Immunoreactive Trypsinogen Values Research Articles

Immunoreactive Trypsinogen in Infants Born to Women with Cystic Fibrosis Taking Elexacaftor–Tezacaftor–Ivacaftor

Most people with cystic fibrosis (CF) are diagnosed following abnormal newborn screening (NBS), which begins with measurement of immunoreactive trypsinogen (IRT) values. A case report found low concentrations of IRT in an infant with CF exposed to the CF transmembrane conductance regulator (CFTR) modulator, elexacaftor-tezacaftor-ivacaftor (ETI), in utero. However, IRT values in infants born to mothers taking ETI have not been systematically assessed. We hypothesized that ETI-exposed infants have lower IRT values than newborns with CF, CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis (CRMS/CFSPID), or CF carriers. IRT values were collected from infants born in Indiana between 1 January 2020, and 2 June 2022, with ≥1 CFTR mutation. IRT values were compared to infants born to mothers with CF taking ETI followed at our institution. Compared to infants identified with CF (n = 51), CRMS/CFSPID (n = 21), and CF carriers (n = 489), ETI-exposed infants (n = 19) had lower IRT values (p < 0.001). Infants with normal NBS results for CF had similar median (interquartile range) IRT values, 22.5 (16.8, 30.6) ng/mL, as ETI-exposed infants, 18.9 (15.2, 26.5). IRT values from ETI-exposed infants were lower than for infants with abnormal NBS for CF. We recommend that NBS programs consider performing CFTR variant analysis for all ETI-exposed infants.

Immunoreactive Trypsinogen Levels in Infants Born to Women with Cystic Fibrosis Taking Elexacaftor-Tezacaftor-Ivacaftor

Background/Objective:Cystic Fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene affecting people of every race and ethnicity in the US. Highly effective modulator therapies (HEMT), such as elexacaftor-tezacaftor-ivacaftor (ETI), correct misfolding and/or improve functioning of the abnormal CFTR protein to lessen disease severity. Most people with CF are diagnosed following abnormal newborn screening (NBS), which involves measuring levels of immunoreactive trypsinogen (IRT). There have been case reports of falsely low IRT levels among infants with CF exposed to ETI in utero, but an overall assessment of IRT levels among these infants has not been conducted. We hypothesize that infants born to mothers with CF taking ETI (ETI-exposed) may have lower IRT levels than newborns with CF, CFTR-related metabolic syndrome (CRMS), or CF carriers.Methods:NBS data from infants born between 2020-22 in Indiana with at least one CFTR mutation were collected and compared to infants born to mothers with CF taking ETI followed at Indiana University, regardless of CFTR mutation status. Infants were categorized as: CF, CRMS, Carrier, ETI-exposed, and Unknown (i.e., diagnosis not determined). An ANOVA test was performed on log-transformed data, with p-values adjusted for Dunnett’s to compare IRT levels of infant groups to ETI-exposed group.Results:There were 51 children with CF, 21 with CRMS, 489 CF carriers, and 19 ETI-exposed infants. Compared to other groups, ETI-exposed infants had a lower median IRT value and IQR (p&lt;0.0001). To our knowledge, there are no CF diagnoses among ETI-exposed infants.Conclusion:IRT levels for ETI-exposed infants, who are obligate CF carriers, were lower than for other infants with CF-related diagnoses, raising the likelihood of false normal NBS results. ETI-exposed infants should have CFTR mutation analysis performed to correctly categorize them as CF, CRMS, or CF carriers.

Evaluation of specificity and sensitivity of IRT/IRT protocol in the cystic fibrosis newborn screening program: 6-year experience of three tertiary centers.

