Effect of an 8-month treatment with (omega)-3 fatty acids (eicosapentaenoic and docosahexaenoic) in patients with cystic fibrosis
De Vizia, Basilio
ABSTRACT. Background: Supplementation of the diet with eicosapentaenoic acid and docosahexaenoic acid, the main long-chain w-3 fatty acids in cell membranes, may have beneficial effects in patients with cystic fibrosis. Methods: A prospective study involving 30 patients and 20 control subjects was carried out; eicosapentaenoic plus docosahexaenoic acid was equal to 1.3% of caloric intake in the cystic fibrosis patients. Our present study included the evaluation of eicosapentaenoic and docosahexaenoic acid incorporation into erythrocyte membranes and biological and clinical effects in response to long-term (8 months) supplementation with fish oil as a source of eicosapentaenoic and docosahexaenoic acids in patients with cystic fibrosis. Results: Baseline erythrocyte membrane fatty acids showed low levels of linoleic acid and eicosapentaenoic acid and mild elevation of 18:3n6, but similar docosahexanoic acid and other fatty acids in cystic fibrosis patients compared with controls. Fish oil supplementation led to a 1.7-fold (p
Cystic fibrosis (CF) occurs in about 1 in 2500 births and is the most common lethal genetic disease of Caucasians. Chronic and progressive lung disease, the main cause of morbidity and mortality, is the result of pulmonary bacterial colonization by Staphylococcus and Pseudomonas, infection, and inflammation. A characteristic feature of pulmonary inflammation in CF patients is the abnormal number of neutrophils present in the lung. Leukotriene B4 (LTB-4) and tumor necrosis factor alpha (TNF-ot) have been implicated in the enhanced influx of neutrophils into the lung.1,2 LTB-4, a prostanoid, which is the major product of arachidonic acid metabolism by the 5-lipoxygenase pathway in human alveolar macrophages and neutrophils, has been shown to be a potent chemotactic agent for neutrophils in the human lung.3 When instilled endotracheally, LTB-4 drives a large number of active neutrophils from the circulation into the airways.1,3 LTB-4 has been found in the bronchoalveolar lavage fluid, sputum, and urine of patients with CF.4-6 Increased TNF-alpha levels have been reported in plasma and sputum of CF patients at the time of pulmonary relapse.7-10 The production of these inflammatory mediators can be reduced by dietary supplementation with the omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Both EPA and DHA competitively inhibit the Delta5 and Delta6 desaturase activities and the use of arachidonic acid in the 5-lipoxygenase pathway.12,13 Dietary supplementation with omega-3 fatty acids in human volunteers has been reported to increase EPA and DHA in cell membrane phospholipids and to inhibit release of LTB-4 by neutrophils.14 On the other hand, leukotriene B5, a 5-lipoxygenase product of EPA, has little chemotactic effect compared with LTB-4.15,16 Moreover, omega-3 fatty acid dietary supplementation reduced the synthesis of TNF-alpha and interleukin-1.17
Anti-inflammatory effects of dietary supplementation with omega-3 fatty acids have been documented in several chronic diseases, including rheumatoid arthritis, psoriasis, and Crohn’s disease.18 In patients with CF, omega-3 fatty acid supplementation for a period of 6 weeks19-22 led to increased incorporation of EPA and DHA into plasma, platelet,20 and erythrocyte19 phospholipids. Longer dietary supplementation with EPA alone (up to 12 months) has been reported by Thies. Other lines of research have suggested that pulmonary inflammation in patients with CF could be secondary to a cell membrane fatty acid imbalance rather than to infection. Elevated levels of arachidonic acid (AA) along with low DHA have been found in some tissues of a mouse model of CF,24 and abnormal incorporation of essential fatty acids into membrane phospholipids was produced by blocking the chloride channel in normal epithelial cells in vitro.25 Therefore, elevated levels of AA, an agonist of inflammatory pathways, in the phospholipid fraction from bronchoalveolar lavage fluids of CF patients 26 could be secondary to abnormal fatty acid metabolism rather than the result of infection.
The present study was conducted in order to determine whether long-term (8 months) dietary supplementation with long-chain omega-3 fatty acids has beneficial effect on lung inflammation in CF patients.
