Original Article
Pancreatic Function in Infants Identified as Having Cystic Fibrosis in a Neonatal Screening Program
N Engl J Med 1990; 322:303-308February 1, 1990
- Abstract
- Abstract
The use of the dried-blood immunoreactive-trypsin assay for the detection of cystic fibrosis in newborns has been questioned on the grounds that it may fail to identify patients with enough pancreatic function to have normal fat absorption. To investigate this possibility, we assessed pancreatic function in 78 patients identified in a neonatal screening program as having cystic fibrosis. The diagnosis of cystic fibrosis was confirmed by abnormal results on a sweat chloride test.
The results of measurements of fecal fat excretion, pancreatic-stimulation tests, and estimations of the serum level of pancreatic isoamylase indicated that 29 of the 78 children (37 percent) had substantial preservation of pancreatic function. These children (median age, four years) had growth that was close to normal and comparable to growth in children with severe pancreatic insufficiency who received oral enzyme therapy. Pancreatic insufficiency subsequently developed in 6 of the 29 patients, at 3 to 36 months of age.
We conclude that the serum immunoreactive-trypsin assay used in neonatal screening programs identifies patients with cystic fibrosis who have sufficient pancreatic function to have normal fat absorption and that a substantial proportion of infants identified as having cystic fibrosis are in this category. (N Engl J Med 1990; 322: 303–8.)
Article Activity
- Article
NEONATAL screening for cystic fibrosis with use of the immunoreactive-trypsin assay on dried blood samples has been adopted by many medical centers worldwide.1 2 3 4 5 The rationale for screening is that early diagnosis permits early therapy, which in turn may decrease morbidity and mortality, and makes possible more effective genetic counseling. Screening is not universally accepted, however, because improvements in outcome with screening have yet to be demonstrated. Moreover, a 1983 task force considered data indicating that the trypsin screening technique might have an inherent false negative rate of 10 percent, since it had not been validated for the estimated 10 percent of patients with cystic fibrosis who have "normal" pancreatic function.6
This subgroup of patients has become increasingly important in the investigation of gene mutation,7 pathophysiology,8 and pancreatic dysfunction9 in this disease. Although they have normal fat absorption, these patients do not, in fact, have normal pancreatic function, as is evident from their range of values for pancreatic colipase and lipase secretion, which may vary from as low as 1 and 2 percent of normal values, respectively, to values within the normal range.10 They are therefore considered to have sufficient pancreatic function to prevent malabsorption ("pancreatic sufficiency"). In contrast to those with malabsorption, these patients have milder lung disease,11 lower mortality,12 and less severe deficits in fluid and electrolyte secretion,13 and they rarely have liver disease, malnutrition, or intestinal obstruction.14 15 16 Failure to identify such patients in screening programs could not only lead to longer delays in diagnosis but also interfere with the longitudinal assessment of the patients and the screening program.
This study was undertaken to investigate whether screening with the immunoreactive-trypsin assay could detect patients with pancreatic sufficiency and, if so, to determine the proportion of such infants in the population with cystic fibrosis and to identify their clinical characteristics in early life.
Methods
Diagnosis of Cystic Fibrosis
In the New South Wales state screening program, immunoreactive trypsin is measured in dried blood samples, and a second blood sample is analyzed for babies whose initial values are elevated.2 If the trypsin levels are elevated on both occasions, the patients are referred for sweat electrolyte testing by the standard Gibson—Cooke method.17 A sweat chloride level of 60 mmol per liter or more is regarded as diagnostic of cystic fibrosis. For patients with borderline results (40 to 60 mmol per liter), the diagnosis is established by the demonstration of exocrine pancreatic acinar dysfunction, ductal dysfunction, or both on direct pancreatic-stimulation testing and by repetition of the sweat test at a later date.
Patients
Ninety-eight infants identified as having cystic fibrosis by immunoreactive-trypsin screening were referred to the cystic fibrosis clinic at the Children's Hospital, Camperdown, between July 1981 and July 1988. This clinic specializes in the care of patients in New South Wales who have cystic fibrosis, but referrals are made according to geographic area by a network of physicians and are unrelated to clinical considerations.
