologies (n=49) IRT levels were significantly higher in the CF–MI group than the non-cystic controls (P<0.001). There was no statistical difference in IRT levels between the simple or complicated MI groups. In the MI group there was no statistical difference between those who required operation, no difference between the pre- and post-operative IRT levels and no significant relationship between IRT levels and birth weight or gestation. Serum IRT levels are significantly elevated in neonates with CF and MI compared with non-cystic, non-MI neonates. The results of this observational study highlight that a single raised level of IRT in a neonate should prompt the analysis for CF regardless of any underlying surgical pathology.     

Surveillance for cystic fibrosis-associated hepatobiliary disease: early ultrasound changes and predisposing factors

OBJECTIVE: To investigate routine ultrasonography (US) as an early marker and to identify risk factors for the development of cirrhosis and portal hypertension (PHT) in cystic fibrosis (CF). STUDY DESIGN: A cohort of 106 children with CF aged 5.9+/-2.3 years were followed for 10.4+/-0.2 years in a CF clinic. RESULTS: At enrollment, the US was normal, but biochemical and/or clinical disease was present in 10%. By the end of the study, 19 had developed US changes, eight with evidence of PHT. At the time of the initial US change, only 36.4% of those had, at the end of the study, either a heterogeneous or a nodular parenchyma, and only 50% of those with PHT had biochemical and/or clinical disease. Of the 30 patients treated with ursodeoxycholic acid for biochemical and/or clinical disease with (n=15) and without (n=15) associated US changes, PHT developed in six of the former and two of the latter. Univariate analysis and logistic regression showed that children with more severe disease in terms of forced expiratory volume in one second were at somewhat greater risk (P<.06) of PHT developing. CONCLUSION: US was an early marker of liver disease and more severe CF disease, a predictor of progressive liver disease. A controlled trial should be done to assess isolated US-detected disease as an indication for UDCA.     

The need for vigilance: the case of a false-negative newborn screen for cystic fibrosis

Cystic fibrosis (CF) is the most common life-limiting recessive genetic disorder in the white population. CF is caused by abnormalities in the gene that codes for the cystic fibrosis transmembrane conductance regulator protein (CFTR) and may result in severe chronic lung disease, poor growth, and malnutrition. Physicians often do not consider CF in the differential diagnosis of an infant with failure to thrive in the presence of a negative newborn screening (NBS) result. In Minnesota, newborn infants are screened for CF by immunoreactive trypsinogen (IRT) testing followed by DNA analysis if the IRT screen result is abnormal. All positive NBS results are followed by confirmatory sweat-testing by pilocarpine iontophoresis. We present here the case of a 1-month-old white boy with failure to thrive, chronic diarrhea, and severe malnutrition. Minnesota state CF NBS results were negative at birth (IRT: 43 ng/mL [96% cutoff value: 52 ng/mL]). Clinical symptoms resulted in sweat-testing by Gibson-Cooke pilocarpine iontophoresis at 1 month of age, and the result was positive (102 mmol Cl(-)/L [normal: ≤30 mmol Cl(-)/L]). CFTR mutation analysis confirmed a homozygous f508del genotype, and stool pancreatic elastase testing revealed severe exocrine pancreatic insufficiency. This case represents the first known false-negative result in Minnesota since the initiation of NBS for CF in 2006, which illustrates the importance of considering CF in the evaluation of an infant with failure to thrive and symptoms of malabsorption, regardless of NBS results.     

