Is the Sweat Test Infallible in Cystic Fibrosis?

ABSTRACT. The diagnosis of cystic fibrosis is straight forward if the clinical findings and sweat sodium are considered together. We describe 3 patients where the diagnosis has proved difficult as both the clinical features and sweat sodium have varied between normal and abnormal.     

Comparison of Classic Sweat Test and Crystallization Test in Diagnosis of Cystic Fibrosis

Objective

Sweat chloride measurement is considered a standard diagnostic tool for cystic fibrosis (CF). This study was performed to compare sweat chloride values obtained by quantitative pilocarpine iontophoresis (classic test) with sweat crystallization detected by direct observation of a drop of perspiration under light microscopy in patients with and without CF.

Methods

The tests using both techniques were performed simultaneously in patients with and without CF. Cutoff values of ≥60 mmol/L of chloride concentration for the classic sweat test was considered for diagnosis of CF. In crystallization method, observation of typical dendritic forms of salt crystals under light microscopy was interpreted positive.

Findings

Sixty patients suspected to CF (31 males and 29 females) with age range of 9 months to 2 years underwent the sweat test using both techniques. Median sweat chloride values was 26.13+10.85 in group with negative and 72.76+12.78 mmol/L in group with positive sweat test, respectively. All the patients who had positive sweat test in classic method showed typical dendritic forms of salt crystal in sweat crystallization test, which provided the test with 100% sensitivity (95%CI: 93.1–100). Only one of the 31 subjects with negative results for classic sweat test had positive result for crystallization sweat test, which provided the test with 96.7% specificity (95%CI: 92.9–100). Time spent to perform the crystallization test was significantly shorter than the classic method whereas its cost was also lower than the second method.

Conclusion

There was a good correspondence between two studied methods of sweat test. These results suggested the sweat crystallization test as an alternative test for detecting CF disease with high sensitivity and specificity.     

Physiological Measurements Confirming the Diagnosis of Cystic Fibrosis: the Sweat Test and Measurements of Transepithelial Potential Difference

Post-natal screening allied with genetic mutation testing has altered our perception of cystic fibrosis (CF) as a clinical entity. Increasingly, infants identified through screening programmes have few or no symptoms or present with atypical forms of the disease. We review how the sweat test has evolved to be the gold standard for confirming the diagnosis of CF and examine its limitations. Other physiological measurements, including nasal potential difference and intestinal current measurement, which might aid in establishing the diagnosis, particularly in patients exhibiting a mild phenotype, are also considered.     

Decreased Renal Clearance of Sodium in Cystic Fibrosis

ABSTRACT. In 10 patients with cystic fibrosis (CF) and 10 controls of similar age quantitative segmental handling of sodium was estimated by lithium clearance. In the CF group, there was tendency for an increased glomerular filtration rate (GFR) and increased absolute proximal sodium reabsorption. The fractional distal sodium reabsorption was significantly ( p =0.015) increased and sodium clearance was significantly ( p ≤0.01) decreased in CF.     

Bile Acid Metabolism in Children with Cystic Fibrosis

ABSTRACT. Recycling of bile acids through the enterohepatic cycle is very efficacious. Bile acids contribute to bile formation and, by forming micelles, participate in lipid solubilization and absorption. The small fraction which escapes in the feces, is synthesized daily by the liver to compensate for losses. In CF, bile acid malabsorption has been documented; these large losses are accompanied by an interruption in the enterohepatic circulation with concomitant reduction in bile acid pool and disturbances in biliary composition. The various intraluminal factors implicated in bile acid malabsorption include: unhydrolysed triglycerides and phospholipids, precipitation of bile acids in acidic duodenal content, adsorption to residues and modification of colonic microflora. A defect in bile acid ileal uptake has also been advocated. These disturbances in bile acid metabolism associated with CF might lead to aggravation of diarrhea and steatorrhea, cholelithiasis and perhaps liver disease.     