By January 1984, 41 patients had been referred to the clinic by the screening program. Thirty-four of these patients remained at the clinic and subsequently underwent routine assessments of their pancreatic function. A total of 57 infants were referred after January 1984, and the parents of 44 consented to a pancreatic-testing procedure near the time of diagnosis. Thus, a total of 78 patients (80 percent of those referred by the screening program) formed the study group. Informed consent was obtained from the parents of all infants who underwent pancreatic-assessment procedures.
Assessment of Pancreatic Function
Fecal-Fat Estimation
The parents of infants who were fed a standard cow's-milk formula, solid food, or both completed records of weighed food intake for five days; on days 3 through 5, the children's feces were collected. Fat intake was estimated by reference to computerized Australian food-composition tables.18 Fecal fat was estimated by the standard technique,19 and fat malabsorption was defined as a loss of 8 percent or more of fat intake in the feces, as defined previously.10 In exclusively breast-fed infants, the fecal fat loss was considered abnormal if the excretion of fat exceeded 1.5 g per day during a three-day period, an amount derived from selected studies compiled by Fomon.20 In patients who were receiving oral pancreatic-enzyme supplements, this medication was discontinued 24 to 48 hours before the beginning of the fat-balance study.
Pancreatic-Stimulation Tests
Pancreatic-stimulation tests were performed to determine the degree of pancreatic function in infants with borderline values for fecal fat excretion, to confirm the results of measurements of pancreatic isoamylase, or as the primary test of pancreatic function. After a four-hour fast (or an overnight fast in older children), the infants were sedated with oral secobarbital (10 mg per kilogram of body weight) and were simultaneously given oral metoclopramide (0.25 mg per kilogram). The test used a marker-perfusion system (10 μg of gentamicin per milliliter in 5 percent mannitol), a modification of the technique described previously.21 After a 20-minute equilibration period, an intravenous infusion of secretin (KabiVitrum; 0.0625 clinical unit per kilogram per minute) and cholecystokinin (Kinevac, Squibb; 0.01 μg per kilogram per minute) was administered over a period of one hour. Colipase and lipase concentrations were measured in the duodenal aspirate, and the rates of secretion of these substances were calculated as described previously.10 , 21 A rate of colipase secretion greater than 120 units per kilogram per hour (i.e., more than 1 percent of average normal values) was considered evidence of pancreatic sufficiency.10
Measurements of Serum Pancreatic Isoamylase
Estimations of the level of pancreatic isoamylase in serum, with use of the Phadebas Isoamylase test (Pharmacia Diagnostics), were made for 27 children over two years of age. By this method, the mean value for the pancreatic isoamylase level in normal children 2 to 4.9 years old is 51 U per liter (reference range, 13 to 89 U per liter [mean ±2 SD]).22
Overall, five patients had all three tests of pancreatic function, eight had pancreatic-stimulation tests and fecal-fat estimations, eight had fecal-fat estimations and measurements of serum pancreatic isoamylase, and two had pancreatic-stimulation tests and isoamylase estimations. Thirty-nine had only fecal-fat estimations, 4 had only pancreatic-stimulation tests, and 12 had only measurements of serum pancreatic isoamylase.
Growth Assessment
The height and weight of the 69 children who were at the clinic within six months of the end of the study period (July 1988) were standardized for age and sex against international reference values assembled by the U.S. National Center for Health Statistics and published by the World Health Organization.23 Because weight distributions are not symmetrical in this reference population, separate standard deviations have been calculated for the upper and lower halves of each distribution by the U.S. Centers for Disease Control24 to ensure approximation to normal values. Using this correction, we calculated standard-deviation scores (z-scores) by the equation z = (y — x)/SD of x, where y is the child's height or weight, x is the median height or weight of a normal child of the same age and sex, and SD of x is one SD above or below the median reference value.