Benefits of breastfeeding in cystic fibrosis: a single-centre follow-up survey

AIM: To study the effect of breastfeeding (BF) on growth, lung function and number of infections during the first 3 years of life in children with cystic fibrosis (CF). MATERIAL AND METHODS: One hundred forty-six CF patients, 5-18 years old, were recruited at their annual care visit. Information about infant feeding, psychosocial and socioeconomic conditions and smoking exposure was obtained by interviews. Anthropometric parameters at 1 year of age and the number of infections and hospitalisations during the first 3 years of life were obtained from clinical charts. Anthropometrics and pulmonary function parameters were obtained at enrollment. RESULTS: In CF patients, particularly those with pancreatic insufficiency, the prevalence of BF was lower than the general Italian population. After multivariate analysis patients with prolonged BF showed higher values of CED expiratory volume in 1 sec (FEV-1) (p = 0.001) and a lower number of infections during the first 3 years of life (p = 0.098). CONCLUSION: Prolonged BF is beneficial in children with CF and may protect them against decline of pulmonary function. Particular attention should be paid to promote BF in infants with CF.     

Age-related alterations of immunoreactive pancreatic cationic trypsinogen in sera from cystic fibrosis patients with and without pancreatic insufficiency

Serum immunoreactive cationic trypsinogen levels were determined in 99 control subjects and 381 cystic fibrosis (CF) patients. To evaluate the status of the exocrine pancreas all CF patients had previously undergone fecal fat balance studies and/or pancreatic stimulation tests. Three hundred fourteen CF patients had fat malabsorption and/or had inadequate pancreatic enzyme secretion (pancreatic insufficiency) requiring oral pancreatic enzyme supplements with meals. Sixty-seven CF patients did not have fat malabsorption and/or had adequate enzyme secretion (pancreatic sufficiency) and were not receiving pancreatic enzyme supplements with meals. Mean serum trypsinogen in 99 control subjects was 31.4 +/- 14.8 micrograms/liter (+/- 2 SD) and levels did not vary with age or sex. In CF infants (less than 2 yr) with pancreatic insufficiency, mean serum trypsinogen was significantly above the non-CF values (p less than 0.001). Ninety-one percent of the CF infants had elevated levels. Serum trypsinogen values in the pancreatic insufficient group declined steeply up to 5 years, reaching subnormal values by age 6. An equation was developed which described these age-related changes very accurately. Only six CF patients with pancreatic insufficiency had serum trypsinogen levels above the 95% confidence limits of this equation. In contrast, there was no age related decline in serum trypsinogen among the CF group with pancreatic sufficiency. Under 7 yr, serum trypsinogen failed to distinguish the two groups. In those over 7 yr of age, however, serum trypsinogen was significantly higher than the CF group with pancreatic insufficiency (p less than 0.001), and 93% had values within or above the control range.(ABSTRACT TRUNCATED AT 250 WORDS)     

Detection and follow up of exocrine pancreatic insufficiency in cystic fibrosis: a review

Pancreatic function testing is particularly difficult when the degree of remaining function has to be quantified. Detection of pancreatic insufficiency can suggest the diagnosis of cystic fibrosis (CF). It is, however; also important to follow the degree of pancreatic insufficiency in CF since its function can decline with age. Adaptation of pancreatic enzyme replacement therapy on residual function is necessary. Different tests with their advantages and disadvantages are critically reviewed in this article with respect to specificity, sensitivity, performance and cost-effectiveness. Conclusion Elastase-1 detection in faeces is probably the easiest test for the detection of pancreatic insufficiency in cystic fibrosis. For clinical follow-up tests, measuring the fat assimilation such as steatocrit and breath tests are more suited. Received: 25 November 1999 / Accepted: 8 March 2000     

Use of fecal elastase-1 to classify pancreatic status in patients with cystic fibrosis