Sweat testing for cystic fibrosis: A review of New Zealand laboratories

BACKGROUND: Evolving diagnostic criteria for cystic fibrosis, broadening of the populations being tested and the need to interpret intermediate sweat test results have imposed a much greater need to standardize the collection and analysis of sweat. AIM: To identify variations in sweat testing in New Zealand laboratories and compare these with guidelines from the UK and the USA. METHODS: All laboratories in New Zealand offering sweat testing were identified and data collected from these laboratories by structured questionnaire. RESULTS: There were no New Zealand laboratories that conformed to either set of guidelines. Inconsistencies were observed in minimum sweat quantities, the nature of the iontophoresis solution, the sweat electrolytes analysed, quoted reference ranges and recommendations made as a consequence of the result. CONCLUSIONS: Conformity to the guidelines would help to minimize variation in sweat testing in New Zealand. Performance of a sufficient number of tests to maintain expertise is critical, but geographical constraints make patient travel to distant centres difficult in a small, scattered population. A possible solution, where numbers permit, may be the collection of sweat locally, with referral to a major laboratory for analysis. This is only possible with adequate training in collection and follow-up audit of the sweat testing procedure both in the collection and in the analytical phase.     

Determinants of Serum Vitamin D Levels in Preadolescent Cystic Fibrosis Children

ABSTRACT. The effects of liver disease, fat malabsorption and sunlight exposure on serum vitamin D levels were determined in 21 optimally treated preadolescent cystic fibrosis (CF) children over a 12-month period. Manifest liver disease and fat malabsorption appeared not to affect the vitamin D level. However, the level fell significantly in winter, although not below the normal range, suggesting that sunlight exposure is a more important determinant of vitamin D levels in preadolescent CF children than liver disease and fat malabsorption.     

Linear Growth in Children with Cystic Fibrosis: I. Birth to 8 Years of Age

ABSTRACT. The linear growth of Swedish children with cystic fibrosis (CF), is described using the infancy–childhood–puberty (ICP) growth model. Length/height was studied in 51 patients during their first 8 years of life. The median age at diagnosis was 0.4 years (range 0.0–6.1 years). At birth, their mean length was close to normal, but the gain in length over the first 0.25 years of life was significantly below normal, resulting in a mean length SDS of -1.3. Length remained subnormal up to 1.0 year of age. Thereafter, catch-up growth occurred, resulting in almost normal height (mean SDS -0.3) at 5.0 years of age. Between 5.0 and 8.0 years of age growth was normal. The mean age at onset of the childhood component was not significantly different from the controls. Hence, the catch-up growth did not occur until after the onset of the childhood component. This study shows that the postnatal linear growth rate is retarded in children with CF during the first months of life. This is almost completely compensated for by a supranormal growth rate that starts at the end of the first year of life.     

Aldosterone in Cystic Fibrosis: Measurement in Saliva and Correlation with Disease Severity

ABSTRACT. Aldosterone was measured in the saliva of 20 patients with cystic fibrosis and a group of 20 normal children matched for age and sex. Mean levels were higher in the patient group but overall differences were small and statistically not significant. For the first time a link between aldosterone level and disease severity in patients with cystic fibrosis was established using a simple scoring system to assess disease activity. Urinary and salivary electrolytes were similar in the two groups. The results do not support the proposed hypothesis that the salivary glands of patients with cystic fibrosis are insensitive to aldosterone.     

Glucose Tolerance and Insulin Receptor Binding to Monocytes and Erythrocytes in Patients with Cystic Fibrosis

ABSTRACT. Cystic fibrosis (CF) is the most frequent life threatening hereditary disease in the Western World with an incidence of approximately 1:2000. Due to increasing survival rates the high frequency of abnormal glucose tolerance has become an important problem. We compared insulin concentrations during oral glucose tolerance test and insulin receptor binding to both monocytes and erythrocytes from 9 patients with CF, with results from 10 healthy controls of similar body weight. The insulin: glucose ratio was increased in the fasting state ( p < 0.05) in patients with CF compared to controls, indicating an increased insulin resistance in CF-patients. The total insulin secretion during oral glucose tolerance test as judged by the area beneath the insulin curve was similar in the two groups, but insulin secretion was significantly delayed in patients with CF. Insulin receptor binding to monocytes and the number of receptors were significantly increased ( p < 0.01 and 0.02, respectively) in patients with CF whereas the dissociation constant was similar in patients with CF and controls. No difference was observed in insulin receptor binding to erythrocytes between the two groups. No correlations were found between insulin receptor binding to monocytes or erythrocytes and glucose tolerance or insulin concentrations.     