We aimed to evaluate cutoff values of immunoreactive trypsinogen (IRT)/IRT and determine relationship between IRT values and clinical characteristics of children with cystic fibrosis (CF). This study is cross-sectional study. Data of children with positive newborn screening (NBS) between 2015 and 2021 were evaluated in three pediatric pulmonology centers. Age at admission, sex, gestational age, presence of history of meconium ileus, parental consanguinity, sibling with CF, and doll-like face appearance, first and second IRT values, sweat chloride test, fecal elastase, fecal fat, biochemistry results, and age at CF diagnosis were recorded. Sensitivity and specificity of IRT cutoff values were evaluated. Of 815 children with positive NBS, 58 (7.1%) children were diagnosed with CF. Median values of first and second IRT were 157.2 (103.7-247.6) and 113.0 (84.0-201.5) μg/L. IRT values used in current protocol, sensitivity was determined as 96.6%, specificity as 17.2% for first IRT, and 96.6% sensitivity, 20.5% specificity for second IRT. Positive predictive value (PPV) was determined as 7.1%. When cutoff value for first IRT was estimated as 116.7μg/L, sensitivity was 69.0% and specificity was 69.6%, and when cutoff value was set to 88.7μg/L for second IRT, sensitivity was 69.0% and specificity was 69.0%. Area under curve was 0.757 for first and 0.763 for second IRT (p < 0.001, p < 0.001, respectively). PPV was calculated as 4.3%. Conclusion: Although sensitivity of CF NBS is high in our country, its PPV is significantly lower than expected from CF NBS programs. False-positive NBS results could have been overcome by revising NBS strategy. What is Known: • Although immunoreactive trypsinogen elevation is a sensitive test used in cystic fibrosis newborn screening, its specificity is low. • In countries although different algorithms are used, all strategies begin with the measurement of immunoreactive trypsinogen in dried blood spots. What is New: • In our study, it was shown that use of the IRT/IRT protocol for cystic fibrosis newborn screening is not sufficient for the cut-off values determined by the high number of patients. • Newborn screening strategy should be reviewed to reduce false positive newborn screening results.

Immunoreactive trypsinogen in healthy newborns and infants with cystic fibrosis

ObjectiveNewborn screening (NBS) for cystic fibrosis (CF) was introduced in Switzerland in 2011 based on an immunoreactive trypsinogen (IRT)-DNA-IRT protocol. CF diagnosis was confirmed by sweat test and/or genetics but...

Newborn screening for CF in France: An exemplary national experience

Newborn screening (NBS) for cystic fibrosis (CF) was implemented throughout France since 2002, with a 3-tiered strategy consisting in an immunoreactive trypsinogen (IRT) measurement at day-3, a search for the most common mutations responsible for CF when the IRT value is above the cut-off level, and, if necessary, a safetynet retesting of IRT at day-21. Coordination and follow-up are ensured at the national level and NBS is carried out through a regional organization involving NBS centers, biochemical and molecular genetics laboratories. Sweat testing and comprehensive mutation gene analysis are then performed according to a defined algorithm. Between 2002 and 2014, screening for the 30 most common mutations identified 87% of the alleles and comprehensive mutation gene analysis performed when applicable identified more than 300 additional mutations and resulted in a detection rate of 99.8% of the mutated alleles. Program surveillance ensured at a national level allowed to carry out adaptation of cut-off levels and removal of the p.Arg117His mutation. Thanks to these modifications, the performance of the French NBS program for CF meets the European guideline standards regarding positive predictive values, sensitivity and time to initial visit at the CF center, thus making the strategy effective. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Perinatal Reduced Blood Concentrations of Free Carnitine and Acylcarnitines in Infants with Cystic Fibrosis.

Cystic fibrosis (CF) is a multisystemic inherited disease. The aim of this study was to determine free carnitine (FC) and acylcarnitine concentrations in CF newborns with various mutations of the CFTR gene perinatally. FC/acylcarnitines were determined in dried blood spots via liquid chromatography-tandem mass spectrometry (LC-MS/MS) on the third day of life of full-term normal (n = 50) and CF (n = 28) newborns. For infants with elevated immunoreactive trypsinogen values, FC/acylcarnitines were quantified again 48 hours later, followed by mutational analysis of CFTR gene via Sanger sequencing. Initial FC and sums of acylcarnitine concentrations were statistically significantly lower in CF patients than in controls and even lower 48 hours later. The mutations F508del and 621 + 1G > T were predominantly identified among CF patients. Low FC and acylcarnitine concentrations were measured perinatally in CF patients, for all CFTR mutations detected. Carnitine supplementation of breastfeeding mothers could be beneficial.