OBJECTIVE: To test the hypothesis that some patients with cystic fibrosis (CF) are misclassified as pancreatic insufficient, using fecal elastase-1 (FE-1) to define pancreatic status. STUDY DESIGN: Subjects with CF at 33 CF centers filled out questionnaires and submitted a stool specimen that was analyzed for FE-1. Subjects taking pancreatic enzyme supplements (PES) were asked to discontinue them and perform a 3-day fecal fat balance study if their FE-1 was >200 microg/g stool and they had never had pancreatitis. RESULTS: The median value for FE-1 in 1215 subjects was 0 microg/g stool (range, 0-867). There was a significant difference between patients who had been prescribed PES (n=1131) and those who had FE-1 <200 microg/g stool (n=1074; P<.0001). Sixty-seven subjects met criteria for discontinuation of PES. The mean coefficient of fat absorption for these subjects was 96.1%. CONCLUSIONS: FE-1 is an accurate, easily obtained screening test to classify pancreatic status in patients with CF. This information is important for prognostication, treatment, and to avoid misclassification in clinical research. Measurement of FE-1 should become a standard of care for patients with CF.     

Non-specific elevation of immunoreactive trypsinogen in sick infants

To determine the effect of neonatal illness on immunoreactive trypsinogen (IRT) levels, the IRT values obtained in sick infants transferred to a neonatal intensive care ward were compared with those found in matched controls. IRT levels from dried blood spots collected on day 4–5 of life from 372 sick infants had a mean value of 0.095 log transformed multiples of the median, whilst controls had a mean of –0.013: a highly significant difference. Classification of the sick infants into principal diagnostic categories failed to show any group contributing disproportionately to the observation. In particular, the level of elevation observed in 33 infants with gut abnormalities such as bowel obstruction, duodenal atresia, exomphalos and gastroschisis, in which some degree of pancreatic obstruction might be expected, was not greater than in other hospitalised infants. These data show that sick infants are at increased risk of being identified by an IRT screening programme aimed at detecting infants with cystic fibrosis.     

Effect of exocrine pancreatic function on resting energy expenditure in cystic fibrosis

AIM: To prove the hypothesis that exocrine pancreatic function determines resting energy expenditure (REE) in cystic fibrosis (CF). METHOD: Thirty-eight CF individuals, 9-34 (19.98 +/- 1.0) years, were divided into three groups: Six pancreatic sufficient patients (PS; group A), 21 pancreatic insufficient patients (PI), whose pulmonary function was comparable to that of group A (group B1) and 11 PI patients, whose pulmonary function was significantly worse than that of group A (group B2). REE was estimated by indirect calorimetry. Predicted REE was based on Schofield equations. Measured REE was expressed as % of the predicted. BMI, BMI z-scores, serum albumin, cholesterol and triglycerides levels were related to REE. Results were expressed as mean +/- standard error. RESULTS: Groups B1 and B2 had significantly higher REE% (111.7 +/- 2.75% and 119.94 +/- 3.8, respectively) as opposed to group A (98.9 +/- 3.81%; p = 0.022 and 0.035, respectively) whose REE% was similar to that predicted. REE% between group B1 and B2 was not statistically significant. In groups A, B1 and B, mean FEV1% was 86.33 +/- 10.1%, 90.24 +/- 4.39%, 44.54 +/- 3.47%, respectively, mean BMI was 25.6 +/- 2.06, 19.48 +/- 0.64 and 20.09 +/- 8.8, respectively, BMI z-scores were 0.75 +/- 0.51, -0.52 +/- 0.24 and -1.07 +/- 0.37, respectively. Significant correlation was demonstrated between REE%, BMI z-scores and cholesterol levels in group A. CONCLUSION: Clinically stable CF patients, who had comparable pulmonary function, exhibited increased REE% only in the presence of exocrine pancreatic insufficiency. REE% strongly correlated with BMI z-scores in pancreatic sufficiency. These findings support the hypothesis that pancreatic rather than pulmonary function may determine nutritional status as well as REE in CF.     