Estimated Risk of Cross-Infection with Pseudomonas aeruginosa in Danish Cystic Fibrosis Patients

ABSTRACT. During the period 1970–1987 the number of cystic fibrosis (CF) patients treated at the Danish CF Centre increased from 54 to 226. The prevalence of patients with chronic P. aeruginosa infection (CF + P) increased from 35% to 59%, whereafter it decreased to 54%. The yearly incidence of new CF + P patients averaged 8.4% in 1970–1975, 17% in 1976–80, 6.5% in 1981–85, and 3% in 1986–87. These changes correlated to the increased "contact density" between CF + P and non-infected CF patients (CF-P) due to intensified treatment starting in 1976, and the reduced "contact density" due to separation of the two groups starting in 1981. The same trends were observed during an epidemic spread of a multiply resistant P. aeruginosa in the CF + P group, which was also interrupted by separation of two groups of patients, with and without the multiply resistant strain. The observed prevalences of CF + P in different age groups of patients are in accordance with a 20% incidence/year in patients older than three years. The highest probability of aquiring chronic P. aeruginosa infection was calculated to be 2%/day and the lowest 0.09%/day spent in the Centre. By employing a simple mathematical model of the spread of infectious diseases it can be shown, that the highest incidence of CF + P is present when the prevalence of CF + P is 20–80%, and that an increase in the total number of patients also increases the incidence of CF + P unless the patients are divided into smaller groups. The observations in the Danish CF Centre are in accordance with this model.     

Low Concentrations of Sodium and Magnesium in Erythrocytes from Cystic Fibrosis Heterozygotes

ABSTRACT. The concentrations of electrolytes and trace elements in erythrocytes were determined in eight children with cystic fibrosis (CF) and the parents of four of the children and compared with age- and sex-matched healthy controls. The children with CF had significantly lower median erythrocyte concentrations of sodium, magnesium and zinc and a higher median concentration of calcium than both the healthy control children and the parents of the CF children. Although the sodium and magnesium median values were higher in CF parents than in CF children they were nevertheless significantly lower than in adult controls. These data indicate a system for heterozygote detection.     

Pancreatic Islets in Older Patients with Cystic Fibrosis with and without Diabetes Mellitus: Morphometric and Immunocytologic Studies

Forty patients with cystic fibrosis (CF), including 34 who died above age 10 years without having developed clinical diabetes mellitus and 6 who died with both cystic fibrosis and diabetes mellitus, were studied. The mean age of the female patients with CF but not diabetes was 15.8± 5.6 years; of males without diabetes, 17.2± 6.4 years; of female patients with CF and diabetes mellitus, 20.2± 6.9 years; and of males with CF and diabetes, 21.3± 6.6 years. The mean number of pancreatic islets in microscopic sections for patients with cystic fibrosis but not diabetes was 4.18± 2.76/mm², and the value for patients with both cystic fibrosis and diabetes mellitus was 2.61± 2.07/mm². The lowest density of pancreatic islets (1.69± 0.48/mm²) for cystic fibrosis was found in patients with the latest-stage pathologic lesion. Nesidioblastosis (presence of ductuloinsular complexes) was identified in 14 of 38 cystic fibrosis patients, both with and without diabetes mellitus. The pancreatic islets of both diabetic and nondiabetic patients with CF showed hypertrophy; the mean volume of the three largest pancreatic islets for CF only was 0.0117± 0.00657³ mm and that for cystic fibrosis and diabetes was 0.00795± 0.00599 mm³, both values being larger than normal. Ratios of the amounts of islet endocrine cells, A cells, B cells, and D cells, were determined by peroxidase-anti-peroxidase labeled antibody staining. The B cells composed 43.0% of endocrine cell mass in cystic fibrosis alone and 30.1% in cystic fibrosis with diabetes mellitus, which were lower than normal proportions. The D cell values, 11.9% in cystic fibrosis and 15.1% in cystic fibrosis with diabetes mellitus, on the other hand, were greater than normal ratios.     