Secondhand Smoke Exposure and Serum Trypsinogen in Cystic Fibrosis Carriers.

The objective of this study was to determine if infants carrying 1 cystic fibrosis transmembrane receptor (CFTR) mutation demonstrate pancreatic inflammation in response to tobacco exposure. Cystic fibrosis carrier infants aged 4 to 16 weeks were prospectively enrolled. Tobacco exposure was assessed by survey and maternal hair nicotine analysis. Serum immunoreactive trypsinogen (IRT) levels at birth and at the time of recruitment were analyzed relative to the presence or absence of tobacco exposure. The effect of the severity of the CFTR mutation carried by the infant on the tobacco-IRT relationship was also analyzed. Forty-eight infants completed the study. Newborn screen and follow-up IRT levels were not different between exposed infants (19 by hair analysis) and nonexposed infants (29 by hair analysis). Follow-up IRT levels were lower in infants with more severe CFTR mutations (P = 0.005). There was no difference in follow-up IRT based on CFTR mutation severity in exposed infants. Nonexposed infants with milder CFTR mutations had higher median IRT values on follow-up testing than those with more severe CFTR mutations (P < 0.05). The pancreas of cystic fibrosis carrier infants is affected by tobacco exposure, and those carrying less severe CFTR mutations may be more susceptible to tobacco effects.

An Enzyme Immunoassay for Determining Immunoreactive Trypsinogen (IRT) in Dried Blood Spots on Filter Paper Using an Ultra-Microanalytical System.

Cystic fibrosis (CF) is a severe autosomal recessive disorder. It is caused by mutations in the CF transmembrane conductance regulator gene. Early diagnosis of CF can be carried out by determining high immunoreactive trypsinogen (IRT) blood values in newborns. A simple sandwich-type ultramicroELISA assay (UMELISA®) has been developed for the measurement of IRT in dried blood spots on filter paper. Strips coated with a high affinity monoclonal antibody directed against IRT are used as solid phase, to ensure the specificity of the assay. The assay is carried out within 20h. The useful rank of the curve is 0-500ng/mL, and the lowest detectable concentration is 4.8ng/mL. Intra- and inter-assay coefficients of variation were lower than 10%. The recovery mean value was 100.3±11.2%. Cross-reactivity with proteins structurally related to IRT (α2-macroglobulin, α1-antitrypsin, and human chymotrypsin) was lower than the detection limit of the assay. Four thousand four hundred six newborn samples from the Cuban Newborn Screening Program were analyzed, and the mean IRT concentration was 12.8ng/mL. Higher IRT values were obtained when samples were eluted overnight. Regression analysis showed a good correlation with the commercially available AutoDELFIA® Neonatal IRT kit (n = 3948, r= 0.885, ƙ = 0.976, p < 0.01). The analytical performance characteristics of our UMELISA® TIR Neonatal suggest that it can be used for the neonatal screening of CF.

Quality of sweat test (ST) based on the proportion of sweat sodium (Na) and sweat chloride (Cl) as diagnostic parameter of cystic fibrosis: are we on the right way?

