Kevin J. Gaskin

Pancreatic Fluid Secretion and Protein Hyperconcentration in Cystic Fibrosis

To study pancreatic protein and water secretion in 28 patients with cystic fibrosis and 21 controls matched for pancreatic acinar function as defined by trypsin secretion, we used a quantitative-marker perfusion technique and continuous intravenous secretin-pancreozymin stimulation. Regardless of the level of pancreatic acinar function, secretions from the patients contained significantly higher concentrations of protein than those from the controls. Total protein output and albumin:protein ratios were not increased in secretions from the patients, but their fluid secretion was significantly decreased at any level of pancreatic function. A significant linear correlation was found between protein and volume secretion in the patients (r = 0.86, P less than 0.001), most of whom had a fluid output of less than 4.2 ml per kilogram of body weight per hour. No such relation was found in the control subjects, whose flow was always above 4.2 ml per kilogram per hour. We conclude that fluid secretion in patients with cystic fibrosis may be a rate-limiting factor in protein output and that a limited flow of hyperconcentrated protein secretions may predispose to protein precipitation and ductal obstruction in the pancreas.

European best practice guidelines for cystic fibrosis neonatal screening

There is wide agreement on the benefits of NBS for CF in terms of lowered disease severity, decreased burden of care, and reduced costs. Risks are mainly associated with disclosure of carrier status and diagnostic uncertainty. When starting a NBS programme for CF it is important to take precautions in order to minimise avoidable risks and maximise benefits. In Europe more than 25 screening programmes have been developed, with quite marked variation in protocol design. However, given the wide geographic, ethnic, and economic variations, complete harmonisation of protocols is not appropriate. There is little evidence to support the use of IRT alone as a second tier, without involving DNA mutation analysis. However, if IRT/DNA testing does not lead to the desired specificity/sensitivity ratio in a population, a screening programme based on IRT/IRT may be used. Sweat chloride concentration remains the gold standard for discriminating between NBS false and true positives, but age-related changes in sweat chloride should be taken into account. CF phenotypes associated with less severe disease often have intermediate or normal sweat chloride concentrations. Programmes should include arrangements for counselling and management of infants where the diagnosis is not clear-cut. All newborns identified by NBS should be managed according to internationally accepted guidelines. CF centre care and the availability of necessary medication are essential prerequisites before the introduction of NBS programmes. Clear explanation to families of the process of screening and of implications of normal and abnormal results is central to the success of CF NBS programmes. Effective communication is especially important when parents are told that their child is affected or is a carrier. When establishing a NBS programme for CF, attention should be given to ensuring timely and appropriate processing of results, to minimise potential stress for families.

Liver Disease and Common-Bile-Duct Stenosis in Cystic Fibrosis

To determine the incidence of common-bile-duct lesions and their relation to liver disease in cystic fibrosis, we performed hepatobiliary scanning in 50 of 61 patients with cystic fibrosis who had hepatomegaly, abnormal liver function, or both and in 31 of 92 patients with cystic fibrosis who did not have hepatomegaly or abnormal liver function. Ninety-six percent of the patients with liver disease had evidence of biliary tract obstruction, which was defined cholangiographically as a stricture of the distal common bile duct in the majority of cases. All the patients without liver disease had normal intrahepatic and common-duct excretion of tracer. Abdominal pain was significantly more common in patients with common-duct obstruction (P less than 0.001), and enlarged gallbladders occurred only in such patients. Since fasting levels of serum bile acids were elevated in nearly half these patients, irrespective of the severity of their liver disease, serum bile acids may be markers of the severity of the common-duct lesion. We conclude that strictures of the distal common bile duct are common in patients with cystic fibrosis and liver disease. This association requires further study, since surgical relief of common-duct obstruction may prevent or ameliorate the hepatic complications of cystic fibrosis.

Clinical outcomes of newborn screening for cystic fibrosis.