Statistical Analysis
Where applicable, the results have been presented as means ±SD. Comparisons of means have been made with the two-tailed Student's t-test, with the rejection level set at 0.05.
Results
Pancreatic function was assessed in all 78 patients in the study group. The mean age at testing in the 34 patients who received the diagnosis of cystic fibrosis before 1984 was 2.3 years (range, 1 month to 4 years), whereas the mean age at pancreatic assessment in the 44 patients who received the diagnosis from 1984 to 1988 was 2 months (range, 1 to 4 months). Of the 78 patients, 74 had the diagnosis of cystic fibrosis confirmed by sweat testing. Four patients had borderline results on the sweat test. Two of these patients later had repeat sweat tests that were diagnostic. The remaining two patients have not had repeat sweat tests, but had results on pancreatic-stimulation tests that were consistent with the diagnosis of cystic fibrosis. Twenty-nine infants (37 percent) were found to have evidence of pancreatic sufficiency.
Fecal Fat Excretion
The estimates of fecal fat excretion in 60 infants are shown in Figure 1Figure 1
Fecal Fat Excretion in 60 Infants.. For 26 children who were bottle-fed or eating a normal diet for their age, estimates of fecal fat excretion, expressed as a percentage of oral fat intake, ranged from 3 to 65 percent. Of the eight patients in whom fat excretion was normal or borderline (3 to 7.8 percent), six had their level of pancreatic function confirmed by pancreatic-stimulation test (open squares in Fig. 1). In 33 exclusively breast-fed infants and one other 17-month-old child (with a fat loss of 20 g per day), the results are expressed as grams of fat excreted in the feces per day. The fat excretion of the breast-fed infants ranged from 0.1 to 15 g per day, and the results were normal or borderline in 16. Pancreatic-stimulation tests were performed in four of the breast-fed group (open squares) to determine their levels of pancreatic function.Pancreatic-Stimulation Tests
Pancreatic-stimulation tests were performed in 19 children (Fig. 2Figure 2
Results of Pancreatic-Stimulation Tests, Expressed as a Percentage of Normal Colipase-Secretion Rates.). Colipase secretion ranged from less than 1 percent to 77 percent of the previously defined average normal values,10 with actual secretion rates ranging from less than 1 unit to 9800 units per kilogram per hour.Pancreatic sufficiency was confirmed in 14 patients. Ten of these (represented by open squares in Fig. 1) had undergone fat-balance studies and had normal fat excretion. In one other child, the pancreatic-stimulation test was used to confirm the results of the isoamylase assay; the pancreatic-stimulation test was the only test of pancreatic function in the remaining three children (these four patients are represented by solid squares). The actual colipase-secretion rates in the group with pancreatic sufficiency varied from 127 to 9800 units per kilogram per hour (>1 percent to 77 percent of normal). Four of the patients with pancreatic sufficiency had initially borderline results on sweat chloride tests (49 to 60 mmol per liter), and the pancreatic-stimulation test was used to confirm their diagnoses. Repeat sweat tests subsequently verified the diagnosis of cystic fibrosis in two of these patients.
Pancreatic insufficiency (<1 percent of normal colipase secretion) was confirmed in five patients — in two at the initial assessment (triangles) and in the remaining three at a follow-up assessment two to three months after the documentation of normal fecal fat excretion (open circles).
