Gordon G. Forstner

Improved respiratory prognosis in patients with cystic fibrosis with normal fat absorption

The clinical presentation, courses, and sweat chloride values of 72 CF patients with normal fat absorption are described. In general, these patients had milder clinical symptoms and a lower mean sweat chloride value than their counterparts with steatorrhoea. Pulmonary function tests, including FEV1, FVC, FEF25%-75%, PaO2, and RV/TLC%, were significantly better in patients with normal fat absorption compared with both male and female patients who had steatorrhoea. The maintenance of better pulmonary function, coupled with the low mortality, suggests that patients without steatorrhoea have a better prognosis. This difference remains unexplained, but may be contributed to by nutritional, genetic, or pancreatic factors.

Impaired chloride secretion, as well as bicarbonate secretion, underlies the fluid secretory defect in the cystic fibrosis pancreas

Pancreatic fluid and electrolyte secretion was assessed in 56 patients with cystic fibrosis (CF) and 56 non-CF control subjects undergoing pancreatic function testing while stimulated with cholecystokinin and secretin. Both CF patients and control subjects exhibited a wide range of pancreatic function. Fluid and trypsin outputs were positively correlated in both groups. Fluid output in CF subjects was significantly lower, however, than that of control subjects at any given level of trypsin output. Sodium, bicarbonate, and chloride secretions were all significantly decreased in CF subjects. Bicarbonate and chloride were important determinants of fluid secretion, but at any given bicarbonate or chloride output CF subjects secreted significantly less fluid than control subjects. When bicarbonate and chloride were analyzed as simultaneous predictor variables, adjusted fluid secretion was not significantly different in CF and control subjects. Diminished fluid secretion in CF subjects is therefore caused by impaired chloride, as well as bicarbonate, secretion.

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.

Microvillus inclusion disease: an inherited defect of brush-border assembly and differentiation

IN 1978 we described a group of infants who presented with an apparently familial enteropathy characterized by protracted diarrhea from birth and hypoplastic villous atrophy.1 Electron microscopica...

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.

Plasma membrane and mucosal glycosphingolipids in the rat intestine

Abstract 1. 1. Glycosphingolipids were extracted from rat intestinal mucosa, brush border membranes, and isolated microvillus membranes and analyzed both qualitatively and quantitatively. 2. 2. The major glycosphingolipids in rat small intestinal mucosa were monohexosylceramide, trihexosylceramide and a ganglioside, containing neuraminidase-sensitive N -glycolyl sialic acid. Three additional fractions, (Complexes 1, 2 and 3), two of which contained fucose, were also identified. 3. 3. The distribution of glycosphingolipids was proportionately similar in the plasma membrane except for the appearance of substantial dihexosylceramide in two of three preparations. Gas-liquid Chromatographic analysis of sugars in monohexosylceramide, trihexosylceramide and in Complexes 1, 2 and 3 revealed almost identical sugar composition for corresponding membrane and mucosal fractions. Therefore membrane glycosphingolipids do not differ substantially from mucosal glycosphingolipids. 4. 4. The microvillus membrane contained four times as much glycosphingolipid expressed as percentage of total lipid, as did the intestinal mucosa. The relative enrichment of the membrane with glycosphingolipid was greater than with cholesterol. 5. 5. A minimum of 19.1 % of microvillus membrane lipid is made up by glycosphingolipid. This concentration is much higher than levels previously reported for extraneural mammalian plasma membrane.

Effect of cimetidine and sodium bicarbonate on pancreatic replacement therapy in cystic fibrosis.

Fifteen patients with cystic fibrosis and pancreatic insufficiency were studied during four randomised seven day treatment periods in which they received only pancreatic supplement (Pancrelipase, 27 capsules per day) or supplement plus cimetidine (20 mg/kg body weight/24 h) or sodium bicarbonate (15 g/m2/24 h) alone or in combination. Dietary intake was not fixed but was restricted to foods of known fat and nitrogen content from which daily intakes could be computed. Faecal fat and nitrogen were calculated as g/24 h and percentage of intake. Addition of either cimetidine or bicarbonate resulted in significant improvement in fat and nitrogen excretion, which was not greater with the combination of both drugs. Cimetidine and sodium bicarbonate in these doses are therefore sufficient to produce maximal improvement in digestive activity of pancreatic supplements. Fat excretion per gram of intake fell with cimetidine and bicarbonate from 12 times the normal level, to normal, in patients consuming less than 120 g fat daily. Above this intake the dose of pancreatic supplement appeared to be inadequate. Faecal nitrogen excretion increased with nitrogen intake in all four periods, but, in contrast with fat excretion, the response to cimetidine and bicarbonate was not affected by the level of intake. Dietary intake appears to be a significant factor in determining the faecal output of fat and nitrogen in patients with pancreatic insufficiency and should be considered when determining the optimum amount of pancreatic supplementation.