AIM To determine how early diagnosis of cystic fibrosis, using neonatal screening, affects long term clinical outcome. METHODS Fifty seven children with cystic fibrosis born before neonatal screening was introduced (1978 to mid 1981) and a further 60 children born during the first three years of the programme (mid 1981 to 1984), were followed up to the age of 10. The cohorts were compared on measures of clinical outcome, including height, weight, lung function tests, chest x-ray picture and Shwachman score. RESULTS Age and sex adjusted standard deviation scores (SDS) for height and weight were consistently higher in children screened for cystic fibrosis than in those born before screening. At 10 years of age, average differences in SDS between groups were 0.4 (95% CI −0.1, 0.8) for weight and 0.3 (95% CI −0.1, 0.7) for height. This translates to an average difference of about 2.7 cm in height and 1.7 kg in weight. Mean FEV1 and FVC (as percentage predicted) were significantly higher in the screened cohort at 5 and 10 years of age, with an average difference of 9.4% FEV1(95% CI 0.8, 17.9) and 8.4% FVC (95% CI 1.8, 15.0) at 10 years. Chest x-ray scores were not different between the groups at any age, but by 10 years screened patients scored an average 5.3 (95% CI 1.2, 9.4) points higher on the Shwachman score. CONCLUSION Although not a randomised trial, this long term observational study indicates that early treatment made possible by neonatal screening may be important in determining subsequent clinical outcomes for children with cystic fibrosis. For countries contemplating the introduction of neonatal screening for cystic fibrosis, its introduction to some areas in a cluster randomised design will permit validation of studies performed to date.

Pancreatic function in infants identified as having cystic fibrosis in a neonatal screening program

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.

Evidence for a Primary Defect of Pancreatic HCO3− Secretion in Cystic Fibrosis

Summary: The specificity of impairment of pancreatic water and HCO3− secretion in cystic fibrosis (CF) and the role of this impairment in diagnosing CF were studied in 62 CF patients and 66 non-CF controls. A quantitative pancreatic stimulation test using a duodenal bromsulphthalein marker perfusion technique was performed on each subject. The hourly secretion of trypsin, HCO3−, and water was measured. Over three ranges of tryptic activity (<50, 50–1000, and >1000 units per kg body weight per h, selected to represent low, intermediate, and normal acinar function respectively), mean water secretion was significantly lower in CF patients than in controls only when acinar function was low or intermediate. Mean water secretion per kg body weight per h did not vary among controls. In the CF patients, water secretion per kg body weight per h was significantly greater in those with trypsin secretion >1000 (8.28 ± 3.52 ml) than in those with trypsin secretions <50 (4.22 ± 5.8 ml, P < 0.02) or 50–1000 (3.07 ± 2.46 ml, P < 0.001). Mean HCO3− secretion in the CF patients was significantly impaired over all three ranges of tryptic activity when compared with controls. In both CF patients and controls there was a significant positive correlation between HCO3− and trypsin secretion. Analysis of covariance showed that HCO3− secretion was significantly impaired in the CF patients as compared with the controls over the total range of trypsin secretion.These data demonstate that CF patients have impairment of pancreatic water secretion in association with impaired acinar function but in those with normal acinar function, water secretion appears intact. The impairment of water secretion is thus probably the result of destruction of pancreatic tissue. Pancreatic HCO3− secretion, however, is generally impaired in CF patients even in those with normal pancreatic enzyme and water secretion. Because impairment of HCO3− secretion appears to occur independently of the extent of pancreatic damage, it may represent a primary secretory defect which is related to the defective CF gene. Inasmuch as a few CF patients had HCO3− secretory rates within the control range, the diagnosis cannot be excluded by the demonstration of HCO3− values within this range.Speculation: Patients with cystic fibrosis have evidence of exocrine gland dysfunction specifically in regard to electrolyte secretion. In the pancreas, impaired HCO3− secretion may be the result of a primary genetic defect. Further investigation of pancreatic HCO3− secretion is warranted to elucidate the nature and controlling factors of secretion as they may provide evidence for the underlying abnormality in cystic fibrosis.

