Energy supplements rich in linoleic acid improve body weight and essential fatty acid status of cystic fibrosis patients

BACKGROUND: Patients with cystic fibrosis who have steatorrhea frequently are underweight and have essential fatty acid (EFA) depletion, which is associated with a poor clinical course. It has been stated that poor EFA status is difficult to correct in patients with cystic fibrosis, and an impaired EFA metabolism with reduced synthesis of long-chain polyunsaturated fatty acids has been proposed. In this study, the effects of an oral energy supplement rich in linoleic acid were investigated in patients with cystic fibrosis who had a body weight below 95% of normal for height. METHODS: Thirty-six patients (16 girls) more than 4 years of age were randomized either to a control group (n = 20, age 13.3 +/- 3.8 years, mean +/- SD) receiving intensive dietary counseling only, or an intervention group (n = 16, age, 10.4 +/- 4.3 years) treated for 3 months with dietary counseling plus 628 +/- 254 mL (= kcal) per day of an energy supplement rich in fat (31% of energy) and linoleic acid (16% of energy). RESULTS: In contrast to the control group, the patients with supplemented diets achieved significant increases of energy intake (2189 +/- 731 kcal/day vs. 2733 +/- 762 kcal/day), weight for height (82.8% +/- 8.6% vs. 84.8% +/- 9.6% of normal), and body fat (5.1 +/- 1.7 kg vs. 5.8 +/- 2.2 kg) as well as the initially low values of plasma phospholipid linoleic acid (11.8% +/- 1.1% vs. 17.6% +/- 1.6% of total phospholipid fatty acids) and its main metabolite arachidonic acid (4.4% +/- 0.4% vs. 5.9% +/- 0.3%). CONCLUSIONS: Patients with cystic fibrosis with low body weight and poor EFA status benefit from EFA-rich energy supplements and can synthesize arachidonic acid from the precursor linoleic acid.     

Essential fatty acid deficiency in well nourished young cystic fibrosis patients

Essential fatty acid deficiency is well known in cystic fibrosis patients, but its pathogenesis remains unclear. It might be related to protein-energy malnutrition which is a common feature of cystic fibrosis or to some specific defects in fatty acid metabolism. To avoid the deleterious effects of protein-energy malnutrition, this study assesses the plasma phospholipid fatty acid pattern in well nourished young cystic fibrosis subjects. Sixteen cystic fibrosis subjects aged 6.6–20.0 years were studied and compared to 16 healthy controls matched for gender, age and nutritional status. Plasma phospholipids were separated by thin layer chromatography and phospholipid fatty acid pattern was determined by gas liquid chromatography. Anthropometry and dual-energy X-ray absorptiometry showed that lean body mass, fat-free mass and fat mass were similar in the two groups. Nutritional inquiry showed higher ingestion of macronutrients by cystic fibrosis subjects than by controls. Plasma phospholipid palmitoleic acid and eicosatrienoic acid were higher, and by contrast linoleic acid and docosahexaenoic acid were lower in cystic fibrosis subjects than in controls. The ratio linoleic acid/arachidonic acid was lower and the ratio eicosatrienoic acid/arachidonic acid was higher in cystic fibrosis subjects than in controls. Conclusion Essential fatty acid deficiency is present in young cystic fibrosis subjects in the absence of protein-energy malnutrition. It means that this deficiency is probably related to specific defects in fatty acid metabolism. Received: 1 December 1997 and in revised form: 3 July 1997 / Accepted 8 July 1997     

Essential fatty acid deficiency in relation to genotype in patients with cystic fibrosis.

OBJECTIVE: To determine if the serum phospholipid fatty acid pattern in patients with cystic fibrosis (CF) was related to the major cystic fibrosis transmembrane conductance regulator gene mutations. METHODS: Patients with CF (n = 110) aged 3 months to 56 years were studied. Serum samples were analyzed for phospholipid fatty acid with gas-liquid chromatography, and cystic fibrosis transmembrane conductance regulator mutations were determined with standard methods. RESULTS: Patients with CF had significantly lower molar percentages of linoleic acid and docosahexaenoic acid in the serum phospholipid than healthy controls (mean +/- standard deviation, 20.3 +/- 4.5 and 2.6 +/- 0.9 vs 22.4 +/- 2.2 and 3.1 +/- 0.7, respectively; P <.001). Palmitoleic and oleic acids were significantly increased (P <.001) but arachidonic acid was not different from controls. Homozygotes for DeltaF508 and heterozygotes/homozygotes for 394delTT showed significantly lower concentrations of linoleic acid and docosahexaenoic acid than the other groups. Low values were not correlated to anthropometric data or lung function. Patients with pancreatic insufficiency showed similar differences to those with sufficient pancreatic function, reflecting the different genotypes. CONCLUSION: Serum concentrations of linoleic acid and docosahexaenoic acid were significantly lower in patients with severe cystic fibrosis transmembrane conductance regulator mutations, suggesting an association between the basic defect and abnormal essential fatty acid metabolism in CF patients.     