Measurements of Serum Pancreatic Isoamylase
We estimated the serum levels of pancreatic isoamylase in 27 children more than two years of age. Figure 3Figure 3
Serum Levels of Pancreatic Isoamylase in 27 Infants More than Two Years of Age. shows that, in general (with one obvious exception), the patients can be divided according to the results into two groups: one with undetectable or low-normal isoamylase levels (0 to 32 U per liter) — the patients with steatorrhea; and one with normal or high levels (81 to 216 U per liter) —the patients with pancreatic sufficiency.Repeat Tests
By the end of the study (July 1988), the median duration of follow-up for those who maintained sufficient pancreatic function to prevent malabsorption of fat was 2.8 years. In six infants who had pancreatic sufficiency at the initial assessment, pancreatic insufficiency subsequently developed (Table 1Table 1
Development of Pancreatic Insufficiency in Six Infants.*). Pancreatic function was retained only for short periods in three patients in whom the deterioration of exocrine pancreatic activity occurred between the demonstration of a normal fat balance and the time the pancreatic-stimulation test was performed (open circles in Fig. 2). These children were between three and five months of age, were not receiving enzyme supplements, and had had no symptoms of malabsorption. The other three patients (age, 16 months to 3 years) were reexamined when symptoms of malabsorption were reported. Previously, these patients had been thriving without pancreatic-enzyme—replacement therapy.Immunoreactive-Trypsin Screening
The diagnosis of cystic fibrosis was delayed beyond the neonatal period in 4 of the 78 patients referred by the screening program. The delay was due to a negative result on the immunoreactive-trypsin assay in the cases of two infants, was attributable to postal delays in the case of another, and was due to a borderline result on the immunoreactive-trypsin assay and repeatedly borderline results on sweat tests in the case of the fourth. The last child has retained pancreatic sufficiency, but the others were found to have fat malabsorption when tested at the time of the diagnosis.
From 1981 until early 1987, the test used to screen newborns in New South Wales was a radioimmunoassay. During this period there was no significant difference between the mean immunoreactive-trypsin value in samples from the 38 patients with pancreatic sufficiency (418± 175 arbitrary units per liter) and the mean value in samples from the 23 patients with pancreatic insufficiency (406 ± 131).
Growth
Figure 4Figure 4
Cross-Sectional Growth Characteristics of the Screened Infants, Standardized for Age and Sex. illustrates the cross-sectional growth characteristics of the infants with cystic fibrosis up to seven years after the screening program began. Patients with pancreatic sufficiency (squares) clearly conform to normal growth standards. With only one exception, the values for this group at a median age of four years were consistently within 1 SD of the median reference values, or higher. The patients who initially had pancreatic sufficiency but now require pancreatic-enzyme replacement for adequate food absorption are designated by open circles.When adjusted for age and sex, the height and weight measurements of the screened population as a whole were not substantially different from those of the normalized reference population. The mean (±SD) standardized weight was —0.03±1.04, and the height was —0.1 ±1.09; neither was significantly different from the standardized normal value of zero. Only two children (with pancreatic insufficiency) had weights more than 2 SD below the reference value.
Discussion
The results of the present study demonstrate that the neonatal screening program for cystic fibrosis, in which the dried-blood immunoreactive-trypsin assay is used, detects infants with pancreatic sufficiency, who make up a relatively large proportion (37 percent) of the infants referred to our clinic. Furthermore, these patients have a wide range of exocrine pancreatic-function levels, as is evident from their colipasesecretion rates (from 1 to 77 percent of average normal values, consistent with data on older patients not referred by a screening program10). These results thus confirm those of other investigators,1 , 2 who suspected that patients from their screening programs had sufficient pancreatic function on the basis of normal trypsin activity in the stool. Our findings should allay concerns that a cystic fibrosis screening program may not be able to identify such patients.
Currently, we cannot precisely assess the rate of false negative results for patients with pancreatic sufficiency in screening programs, since the diagnosis may be delayed beyond childhood in such patients. However, on the basis of available data, we suspect that the rate is low, particularly because, in the present study, the proportion of patients with pancreatic sufficiency was high and their average immunoreactive-trypsin level was not lower than that of the group with pancreatic insufficiency. Furthermore, in New South Wales, the observed incidence of cystic fibrosis has previously been reported as 1 in 2600 screened infants.25 This rate is close to that expected for our population and is similar to the 1 in 2500 reported from a neighboring state without a screening program.26 Moreover, we have yet to see any additional patients with pancreatic sufficiency who were not identified by screening over the seven-year study period. Thus, considering all the evidence, it is unlikely that the screening program is failing to identify large numbers of such patients.