Improved survival in cystic fibrosis patients diagnosed by newborn screening compared to a historical cohort from the same centre

Background Newborn screening (NBS) for cystic fibrosis (CF) is associated with improved early nutritional outcomes and improved spirometry in children. The aim of this study was to determine whether early diagnosis and treatment of CF with NBS in New South Wales in 1981 led to better clinical outcomes and survival into early adulthood. Methods Retrospective observational study comprising two original cohorts born in the 3 years before (‘non-screened cohort’, n=57) and after (‘screened’; n=60) the introduction of NBS. Patient records were assessed at transfer from paediatric to adult care by age 19 years and survival was documented to age 25 years. Results Non-screened patients (n=38) when compared with screened patients (n=41) had a higher rate and lower age of Pseudomonas aeruginosa acquisition at age 18 years (p≤0.01). Height, weight and body mass index (BMI) z scores (all p<0.01) and forced expiratory volume in 1 s (FEV1)% were better in the screened group (n=41) (difference: 16.7±6.4%; p=0.01) compared to non-screened (n=38) subjects on transfer to adult care. Each 1% increase in FEV1% was associated with a 3% (95% CI 1% to 5%; p=0.001) decrease in risk of death and each 1.0 kg/m2 increase in BMI contributed to a 44% (95% CI 31% to 55%; p<0.001) decrease in risk of death. This accumulated in a significant survival difference at age 25 years (25 vs 13 deaths or lung transplants; p=0.01). Conclusion NBS for CF leads to better lung function, nutritional status and improved survival in screened patients in early adulthood.

Age-Related Alterations of Immunoreactive Pancreatic Cationic Trypsinogen in Sera from Cystic Fibrosis Patients with and without Pancreatic Insufficiency

ABSTRACT: 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 µg/liter (± 2 SD) and levels did not vary with age or sex. In CF infants (< 2 yr) with pancreatic insufficiency, mean serum trypsinogen was significantly above the non-CF values (p<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<0.001), and 93% had values within or above the control range. In conclusion, serum trypsinogen appears to be a useful screening test for CF in infancy. Between 2 and 7 yr of age this test is of little diagnostic value. After 7 yr of age, serum trypsinogen can reliably distinguish between CF patients with and without pancreatic insufficiency.

Volumetric bone mineral density — a potential role in paediatrics

The use of areal bone mineral density (aBMD) in paediatric populations has aroused some concern, as it fails to take the age‐related increase in bone thickness into account. We have developed a measure of true bone density, volumetric bone mineral density (vBMD), which is independent of age and height. In order to examine the relationship between growth parameters, aBMD and vBMD, we studied patients with phenylketonuria (PKU, n = 40), chronic renal failure (CRF, n = 27) and chronic asthma (n = 19). aBMD of the femoral neck and the mid‐femoral shaft was measured using dual energy X‐ray absorptiometry (DXA), vBMD was calculated on the basis of values of bone mineral content and bone dimension provided by DXA, with the assumption that both sites are cylinders. aBMD and vBMD were then compared with the normal reference, expressed as a standard deviation score (SDS). aBMD and vBMD were normal in the femoral neck region of the PKU group, but aBMD, either standardized for age or for height, was low in the femoral shaft region (p < 0.01). In the CRF group, profound growth retardation was seen (mean height SDS, −3.2) and aBMD and vBMD were both low in the femoral shaft region but not in the femoral neck. In the asthma group, aBMD for age was low at both sites, but vBMD did not differ from that seen in normal individuals. We conclude that the true vBMD provides a different interpretation of bone density compared with aBMD and requires further evaluation in paediatrics because of its age and height independence.

Steatorrhea and Pancreatic Insufficiency in Shwachman Syndrome

Fat absorption was assessed on two or more occasions in 12 of 14 patients with Shwachman syndrome. Of 11 children who initially had steatorrhea, 6 were subsequently found to have normal fat excretion. In 10 of these 11 patients the last estimate was smaller than the initial estimate after an interval of 0.3-12.7 yr. The most dramatic improvement occurred under 4 yr of age but improvement appeared to continue over a more extended period where sufficient follow-up was available. All patients had pronounced pancreatic insufficiency as tested by duodenal drainage corrected by nonabsorbable marker under stimulation with cholecystokinin and secretin. Pancreatic lipase secretion was assessed in 3 patients with steatorrhea and 5 without steatorrhea (73% of the surviving patients) using a sensitive assay which used maximum stimulation with colipase. Pancreatic lipase secretion was less than 2% of normal mean secretion in the steatorrheic patients and ranged from 3.7% to 13.6% in the patients without steatorrhea. These results indicate that fat absorption improves in the majority of patients with Shwachman syndrome and appears to be associated with marginal improvement in pancreatic lipase secretion. Due to the occult nature of bowel complaints in older patients, the diagnosis may be overlooked unless careful screening for pancreatic function takes place.