Effect on renal function of essential fatty acid supplementation in cystic fibrosis

Changes in renal hemodynamics, sodium homeostasis, renal acidifying capacity, and aldosterone excretion were studied before and after long-term intravenous essential fatty acid supplementation for a period of 3 years in 11 patients with cystic fibrosis. The mean (+/- SD) glomerular filtration rate was high at the start of the study (133 +/- 18 ml/min/1.73 m2 body surface area) and decreased significantly (p less than 0.05) to within normal values after 1 year of essential fatty acid supplementation. The urinary elimination of an oral sodium load initially was very low (3.6 +/- 2.5 mmol/hr/1.73 m2 body surface area vs control subjects' values of 7.9 +/- 2.0; p less than 0.001) and increased during treatment but was not normalized (p less than 0.05 vs control subjects' values). Free water clearance and distal tubular sodium delivery, which were significantly decreased before treatment (p less than 0.01 and p less than 0.001 vs control subjects' values, respectively) did not increase significantly. The mean urinary aldosterone excretion did not significantly differ from that in control subjects before and after treatment. The acidifying capacity was disturbed, indicating a low renal bicarbonate threshold, and was changed during treatment in only 2 of 10 patients. These data indicate that essential fatty acid deficiency may contribute to the renal disturbances in cystic fibrosis.     

Essential fatty acid deficiency and predisposition to lung disease in cystic fibrosis

Essential fatty acid (EFA) deficiency is a predisposing factor for pulmonary infection with Staphylococcus aureus and Pseudomonas aeruginosa , the two major pathogenic microorganisms in cystic fibrosis (CF). Objective : The goal of this study was to investigate the essential fatty acid status of CF patients from infancy to 20 years old. Materials and methods. Plasma fatty acid profiles for phospholipid (PL) were determined for cord ( n = 6), 4 months ( n = 40), 16 months ( n = 25), 3 y ( n = 8), 5-10 y ( n = 10), and 10-20 y ( n = 10) aged CF patients and compared to their respective control; cord ( n = 22), 1-36 months ( n = 38) and adult ( n = 100). Significance was established by Student's t-test ( p < 0.05). Results : The plasma PL fatty acid profile for all CF patients, except cord, revealed consistent deficiency in ω3 and ω6 EFAs. These deficiencies were most marked at infancy and more pronounced for patients with meconium ileus. Conclusions and relevance : EFA deficiency may contribute to the predisposition of CF infants to develop respiratory disease and to the excess cytotoxic activity found in bronchoalveolar lavage fluid at 2 months of age in the majority of screened infants.     

Short-chain fatty acid absorption in patients with cystic fibrosis.

Patients with cystic fibrosis (CF) often exhibit malabsorption despite the use of supplemental pancreatic enzymes. Unabsorbed carbohydrates and amino acids can serve as substrates for large intestine anaerobic fermentation, thus increasing excretion of short-chain fatty acids (SCFA) in the feces. Nine patients with CF on regular pancreatic enzyme supplementations in the age range of 5-11 years and one older patient were studied. Three-day stool samples were collected, as were 72-h food records. Stools were analyzed for gross energy, total nitrogen, fat content, and SCFA concentration. A significant difference was found between CF and normal controls in total caloric excretion due to fat malabsorption. No significant difference was found between CF and normal controls in protein or SCFA excretion. Fat excretion as percentage of fat intake was significantly increased in CF patients: 35.3 +/- 10.2% versus 8.0 +/- 3.0%, respectively. These data suggest that carbohydrate supplementation could be more widely used to increase caloric intake in CF patients without causing secondary osmotic diarrhea.     

Correction of linoleic acid deficiency in cystic fibrosis

To identify evidence of essential fatty acid deficiency, we screened 64 patients with cystic fibrosis by analyzing total lipid extracts from plasma. Forty-three had an abnormal linoleate (18:2) level (less than 26%). Thirteen deficient patients (aged 10-24 yr) ingested for 1 yr 7% of their total calories as linoleate derived from a daily supplement of Microlipid. Five deficient patients (aged 10-37 yr) served as controls. Plasma and erythrocyte fatty acid composition were monitored by gas chromatography of total lipid extracts seven times during the twelve month period. Prostaglandins E2 and F2 alpha and their 15 keto 13, 14 dihydrometabolite, 6-keto F1 alpha, and thromboxane B2 were measured by radioimmunoassay. Sweat tests, oxygen saturation, growth indices, clinical severity scores, compliance, and possible side effects from taking Microlipid were followed. Results showed that oral supplementation with Microlipid can significantly increase plasma and erythrocytes % 18:2. One compliant patient died during the study and had normal tissue 18:2 levels. Nine of 13 patients gained more weight while taking Microlipid than in the previous year. No significant changes in sweat electrolytes, clinical scores, or oxygen saturation were found during the study year. Prostaglandin metabolites prostaglandin E2 showed an upward trend in supplemented patients, compared to controls. Prostaglandin F2 alpha remained unchanged over 1 yr but showed a trend significantly downward over the final 6 months in supplemented patients. We conclude that linoleate deficiency can be corrected with daily Microlipid supplements and that correction may alter prostaglandin metabolism.     