This study was designed to evaluate the effect of dietary EPA + DHA supplementation on biological parameters.. The effects of supplementation were studied using a longitudinal design whereby each subject served as his/her own control (baseline versus supplementation). In addition, erythrocyte fatty acid distribution was evaluated in a group of 20 healthy subjects who did not participate in the supplementation trial. Approval for the study was obtained from the human ethics committee of the University of Naples. Informed consent was obtained from the parents of children and from the subjects themselves if they were 18 years or older.
The study group consisted of 30 CF patients (10 boys and 20 girls) with a mean age of 12.4 years (range, 0.8 to 24 years) who were selected from among all patients seen in the cystic fibrosis unit of the Department of Pediatrics. The diagnosis in each child rested on a suggestive clinical history plus a sweat chloride level >60 mEq/L and was supported by identification of mutations of the CFT-R gene. All patients were colonized with Pseudomonas and required pancreatic enzyme supplementation. Criteria for exclusion from the study included the following: serum creatinine level >2 mg/dL, use of oral contraceptives, disturbances of hemostasis with prothrombin time (PT) or partial thromboplastin time (PTT) >1.5 times normal or platelet count
A comparison group of 20 normal subjects (age range, 10 to 24 years) was recruited from families of CF patients and the general population. They were selected if they were consuming a primarily fish-free diet and were screened for diabetes and hepatic or renal dysfunction and hyperlipidemia. Their erythrocyte fatty acid distribution was evaluated on one occasion.
EPA + DHA supplementation. Enteric-coated capsules containing either 0.5 or 1 g of fish oil concentrate (Triolip; SOFAR, Milan, Italy) were used. Each 1-g capsule contained at least 400 mg EPA, 200 mg DHA, and 10 mg of vitamin E. The amount of EPA + DHA given provided 1.25% of the total estimated caloric intake. The patients also were encouraged to consume ample amounts of seafood. The mean daily intake of EPA was 1.28 g and of DHA was 0.93 g. Patients continued their usual medical regimen, including pancreatic enzymes and vitamin supplementation.
At baseline and after 4 and 8 months of EPA + DHA supplementation, nutritional assessments and pulmonary function testing were performed, height and weight were determined, and inflammatory response markers and erythrocyte fatty acid analyses were assessed in study patients. Height and weight were measured by standard techniques and expressed as age- and sex-specific z scores. Nutrition assessment included determination of serum albumin, cholesterol, triacylglycerols, PT and PTT, and evaluation of dietary intake with the use of 1-week diet records. The diet records, which were also used to check compliance with the EPA + DHA supplementation regimen, were obtained twice at intervals of 2 months. An experienced dietitian provided detailed instructions to participant or parents about weighing and recording of all food consumed. Each study participant was provided with an electric scale, a set of plastic standard household volume measures, and a food diary with detailed written instructions. On receipt of each 1-week record, the dietitian reviewed it, and if necessary, contacted the participant/parents to resolve any ambiguities. The dietary data were entered into a personal computer equipped with a nutrient content software package that included data on total fat and specific fatty acid content.
The following inflammatory response markers were evaluated by routine laboratory methods: white blood cell count, serum C-reactive protein, serum immunoglobulin (IgG, IgA, and IgM) concentrations, and Ot-1antitrypsin activity. Forced expiratory volume (FEV-1) was measured in children over 5 years of age using standard pulmonary function testing methods with an in-line computer for daily calibration. The results were expressed as percentages of predicted values according to height and sex.
Laboratory methods. Peripheral venous blood was collected in tubes containing ethylenediaminetetraacetic acid (EDTA), and erythrocytes were isolated and membrane lipids extracted as previously described.27,28 The fatty acid composition of erythrocyte membrane phospholipids was determined by the direct transesterification method.29 Gas chromatographic analyses were performed on a Model 5160 gas chromatograph (Carlo Erba, Milan, Italy) with an SP2340 fused silica gel capillary column (30 m X 32 mm X 20 (mu)m; Supelco, Sigma-Aldrich Corp, St Louis, MO).