The proportion of infants with pancreatic sufficiency in our study group far exceeds both the figure anticipated by the task force and the 10 to 15 percent reported from cross-sectional studies of older, nonscreened patients.11 However, this high proportion is in accord with Andersen's original findings at autopsy27 that half of patients with cystic fibrosis who died in early life had less than 90 percent involvement of the exocrine pancreas on histologic examination. Moreover, the discrepancy between the young and older populations could be explained by a decline in pancreatic function with increasing age, as was documented in a preliminary report on an older group of patients28 and as is evident in the results of our study. Thus, we anticipate that pancreatic insufficiency would develop in an even higher proportion of our patients over a longer follow-up period. Such findings would account for the variable older age at which some patients in nonscreened populations present with symptoms of malabsorption.
We observed distinct variations in levels of pancreatic function in patients with cystic fibrosis. Three groups were apparent: patients who had pancreatic insufficiency at or soon after birth; those in whom pancreatic function was initially sufficient but in whom insufficiency developed at a variable older age; and those who continued to have pancreatic sufficiency. A recent study suggests that in patients with pancreatic insufficiency a single mutational event occurs at the locus for the cystic fibrosis gene, whereas in patients with pancreatic sufficiency there are multiple mutations at this locus.7 How these differences influence the development of pancreatic disease remains unknown. Studies in older patients have demonstrated that independent of the degree of acinar dysfunction, there is impaired secretion of bicarbonate and chloride and an associated, dependent fluid-secretion deficit that may predispose the patient to protein precipitation, ductal obstruction, inflammation, and eventual acinar destruction.9 , 13 , 21 Furthermore, quantitative histologic studies of preterm neonates with cystic fibrosis have found dilated pancreatic ducts but morphologically normal acinar tissue.29 It is possible that the severity of the secretion defect and thus the degree of obstruction of the pancreatic ducts is critical in the evolution of pancreatic disease.30 This study emphasizes the need for further investigation of the relation between genetic differences and secretory anomalies in this disease.
The findings of the present study have important implications for the clinical management of cystic fibrosis. Our results indicate that pancreatic function should be assessed in all patients, since it is incorrect to assume that all patients with cystic fibrosis have malabsorption and require enzyme therapy. Not only is this an unnecessary burden for the patient with pancreatic sufficiency, but it is also an extra health care expense. The data on cross-sectional growth provide clear evidence that patients with pancreatic sufficiency can thrive without oral enzyme supplementation, a fact that attests to the long-term adequacy of their own endogenous enzyme production. Obviously, such patients need careful follow-up: poor weight gain or the onset of symptoms of malabsorption would necessitate the reevaluation of the patient's absorptive status. Finally, our results contrast with those of Sproul and Huang,31 who found that the median heights and weights of nonscreened patients with pancreatic insufficiency were consistently below the 10th percentile for the normal population. In our study, the patients with malabsorption were clearly able to achieve normal growth with the early institution of enzyme therapy and without specialized or expensive diets.
Supported by a grant (87/0501 ) from the National Health and Medical Research Council of Australia.
Presented in part at the 10th International Cystic Fibrosis Conference, Sydney, Australia, March 5–10, 1988.
We are indebted to the physicians and staff of the cystic fibrosis clinic for their help and support; to the parents and children for their continued cooperation; and to Miss Cheryl Frazer for assistance in the preparation of the manuscript.
Source Information
From the Departments of Gastroenterology (D.L.W., S.F.A.D., K.J.G., M.A.G.) and Biochemistry (M.O'H.), Royal Alexandra Hospital for Children, Camperdown, Sydney, Australia, and the New South Wales Department of Health, Oliver Latham Laboratory, Sydney, Australia (B.W.). Address reprint requests to Dr. Gaskin at the James Fairfax Institute of Paediatric Nutrition, Royal Alexandra Hospital for Children, Pyrmont Bridge Rd., Camperdown, NSW 2050, Australia.
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