Sodium chloride deficiency in cystic fibrosis patients

Sodium chloride deficiency (SCD) was observed within the 1st year of life in 12 of 46 cystic fibrosis (CF) patients between July 1989 and September 1992. All patients showed sweating, loss of appetite, fever, vomiting, irritation, dehydration, weakness, and cyanosis during an attack. Mean plasma sodium, potassium and chloride levels were 122.9 (range 106–135), 2.5 (range 1.6–3.5), and 73.3 (range 60–90) mEq/l respectively. Alkalosis and elevated plasma renin activity were detected in all patients. Of the patients, 50% showed microscopic haematuria, and hypercalciuria was detected in two out of four patients. Low urinary sodium and high urinary potassium were observed in the four examined patients. Increased creatinine, BUN and uric acid values returned to normal with treatment. All the patients were treated initially with intravenous fluids and electrolyte solutions. All patients were less than 7 months of age during the first attack, five received only breast milk and the others breast milk with formula milk. Their oral salt supplement was 2–4 mEq/kg per day, which is recommended for CF patients, but could be deficient in excessively sweating infants. The genotype of these patients might be cause of high salt losses. F508 is the most common mutation with the frequency of 38% in our CF patients with SCD, but the frequency of unknown mutations is high (54%).     

Abnormal fatty acid composition and impaired oxygen supply in cystic fibrosis patients.

Impaired oxygen supply and deteriorating health, in cystic fibrosis patients, correlates with abnormal changes in the fatty acid composition of blood lipids. As the proportion of oleates increases and that of linoleates decreases, erythrocyte membrane interference with the formation of intracellular oxyhemoglobin increases and arterial oxygen pressure decreases. The physical-chemical basis for these changes seems to be that oleic and linoleic acid differ in their ability to undergo reversible oxygenation in response to changes in oxygen pressure. The oxygen complex of linoleic acid dissociates at relatively high pressures, whereas that of oleic dissociates only at low pressures. Accordingly, excessive substitution of oleic for linoleic acid in membrane lipids would be expected to decrease the intracellular oxygen pressure to a level where hemoglobin oxygenation and any other oxygen-requiring processes would be impaired.     

Relationships between pulmonary function and plasma fatty acid levels in cystic fibrosis patients

Nineteen patients with cystic fibrosis (CF) were studied to determine whether plasma fatty acids correlated with severity of their lung disease as assessed by pulmonary function testing. Results were compared with 19 normal subjects of similar age and sex. Linoleic acid content of all lipid fractions was significantly lower in CF patients than controls including cholesterol ester fraction (CF 31%, control 50%, p less than 0.001), triglyceride fraction (7.6 to 16.6%, p less than 0.001), and phospholipid fraction (13.9 to 21.7%, p less than 0.001). Mean 20:3 omega 9/20:4 omega 6 ratio for CF patients was higher in all lipid classes and was suggestive of essential fatty acid deficiency. Correlations were found to exist between most pulmonary function parameters and fatty acids of plasma phospholipids but not any other lipid class. Positive correlations were found between all ventilatory tests and total omega 3 polyunsaturated fatty acids and also 22:5 omega 3 and 22:6 omega 3. There was no correlation between total saturated fatty acids, total monounsaturates, total omega 6 fatty acids, or triene/tetraene ratios and pulmonary function. Positive correlations were found between pulmonary function parameters and certain omega 6 polyunsaturates including 20:4 and 22:4 but not 18:2.     

Prospective study of fatty acid supplementation over 3 years in patients with cystic fibrosis

Intravenous fatty acid supplementation (10% Intralipid, 10 ml/kg body weight) was given to 10 patients with cystic fibrosis (CF), in intervals for 3 years. One year of intensive treatment with supplementation every fortnight was followed by 1 year of intermission and then 1 year of the same treatment given for 2 days every 2 months. Compared with matched CF patients, the clinical course, evaluated by Shwachmann scoring, showed less deterioration in the treated group, especially during the year of intensive treatment. Single parameters, such as pulmonary function tests, pulmonary X-ray films, clinical infections, bacterial growth of sputa, and sweat electrolyte concentration, showed no differences. It is concluded that if there is any benefit of this kind of treatment in CF, it has to be very intensive. At present, the psychological stress involved in repeated parenteral administrations over long periods prevents its use in clinical routine.     

A therapeutic trial of fatty acid supplementation in cystic fibrosis.

Seven children with cystic fibrosis (CF) have been treated for at least one year with intravenously administered soya oil emulsion. In all, an improvement of at least one biochemical abnormality in character with the disease appeared. The children's clinical course remains benign. This course is remarkably better than that of other children with CF treated without Intralipid in Auckland in the same period, though a placebo effect cannot be discounted. It is postulated that intravenous supplementation with essential fatty acid in CF may in turn partially correct an error of metabolism of prostaglandins present in the disease.     

Iron deficiency in cystic fibrosis.

Iron state was measured as part of the comprehensive assessment of 165 patients with cystic fibrosis. Of 127 patients, 41 (32%) had low serum ferritin concentrations and at least this proportion were iron deficiency. Iron state did not correlate with clinical score, radiological score, or results of sputum culture. There was no evidence that patients with iron deficiency were either in better or worse clinical condition than those with better iron stores.