Phenotypic abnormalities in long-term surviving cystic fibrosis mice.

Mouse models for cystic fibrosis (CF) with no CFTR function(Cftr-/-) have the disadvantage that most animals die of intestinal obstruction shortly after weaning. The objective of this research was to extend the lifespan of CF mice and characterize their phenotype. Weanlings were placed on a nutrient liquid diet, and histologic and functional aspects of organs implicated in the disease were subsequently examined. Approximately 90% of Cftr-/- mice survived to 60 d, the majority beyond 100 d. Cftr-/- mice were underweight and had markedly abnormal intestinal histology. The intestinal epithelia did not respond to challenges with agents that raised intracellular cAMP, consistent with the absence of functional CFTR. No lesions or functional abnormalities were evident in the lungs. Liquid-fed Cftr-/- mice were infertile, although some males weaned to a solid diet were fertile before they died. Thus, we have succeeded in using dietary means to prolong the lives ofCftr-/- mice.

Decline of exocrine pancreatic function in cystic fibrosis patients with pancreatic sufficiency.

ABSTRACT: Patients with cystic fibrosis and pancreatic sufficiency were investigated for evidence of progressive pancreatic disease. From a cohort of 630 patients, 20 pancreatic-sufficient patients became pancreatic insufficient after an average duration of 5.6 y (range 0.6–20.6 y) from diagnosis. Among 54 patients documented to be pancreatic sufficient by direct pancreatic stimulation test, 47 remained pancreatic sufficient and seven developed pancreatic insufficiency. The patients who ultimately developed pancreatic insufficiency were younger and had greatly reduced outputs of enzyme, fluid, and electrolytes. Those who remained pancreatic sufficient showed enzyme secretion close to or within the non-cystic fibrosis control range. Twenty of these patients underwent a second pancreatic stimulation test after an average interval of 4 y (range 1.3–6.2 y). No significant alteration in enzyme, fluid, or electrolyte output was seen in the patients who remained pancreatic sufficient, but there was further reduction in enzyme and fluid output in the patients who developed pancreatic failure. In conclusion, the majority of pancreatic-sufficient patients with pancreatic enzyme secretion within the control range showed no deterioration of function over an extended time period. However, a small number of pancreatic-sufficient patients with reduced enzyme and fluid secretion are at risk of pancreatic failure.

Human intestinal mucin in cystic fibrosis.

Summary: Human intestinal mucins from six subjects with Cystic Fibrosis (CF) and eight subjects without CF were prepared from tissue obtained at surgery (one case) and postmortem. Subjects were not age-matched, but the nonCF mucin was obtained from subjects with ages which bracketed those of the CF subjects. Cesium chloride analytical gradient ultracentrifugation showed that CF mucins were generally denser than nonCF mucins. Sedimentation coefficients were also higher in the CF samples. CF mucins were enriched in fucose, galactose, N-acetylglucosamine and total carbohydrate per mg protein and per oligosaccharide chain (mole/ mole GalNAc). Fucose/sialic acid molar ratios were significantly higher in CF mucins, and the average oligosaccharide chain length was approximately three residues greater in CF as compared with nonCF mucins. There was no difference in amino acid profiles or the number of side chains per molecule. The mean sulfate content was higher in the CF mucins but not to a level of significance; however, in the eight mucins, sulfate content correlated positively with total carbohydrate, N-acetylglucosamine and galactose, and therefore increased with oligosaccharide chain length. CF intestinal mucin was therefore denser and more highly glycosylated than nonCF musin and probably contained more sulfate. The increase in glycosylation resulted from a rise in fucose, galactose, and N-acetylglucosamine without a concomitant rise in sialic acid.Speculation: Hyperglycosylation with an associated increase in average chain length of carbohydrate side chains ought to increase the equivalent hydrodynamic volume of the mucin molecule and so result in enhanced viscosity and gelling. These features may contribute to the hyperviscosity often noted in mucus-rich secretions in CF and could enhance mucus plugging of small ducts. Increased mucin carbohydrate could represent one of the fundamental abnormalities contributing to the pathology of this disease.