BackgroundTo assess the quality of sweat test (ST) based on the proportion of sweat sodium and sweat chloride as diagnostic parameter of cystic fibrosis (CF).MethodsA retrospective study of 5,721 sweat samples and subsequent descriptive analysis were carried out. The test was considered “of good quality” (correct) when: (i) sweat chloride was lower than 60 mEq/L, and sweat sodium was higher than sweat chloride; (ii) sweat chloride was higher than 60 mEq/L, and sweat sodium was lower than sweat chloride.ResultsThe study included 5,692/5,721 sweat samples of ST which had been requested due to clinical presentations compatible with CF and/or neonatal screenings with altered immunoreactive trypsinogen values. Considering the proportion of sweat sodium and sweat chloride as ST quality parameter, the test was performed correctly in 5,023/5,692 (88.2 %) sweat samples. The sweat chloride test results were grouped into four reference ranges for chloride (i) chloride < 30 mEq/L: 3,651/5,692 (64.1 %); (ii) chloride ≥ 30 mEq/L to < 40 mEq/L: 652/5,692 (11.5 %); (iii) ≥ 40 mEq/L to < 60 mEq/L: 673/5,692 (11.8 %); (iv) ≥ 60 mEq/L: 716/5,692 (12.6 %). In the comparative analysis, there was no association between ST quality and: (i) symptoms to indicate a ST [respiratory (p = 0.084), digestive (p = 0.753), nutritional (p = 0.824), and others (p = 0.136)], (ii) sweat weight (p = 0.416). However, there was a positive association with: (i) gender, (ii) results of ST (p < 0.001), (iii) chloride/sodium ratio (p < 0.001), (iv) subject’s age at the time of ST [grouped according to category (p < 0.001) and numerical order (p < 0.001)]. For the subset of 169 patients with CF and two CFTR mutations Class I, II and/or III, in comparative analysis, there was a positive association with: (i) sweat chloride/sodium ratio (p < 0.001), (ii) sweat chloride values (p = 0.047), (iii) subject’s age at the time of the ST grouped by numerical order (p = 0.001).ConclusionsConsidering that the quality of ST can be assessed by levels of sweat sodium and sweat chloride, an increasing number of low-quality tests could be observed in our sweat samples. The quality of the test was associated with important factors, such as gender, CF diagnosis, and subjects’ age.

Newborn Screening for Cystic Fibrosis in California.

This article describes the methods used and the program performance results for the first 5 years of newborn screening for cystic fibrosis (CF) in California. From July 16, 2007, to June 30, 2012, a total of 2,573,293 newborns were screened for CF by using a 3-step model: (1) measuring immunoreactive trypsinogen in all dried blood spot specimens; (2) testing 28 to 40 selected cystic fibrosis transmembrane conductance regulator (CFTR) mutations in specimens with immunoreactive trypsinogen values ≥62 ng/mL (top 1.6%); and (3) performing DNA sequencing on specimens found to have only 1 mutation in step 2. Infants with ≥2 mutations/variants were referred to CF care centers for diagnostic evaluation and follow-up. Infants with 1 mutation were considered carriers and their parents offered telephone genetic counseling. Overall, 345 CF cases, 533 CFTR-related metabolic syndrome cases, and 1617 carriers were detected; 28 cases of CF were missed. Of the 345 CF cases, 20 (5.8%) infants were initially assessed as having CFTR-related metabolic syndrome, and their CF diagnosis occurred after age 6 months (median follow-up: 4.5 years). Program sensitivity was 92%, and the positive predictive value was 34%. CF prevalence was 1 in 6899 births. A total of 303 CFTR mutations were identified, including 78 novel variants. The median age at referral to a CF care center was 34 days (18 and 37 days for step 2 and 3 screening test-positive infants, respectively). The 3-step model had high detection and low false-positive levels in this diverse population.

Screening for cystic fibrosis in New York State: considerations for algorithm improvements.

Considerations for CF screening algorithms should include IRT variations resulting from age at specimen collection, sex, race/ethnicity, season, and manufacturer kit lots. Measuring IRT level in dried blood spots is the first-tier screen for CF. Current algorithms for CF screening lead to substantial false-positive referral rates. IRT values were affected by age of infant when specimen is collected, race/ethnicity and sex of infant, and changes in seasons and manufacturer kit lots The prevalence of CF in NYS is 1 in 4200 with the highest prevalence in White infants (1 in 2600) and the lowest in Black infants (1 in 15,400).