Statistical analysis. Data analysis was performed with an SPSS for Windows 6.0 statistics program (SPSS Inc, Chicago, IL). Differences from baseline to 4 and 8 months were assessed for all variables by paired t test. Differences between groups were also analyzed by t test. The X^sup 2^ test was used to compare the rates of antibiotic treatment. Ap value of
Nutrient intake data for the CF patients and 20 control subjects are reported in Table I. Energy intake in CF subjects was, as expected, higher than in controls. Intake of protein, carbohydrate, total fat, and most fatty acids (as percentage of energy) did not differ appreciably between patients and controls, except for the intake of co-6 series polyunsaturated fatty acids (18:2 and 20:4), which was significantly (p
Of the 30 patients enrolled in the study, all took the EPA-DHA supplement for the entire 8-month period. Eighteen subjects missed taking the supplement for 1 or more days, but no patient missed more than 2 weeks; each patient’s adherence failure included sporadic missed daily doses spread over the 8 months. The occurrence of missed doses observed on the first 4 months was quite less (p
The fatty acid compositions of erythrocyte membrane phospholipids are given in Table II. In CF patients, the baseline distribution of fatty acids showed significantly (p .05) and to 4.83 g/100 g fatty acids after 8 months (p
The effects of EPA + DHA supplementation on nutritional status and inflammatory markers are summarized in Table III. A significant (p
The analysis of FEV-1 obtained at the end of the supplementation period showed mild but significant (p
Compliance with the fish oil supplementation protocol was acceptable during the 8 months of study according to the diet records. No serious adverse effects were noted. Side effects of fish oil supplementation, such as nausea and diarrhea, were kept low presumably by the use of enteric-coated capsules and by providing almost 30% of the extra EPA and DHA from consumption of seafood. No gross derangement of hemostasis was observed.
The consumption of food sources of omega-3 fatty acids, mainly fish, was encouraged in our patients. This strategy was designed to raise omega-3 fatty acid intake to such a level that long-term supplementation would become unnecessary. However, less than 30% of omega-3 fatty acids were consumed by our patients from seafood, apparently because seafood had low appeal among the patients. We set a target value for EPA and DHA intake of 2.25 g/d (equivalent to 1.25% of total energy intake), an amount of omega-3 fatty acids that has been reported to affect eicosanoid production 22 without significant risk of disturbed hemostasis.
There is a growing body of evidence concerning derangement of omega-6 and omega-3 fatty acids in plasma and tissues in CF patients. Low levels of linoleic and AA along with low levels of DHA in plasma lipids have been documented in a number of reports.30-33 Some data are also available for erythrocyte and platelet membrane phospholipids.20,32 Reduced levels of DHA associated with high levels of AA in membrane phospholipids of lung, ileum, and pancreas of CFTR^sup -/-^ mice have been reported by Freedman.24
In the present study we observed, at baseline, reduced levels of EPA and linoleic acid in erythrocyte phospholipids. The observed reduction in linoleic acid is in agreement with similar data reported by previous investigators.20,34 The DHA levels in erythrocyte phospholipids were similar in CF patients and in controls. However, they were low compared with values reported in the literature34,35 for healthy subjects consuming a fish-free diet. On the other hand, plasma phospholipid DHA levels in our CF patients were higher than levels reported for CF patients30-32 and for some tissues of CFTR^sup -/-^ mice. The low erythrocyte DHA levels in our controls were surprising and could be caused by low dietary intake of omega-3 fatty acids compared with CF patients. Erythrocyte phospholipid DHA levels similar to our control values have been reported for infants fed cow’s milk formula by Baur et al.36 Intake of EPA + DHA as a percentage of dietary energy was similar in controls and CF patients, but on an absolute basis, it was higher in the CF patients because of their higher energy intake.
A decreased linoleic concentration in plasma and erythrocyte cell membranes suggests abnormal fatty acid metabolism in CF rather than a nutritional cause, because low linoleic acid concentrations can be observed in the presence of normal intestinal fat absorption and without signs of essential fatty acid deficiency.35,37 It occurs independent of pancreatic sufficiency33 and seems to be caused by increased production of certain eicosanoids.34,38 This is the opposite of what happens in essential fatty acid deficiency.39,40 Increased turnover of AA, possibly because of increased phospholipase activity,41,42 could account for normal or decreased AA levels in plasma and erythrocytes of CF subjects. This is in contrast to high AA levels found in pancreas, lung, and ileum of CFTR^sup -/-^ mice. High AA levels in lungs of CFTR^sup -/-^ mice are in accordance with high AA levels found in the phospholipid fraction of bronchoalveolar lavage fluid (macrophages) of CF patients,26 with the presence of AA derivatives in sputum, urine, and bronchial secretions,4-6,26,43 and emphasize the role of AA and its derivatives in lung inflammation.