Cystic Fibrosis with Fibrosing Colonopathy in the Absence of Pancreatic Enzymes

Fibrosing colonopathy, characterized by dense submucosal fibrosis in the large bowel, is a disorder associated with bowel dysfunction in patients with cystic fibrosis who receive pancreatic enzyme supplementation. Most commonly, patients present with a distended abdomen and abdominal pain. Radiographs frequently demonstrate colonic wall thickening and luminal narrowing. Here I describe a neonate with cystic fibrosis who presented with both clinical and histological features of fibrosing colonopathy who had not received pancreatic enzymes. This report expands our understanding of the pathogenesis of fibrosing colonopathy. Received January 13, 1997; accepted June 5, 1997     

Scanning Electron Microscopic Study of the Airways in Normal Children and in Patients with Cystic Fibrosis and Other Lung Diseases

Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to examine pulmonary tissue from 9 patients with cystic fibrosis (CF), 12 patients with diseases other than CF, and from two surgically resected specimens with no known airways disease. A region of the human airways, the transition zone, was observed between the end of the terminal bronchiole and the type II alveolar cell lining of the respiratory bronchioles. This region was lined predominantly by nonciliated bronchiolar (NCB) cells. Patients with CF exhibited indistinct transition zones, epidermoid metaplasia, large dilated bronchial gland, copious surface mucus, alveolar destruction, and unusual microvilli; no single lesion specific for cystic fibrosis was identified.     

Antibodies to Staphylococcal Teichoic Acid and Alpha Toxin in Patients with Cystic Fibrosis

ABSTRACT. Enzyme-linked immunosorbent assay (ELISA) was used for IgG antibody determination to teichoic acid and a -toxin from Staphylococcus aureus in 65 patients with cystic Fibrosis (CF). In patients chronically colonized with S. aureus , elevated titres to teichoic acid were found in 13/35 (37%) patients, to a -toxin in 12/35 (34%) and to either antigen in 18/35 (51%). Patients with elevated titres to teichoic acid had a significantly lower X-ray score than patients with normal titres. The highest titres against both teichoic acid and a -toxin were seen in patients not receiving optimal treatment. These findings suggest that staphylococci contribute to the tissue damage in CF and that the determination of antibodies especially to staphylococcal teichoic acid might be of value in the diagnosis and management of staphylococcal infections in patients with CF.     

Morphometric Studies of Cystic and Tubulointerstitial Kidney Diseases with Hepatic Fibrosis in Children

Portal tract fibrosis with biliary ductular enlargement or proliferation occurs in a number of genetic diseases that have cystic or tubulointerstitial renal lesions. These include some with renal cystic disease such as autosomal recessive diseases (e.g., infantile polycystic disease, juvenile polycystic disease, and Meckel's syndrome), autosomal dominant diseases (e.g., adult polycystic disease), and, rarely, tuberose sclerosis and dominant glomerulocystic disease. Portal tract fibrosis with biliary enlargement and proliferation occurs also with tubulointerstitial kidney diseases. These probably include at least three disorders in the category nephronophthisis-congenital hepatic fibrosis (one autosomal recessive disease and two either autosomal or X-linked recessive diseases) plus Jeune's syndrome (the tubulointerstitial diseases Fanconi's familial nephronophthisis and anti-tubular membrane antibody disease do not regularly cause hepatic fibrosis). Morphometric data on ratios of bile ductules to connective tissue in hepatic portal tracts show high values for infantile polycystic disease (mean, 0.616) compared to lower values for juvenile polycystic disease (mean, 0.286). That the cystic renal lesions of the first two diseases differ in type and time course is known. Similar data on ratios of glomeruli plus tubules to connective tissue in renal cortices and of tubules to connective tissue in outer medullary zones of kidneys, respectively, are as follows: for Fanconi's nephronophthisis, 0.445 and 0.197; for anti-tubular basement membrane antibody disease, 0.585 and 0.164; and for the three types of nephronophthisis-congenital hepatic fibrosis studied, 0.668 and 0.446, 1.39 and 0.921, and 1.18 and 0.12. These data support clinical impressions that the category nephrophthisis-congenital hepatic fibrosis includes more than one disease entity.     

Excretion of Urinary Collagen Metabolites Correlates to Severity of Pulmonary Disease in Cystic Fibrosis

ABSTRACT. The urinary excretion of collagen metabolites (hydroxylysine, hydroxyproline and proline) was significantly increased in 10 patients with cystic fibrosis and chronic broncho-pulmonary Pseudomonas aeruginosa infection as compared with 14 age matched controls. The increase was significantly correlated to impaired pulmonary function (FVC and FEV₁). The results indicate that urinary collagen metabolites reflect degradation of lung connective tissue and may be an indicator of the severity of pulmonary disease in cystic fibrosis. Parts of the excreted hydroxyproline may be degradation products of elastin.