Combining immunoreactive trypsinogen and pancreatitis-associated protein assays, a method of newborn screening for cystic fibrosis that avoids DNA analysis

OBJECTIVES: To evaluate the performance of a strategy in which, after immunoreactive trypsinogen (IRT) determination, genetic analysis is replaced by a biological test, the pancreatitis-associated protein (PAP) enzyme-linked immunosorbent assay (ELISA). STUDY DESIGN: The French newborn screening program includes cystic fibrosis (CF) screening by the IRT/CFTR mutation strategy. PAP was assayed on screening cards, in parallel with IRT, in all newborns from 5 French regions (n = 204,749). Analysis of PAP values in CF and non-CF newborns with elevated IRT allowed direct comparison between the current strategy and the proposed IRT/PAP strategy. RESULTS: A protocol in which newborns with IRT >50 ng/mL and PAP >1.8 ng/mL and those with IRT >100 ng/mL and PAP >1.0 ng/mL are directly recalled for sweat testing would have the same performance as the IRT/CFTR mutation strategy. CONCLUSIONS: The IRT/PAP strategy is an alternative for CF newborn screening, which avoids the drawbacks of genetic analysis and is cheaper and easier to implement than the current IRT/CFTR mutation strategy.     

Early decline of pancreatic function in cystic fibrosis patients with class 1 or 2 CFTR mutations

BACKGROUND: Most cystic fibrosis (CF) patients develop steatorrhea and require pancreatic enzyme replacement therapy. However, there are few data regarding the decline of exocrine pancreatic function within the first years of life in relation to CF genotype. We assessed the decline of pancreatic function in CF infants carrying class 1 or 2 CFTR mutations who were diagnosed in a neonatal screening program. MATERIALS AND METHODS: Twenty-eight CF patients were included in the study and 27 completed the study. In all subjects, fecal pancreatic elastase-1 concentrations and fecal fat excretion were scheduled to be determined at diagnosis, at 6 months of age and subsequently at 6-month intervals. RESULTS: In all CF patients, fecal pancreatic elastase-1 concentrations of the first assay after diagnosis (3 to 4 months of age) were lower than the cut-off level for normals of <200 microg/g stool. Steatorrhea was found in 81.5% of these subjects. At the age of 6 months, all screened CF subjects had fecal pancreatic elastase-1 concentrations <100 microg/g and at the age of 12 months all were pancreatic insufficient. At that time, having proved pancreatic insufficiency in all studied subjects, we stopped the scheduled further assessment. CONCLUSION: CF patients require careful monitoring of pancreatic status from diagnosis onwards. In patients carrying class 1 or 2 CFTR mutations, pancreatic insufficiency develops in the first months of life. The proper assessment of pancreatic insufficiency and intestinal malabsorption is crucial for the early introduction of pancreatic enzymes.     

Epidemiology of cystic fibrosis-related diabetes

OBJECTIVES: Cystic fibrosis-related diabetes (CFRD) has emerged as an important complication of CF. To better understand who is at risk of developing CFRD, to gain insight into the impact of CFRD on pulmonary and nutritional status, and to assess the association of CFRD with various practice patterns and comorbid conditions, we characterized the Epidemiologic Study of Cystic Fibrosis (ESCF) patient population. STUDY DESIGN: Analyses were performed on the 8247 adolescents and adults who were evaluated at one of 204 participating sites during 1998. CFRD was defined as the use of insulin or an oral hypoglycemic agent at any time during the year. RESULTS: Previously reported risk factors for CFRD including age, gender (female), and pancreatic insufficiency were confirmed in this study. Patients with CFRD had more severe pulmonary disease, more frequent pulmonary exacerbations, and poorer nutritional status as compared with those without diabetes. CFRD also was associated with liver disease. CONCLUSIONS: CFRD is a common complication in adolescents and adults that is associated with more severe disease.     