WS11.6 Interpretation of nasal potential difference (nPD) measurements in difficult cases of possible cystic fibrosis and the role of published equations

Objectives: Norway introduced newborn screening for Cystic Fibrosis (CF) in March 2012 based on a three tier immunoreactive trypsinogen (IRT)/DNA/DNA protocol. The cystic fibrosis transmembrane conductance regulator (CFTR) mutation spectrum of Norwegian CF patients as well as mutations previously not seen in the population were included in the mutation panels. We present the results from the first 22 months of nationwide CF screening in Norway. Methods: IRT was measured using GSPTM (Perkin Elmer) and samples above 60 ng/ml were included in 2nd tier testing. This involved Luminex-based analysis of 71 mutations and Sanger sequencing of a local common mutation. If only one mutation was found, 3rd tier testing included sequencing of an additional panel of clinically rare alleles found in Norwegian CF patients. Infants carrying two mutations were reported for diagnostic follow-up. Results: At the end of 2013, 111 648 samples had been screened for CF and 875 children (0.78%) had tested positive in primary IRT screening. 2nd tier DNA assessments revealed 22 samples carrying two CFTR mutations. 3rd tier DNA testing of 86 samples disclosed one child with two mutations. Based on the 23 reported children the most frequent alleles were p.R117H (32.6%) and p.F508del (30.4%). In addition, five infants where no mutation was found were reported due to very high IRT values (>400 ng/ml). Conclusion: We found fewer children with a clear CF genotype than expected, and the CFTR mutations and allele frequencies were different compared to clinical material. This suggests reviewing the IRT cut-off level and continued reporting of p.R117H variants as well as extending the 2nd tier mutation panel. WS11.6 Interpretation of nasal potential difference (nPD) measurements in difficult cases of possible cystic fibrosis and the role of published equations R. Pabary1,2, M. Waller2, K. Harman2, I. Ya-Tung2, D. Bilton2,3, N.J. Simmonds2,3, E.W. Alton2, J.C. Davies1,2. 1Royal Brompton & Harefield NHS Foundation Trust, Paediatric Respiratory Medicine, London, United Kingdom; 2Imperial College, National Heart and Lung Institute, London, United Kingdom; 3Royal Brompton & Harefield NHS Foundation Trust, Adult Cystic Fibrosis Unit, London, United Kingdom

WS11.5 Newborn screening for cystic fibrosis in Norway

Objectives: Norway introduced newborn screening for Cystic Fibrosis (CF) in March 2012 based on a three tier immunoreactive trypsinogen (IRT)/DNA/DNA protocol. The cystic fibrosis transmembrane conductance regulator (CFTR) mutation spectrum of Norwegian CF patients as well as mutations previously not seen in the population were included in the mutation panels. We present the results from the first 22 months of nationwide CF screening in Norway. Methods: IRT was measured using GSPTM (Perkin Elmer) and samples above 60 ng/ml were included in 2nd tier testing. This involved Luminex-based analysis of 71 mutations and Sanger sequencing of a local common mutation. If only one mutation was found, 3rd tier testing included sequencing of an additional panel of clinically rare alleles found in Norwegian CF patients. Infants carrying two mutations were reported for diagnostic follow-up. Results: At the end of 2013, 111 648 samples had been screened for CF and 875 children (0.78%) had tested positive in primary IRT screening. 2nd tier DNA assessments revealed 22 samples carrying two CFTR mutations. 3rd tier DNA testing of 86 samples disclosed one child with two mutations. Based on the 23 reported children the most frequent alleles were p.R117H (32.6%) and p.F508del (30.4%). In addition, five infants where no mutation was found were reported due to very high IRT values (>400 ng/ml). Conclusion: We found fewer children with a clear CF genotype than expected, and the CFTR mutations and allele frequencies were different compared to clinical material. This suggests reviewing the IRT cut-off level and continued reporting of p.R117H variants as well as extending the 2nd tier mutation panel. WS11.6 Interpretation of nasal potential difference (nPD) measurements in difficult cases of possible cystic fibrosis and the role of published equations R. Pabary1,2, M. Waller2, K. Harman2, I. Ya-Tung2, D. Bilton2,3, N.J. Simmonds2,3, E.W. Alton2, J.C. Davies1,2. 1Royal Brompton & Harefield NHS Foundation Trust, Paediatric Respiratory Medicine, London, United Kingdom; 2Imperial College, National Heart and Lung Institute, London, United Kingdom; 3Royal Brompton & Harefield NHS Foundation Trust, Adult Cystic Fibrosis Unit, London, United Kingdom