The need to counteract lung inflammation mediated largely by AA and its proinflammatory derivatives has been the impetus that led to experimentation with EPA + DHA or EPA supplementation in CF patients. In vitro, the addition of EPA to circulating neutrophils from CF patients suppressed the appearance of 5-lipoxygenase products and reduced the concentration of LTB-4.12,13 Trials with EPA + DHA (fish oil) supple mentation in CF patients lasting up to 6 weeks have documented substantial incorporation of omega-3 fatty acids into plasma and membrane phospholipids without significant changes of AA levels.19,20 In addition, Kurlandsky et al20 reported decreased plasma levels of LTB4 in CF patients treated with fish oil even without a change of platelet AA levels. Lawrence and Sorrel22 supplemented CF patients with 2.7 g of EPA and documented improvement in the Shwachman score, FEV-1, and vital capacity, and increased chemotaxis of circulating neutrophils to LTB-4. Another study with EPA supplementation in CF patients lasting 12 months reported no changes in frequency of hospital admissions and days hospitalized compared with the preceding 2-year period.
In the present study we have shown that, along with EPA and DHA incorporation into erythrocyte phospholipid membranes, AA levels decreased progressively throughout the 8-month period of supplementation. There was an impressive fall of AA levels in erythrocyte phospholipid membranes. If similar changes occur in other tissues (eg, granulocytes), a significant decrease of the AA-derivative, LTB4, an important mediator of lung inflammation in CF patients, can be expected. EPA and DHA levels reached a peak at 4 months, with levels of EPA decreasing at 8 months. The magnitude of the DHA and EPA increase in erythrocyte phospholipid membranes was almost 1.7-fold above baseline level. A still higher increase of EPA, by almost sixfold, has been reported by Henderson et ales for erythrocyte membranes. The higher dose of fish oil supplementation (5.4 g of EPA + DHA compared with 2.2 g in our patients) and the shorter supplementation time (6 versus 34 weeks) could account for the differences between our results and those of Henderson et al.19 The decreasing levels of EPA, and to a lesser degree, of DHA, which we observed in CF patients at 8 months, may have been because of decreasing compliance with the supplementation regimen or to decreasing fatty acid incorporation into liver and erythrocyte membranes. Supporting the former possibility are the data of Von Schacky et al44 and Brown et a135 who found erythrocyte membrane DHA decreasing more slowly than EPA after cessation of omega-3 supplementation. In one of the few previous studies with long-term (o-3 fatty acid supplementation in CF patients, dietary enrichment with EPA for 12 months produced no significant improvement in clinical score or pulmonary function.22 Our study documents that long-term EPA + DHA supplementation leads to beneficial biological as well as clinical anti-inflammatory effects. Growth in height and weight progressed as expected for age, or for height, improved. That EPA + DHA supplementation had anti-inflammatory effects is supported by reduced plasma IgG and alpha-1 antitrypsin, effects that are likely to be mediated by reduced incorporation of AA into phospholipid membranes and reduced release of AA derivatives into lung or other tissues. A clinical anti-inflammatory effect was documented by improvement, albeit to a mild degree, of FEV-1 and by a surprisingly low rate of infectious recurrences (pulmonary relapses), as inferred from a lower rate of antibiotic use during omega-3 supplementation compared with the 8 preceding months. The decrease in serum triacylglycerols concentration observed in our study agrees with reports from the literature.45,46
Long-term supplementation with fish oil (EPA + DHA) may reduce inflammation in CF patients by decreasing AA levels in membrane phospholipids, which in turn may lead to decreased production of proinflammatory eicosanoids. Abnormal fatty acid metabolism resulting in increased production of eicosanoids is thought to be a key mechanism responsible for inflammation in CF. The result of the study also demonstrates an improvement by EPA + DHA supplementation of low plasma and tissues (erythrocytes) DHA levels, another abnormality of fatty acid metabolism in CF patients.
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Basilio De Vizia, MD*; Valeria Raia, MD*; Christian Spano, ChD^; Christiane Pavlidis, BS*; Anna Coruzzo, BS*; and Mariolina Alessio, MD*
From the *Department of Pediatrics, University Federico Il, Napoli, Italy; and ^SOFAR S.p.a., Trezzano Rosa, Milano, Italy
Received for publication, January 30, 2002.
Accepted for publication, July 31, 2002.
Correspondence and reprint requests: Basilio De Vizia, Department of Pediatrics, Napoli, via Pansini 5, 80131 Italy. Electronic mail may be sent to firstname.lastname@example.org.
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