Omeprazole,a proton pump inhibitor,improves residual steatorrhoea in cystic fibrosis patients treated with high dose pancreatic enzymes

Despite treatment with supra-physiological doses of pancreatic enzyme supplements, residual steatorrhoea is a common problem in patients with cystic fibrosis (CF) and pancreatic insufficiency. Strategies to enhance the activity of pancreatic enzymes include decreasing duodenal acidity. The aim of this study was to evaluate the effect of omeprazole (Losec), a proton-pump inhibitor, on fat absorption in CF patients with residual steatorrhoea despite high dose pancreatic enzyme supplements (10,000 U lipase/kg per day). A random cross-over design was chosen. Fat digestion was evaluated with and without omeprazole by means of chemical fat measurements in 3-day stool collections together with 3-day weighed food records for calculation of fat absorption. The results of 15 patients (3 girls and 12 boys) with confirmed steatorrhoea during the control evaluation were analysed. Median age was 8.7 years (range 3.5–15.9 years). Median daily lipase intake was 13,500 U/kg per day (range 10,000–22,000 U/kg per day). During treatment with omeprazole, median faecal fat loss (g fat/day) decreased from 13 g (quartiles 11.5–16.5 g/day) to 5.5 g (quartiles 4.9–8.1 g/day) (P <0.01). The same improvement was noted when fat absorption was calculated: 87% (quartiles 81–89%) without versus 94% (quartiles 90–96%) with omeprazole (P <0.001). Conclusion:omeprazole improves fat digestion and absorption in cystic fibrosis patients with residual faecal fat loss despite maximal pancreatic enzyme substitution.Abbreviations CF cystic fibrosis - PI pancreatic insufficiency     

Pancreatic enzyme therapy and clinical outcomes in patients with cystic fibrosis

OBJECTIVE: To assess the relationship between pancreatic enzyme therapy (PET) and the clinical outcomes of growth, abdominal pain, constipation, gassiness, and number of stools in cystic fibrosis (CF). STUDY DESIGN: Patients (n = 1215) >4 weeks of age from 33 Cystic Fibrosis Foundation accredited sites who had a sweat chloride >60 mmol/L or two CF-causing mutations were enrolled using a proportionate sampling strategy in a nonblinded study. Patients submitted a stool sample and completed a questionnaire. The study coordinator also completed a questionnaire for each patient. Enzyme dosing and growth, abdominal pain, gassiness, constipation, and number of stools were compared. RESULTS: Of the 1215 enrolled patients, 1131 (93.1%) were prescribed PET. Only 14.9% had pancreatic function assessed before enrolling in this study. Stool elastase-1 analysis identified 1074 (89%) patients as pancreatic insufficient (PI). There was no association between PET and the outcomes: growth, abdominal pain, gassiness, constipation, and number of stools. CONCLUSION: PET dose is not correlated with growth or gastrointestinal symptoms. More sensitive outcome measures of the effectiveness of PET in patients with CF are needed to guide treatment of PI.     

Markedly elevated neonatal immunoreactive trypsinogen levels in the absence of cystic fibrosis gene mutations is not an indication for further testing.

AIMS: To investigate the immunoreactive trypsinogen (IRT) values above the usual 99th centile laboratory cut-off and determine the value of offering further testing to those infants with a markedly elevated IRT but no cystic fibrosis transmembrane regulator (CFTR) gene mutation identified by the screening programme. METHODS: All babies born in Victoria, Australia, between 1991 and 2003, were screened by IRT followed by CF gene mutation analysis. RESULTS: Of the 806,520 babies born, 9268 with the highest IRT levels had CFTR mutation analysis. There were 123 DeltaF508 homozygotes and 703 heterozygotes (86 with CF, 617 carriers). A total of 8442 babies had no CFTR gene mutation, of whom 18 (0.21%) had CF. The total number of CF babies with IRT greater than the laboratory cut-off was 227 (2.4%). The IRT results of the CF patients were distributed normally, with the majority above the laboratory cut-off of newborn IRT results. There was no evidence of an excess of babies with CF in the very highest levels of IRT above the 99th centile. CONCLUSIONS: Only a small proportion of babies with a neonatal IRT >99th centile have CF. Additional CF testing for infants with an elevated IRT but no CFTR gene mutation has an extremely low yield, no matter how high the IRT result.