One-Year Evaluation of a Neonatal Screening Program for Cystic Fibrosis in Switzerland

From January 2011 onward, the Swiss newborn screening (NBS) program has included a test for cystic fibrosis (CF). In this study, we evaluate the first year of implementation of the CF-NBS program. The CF-NBS program consists of testing in two steps: a heel prick sample is drawn (= Guthrie test) for measurement of immunoreactive trypsinogen (IRT) and for DNA screening. All children with a positive screening test are referred to a CF center for further diagnostic testing (sweat test and genetic analysis). After assessment in the CF center, the parents are given a questionnaire. All the results of the screening process and the parent questionnaires were centrally collected and evaluated. In 2011, 83 198 neonates were screened, 84 of whom (0.1%) had a positive screening result and were referred to a CF center. 30 of these 84 infants were finally diagnosed with CF (positive predictive value: 35.7%). There was an additional infant with CF and meconium ileus whose IRT value was normal. The 31 diagnosed children with CF correspond to an incidence of 1 : 2683. The average time from birth to genetically confirmed diagnosis was 34 days (range: 13-135). 91% of the parents were satisfied that their child had undergone screening. All infants receiving a diagnosis of CF went on to receive further professional care in a CF center. The suggested procedure for CF-NBS has been found effective in practice; there were no major problems with its implementation. It reached high acceptance among physicians and parents.

Emerging issues in cystic fibrosis newborn screening

There has been a rise in the introduction of cystic fibrosis (CF) newborn screening (NBS) programs in recent years. Despite many long running and successful programs with established protocols, new strategies are being developed in an effort to improve sensitivity and specificity. In light of the emerging issues of NBS, new algorithms have been implemented and are reviewed here. The increase in mixing of populations affects both immunoreactive trypsinogen values and sensitivity of genetic analysis in NBS. Adjustments to the mutation panel are not always possible. Algorithms adding nongenetic tiers may prove to be an alternative. The interpretation of the sweat test in neonates has been changing too, and there is now agreement that the upper limit of a normal sweat chloride is 29 mmol/l. Infants identified by NBS with a sweat chloride of 30-59 mmol/l and no evidence of two CF-causing mutations require further evaluation and often a long clinical follow-up before CF may be confirmed or excluded. Some NBS programs have reported a steady reduction in the incidence of CF, traceable to prenatal diagnosis on subsequent pregnancies and population-based carrier screening. Although there is not one universal CF NBS protocol that will suit the heterogeneous needs of diverse regions, many options for adjusting algorithms to local conditions are now available.

Clarification of Laboratory and Clinical Variables That Influence Cystic Fibrosis Newborn Screening With Initial Analysis of Immunoreactive Trypsinogen

To ensure that each newborn receives an equitable test of the highest possible sensitivity, we recognized the necessity to reassess immunoreactive trypsinogen and DNA issues in cystic fibrosis newborn screening algorithms. Our objectives included clarification of various factors that influence immunoreactive trypsinogen concentrations and resolution of long-standing questions about variations in immunoreactive trypsinogen levels among newborns. Immunoreactive trypsinogen data on 660443 newborns who were born between July 1, 1994, and June 30, 2004, were abstracted from the Wisconsin State Laboratory of Hygiene databases and deidentified for analysis. Using a compiled data set, we analyzed various demographic characteristics to determine their role, if any, in immunoreactive trypsinogen variation. Specifically, season of birth, reagent lot, and birth weight were examined. Sensitivities of the most common cystic fibrosis newborn screening protocols, namely immunoreactive trypsinogen/immunoreactive trypsinogen and immunoreactive trypsinogen/DNA, were also investigated. Mean and 95th percentile immunoreactive trypsinogen levels were shown to vary by both season and reagent lot number and affect sensitivity of the assay. Low birth weight infants had significantly higher immunoreactive trypsinogen values than normal birth weight infants. Sensitivities were also found to vary on the basis of the algorithm used, with the highest sensitivity of 96.2% calculated for an immunoreactive trypsinogen/DNA protocol with 23 cystic fibrosis transmembrane conductance regulator mutation analyses compared with 80.2% with the immunoreactive trypsinogen/immunoreactive trypsinogen method used in 9 states. Floating, rather than fixed, cutoff values for the initial immunoreactive trypsinogen portion of any cystic fibrosis newborn screening protocol are generally necessary on the basis of the seasonal and reagent lot variations observed. Because of its lower sensitivity, immunoreactive trypsinogen/immunoreactive trypsinogen does not optimize detection of patients with cystic fibrosis.

Newborn Screening for Cystic Fibrosis in New York State

To the Editor .— We wish to rectify numerous inaccuracies in the recent article by Giusti et al.1 Although there is no “state coordinator” per se for cystic fibrosis (CF), a follow-up CF team does exist to provide assistance to anyone who contacts the screening program. The authors asserted that an immunoreactive trypsinogen value was unavailable for 1 cited infant; however, to our knowledge, no inquiry was made to the program in that individual case. Section 69–1.7 of the …

Genetic and physiologic correlates of longitudinal immunoreactive trypsinogen decline in infants with cystic fibrosis identified through newborn screening

To characterize the time course and physiologic significance of decline in serum immunoreactive trypsinogen (IRT) levels in infants with cystic fibrosis (CF) by mode of diagnosis and genotype, and to examine IRT heritability. We studied longitudinal IRT measurements in 317 children with CF. We developed statistical models to describe IRT decline. Pancreatic disease severity (Mild or Severe) was assigned using CF genotype and was confirmed in 47 infants through fat malabsorption studies. Infants with severe disease exhibited IRT decline with non-detectable levels typically seen by 5 years of age. Infants with mild disease exhibited a decline in the first 2 years, asymptomatically approaching a level greater than published norms. IRT and fecal fat were inversely correlated. IRT values in infants with meconium ileus (MI) were significantly lower than newborn-screened infants at birth. The high proportion of shared variation in predicted IRT values among sibling pairs with severe disease suggests that IRT is heritable. IRT declines characteristically in infants with CF. Lower IRT values in newborns with MI suggest increased pancreatic injury. Furthermore, IRT is heritable among patients with severe disease suggesting genetic modifiers of early CF pancreatic injury. This study demonstrates heritability of a statistically modeled quantitative phenotype.

Cystic fibrosis carriers have higher neonatal immunoreactive trypsinogen values than non‐carriers

Following cystic fibrosis (CF) neonatal screening implementation, a high frequency of heterozygotes has been reported among neonates with elevated immunoreactive trypsinogen (IRT) and normal sweat chloride levels. We studied the relationship between normal IRT values and CF heterozygosity: 10,000 neonates were screened for CF by IRT measurement and tested for 40 CF mutations; the 294 carriers detected were coupled with newborns negative to the same genetic testing, and the two groups' IRT levels compared. Heterozygotes had higher IRT levels than their controls (mean 35.32 vs. 27.58 microg/L, P<0.001). Even within normal trypsinogen range, the probability of being a CF carrier increases with neonatal IRT concentration.

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.