The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

1962 Kuo PT, Huang NN, Bassett DR. The fatty acid composition of the serum chylomicrons and adipose tissue of children with cystic fibrosis of the pancreas. J Pediatr 1962; 60:394-403. [PubMed]
The first study of fatty acids in blood and tissue lipids of patients with CF. The fatty acid composition of chylomicrons and adipose tissue from children with CF who had variable degrees of fat malabsorption was compared with the values from controls. There was a relative decrease in linoleic acid and increased palmitoleic and oleic acids. Subsequently the abnormalities have been explained as related to liver disease, the basic defect and the intestinal malabsorption. Most recently an association with the presence of diseased infected lungs had been described as the values normalise after lung transplantation (Witters et al, 2013 below).


Prof. Bob Elliott and colleagues from New Zealand published several papers showing improvement in the clinical state with supplements of medium chain triglycerides even to the extent of returning the sweat electrolytes to nearer normal values (Elliott RB. Aust Paediatr J 1972 below; 8:217; Elliott RB, Robinson PG. Arch Dis Child 1975; 50:75-78; Elliot RB. 1976; 57:474-479). However, subsequent studies failed to substantiate their findings (Davidson GP et al. Aust Paediatr J 1978; 14:80-82; Chase et al. Pediatrics 1979; 59:428-432 below)

 

1972 Elliott RB. The effect of essential fatty acid on sweat sodium concentrations in cystic fibrosis. Aust Paediatr J 1972; 8:217
Prof. Bob Elliott and colleagues from Auckland, New Zealand published several papers showing improvement in the clinical state when children with CF were supplemented with medium chain triglycerides even to the extent of returning the sweat electrolytes to nearer normal values (also Elliott RB, Robinson PG. Arch Dis Child 1975; 50:75-78 below; Elliott RB. Pediatrics 1976; 57:474-479 below).
There was considerable discussion as to whether a disturbance of fatty acids resulted in an abnormality of prostaglandins. Rivers JA & Hassam AG suggested an abnormality of fatty acid metabolism such that there was a need for increased linoleic acid (Lancet 1975; ii: 642-643). Subsequent studies failed to substantiate their findings (Davidson GP et al. Aust Paediatr J 1978; 14:80-82; Chase et al. Pediatrics 1979; 59:428-432).

 

1975 Elliott RB, Robinson PG. Unusual course in a child with cystic fibrosis treated with fat emulsion. Arch Dis Child 1975; 50:76-78. [PubMed]
A child with CF received regular intravenous infusions of soya oil emulsion from the first weeks. The authors state that “Sweat tests improved, pancreatic achylia was relieved and the child at present remains entirely well. Correction of fatty acid found in cystic fibrosis may prevent some of the manifestations of the disease”.
Elliott and colleagues from Auckland, New Zealand published several papers on this subject the first showing improvement in the clinical state with supplements of medium chain triglycerides even to the extent of returning the sweat electrolytes to nearer normal values (Elliott RB. Aust Paediatr J 1972; 8:217; Elliot RB. 1976; 57:474-479). Unfortunately, subsequent studies failed to substantiate their earlier findings (Davidson GP et al. Aust Paediatr J 1978; 14:80-82; Chase et al. Pediatrics 1979; 59:428-432 below)

 

1978 Chase HP, Dupont J. Abnormal levels of prostaglandins and fatty acids in the blood of children with Cystic Fibrosis. Lancet 1978; ii: 236-238. [PubMed]
Low levels of linoleic acid in 12 children with CF and higher production of prostaglandin F2 than controls, were corrected by linoleic acid supplements (see Chase et al, 1979 below)..

 

1979 Chase HP, Cotton EK, Elliot RB. Intravenous linoleic acid supplementation in children with cystic fibrosis. Pediatrics 1979; 64:207-213. [PubMed]
This study was performed to investigate the previous observation of Prof. Bob Elliott of clinical improvement after IV Intralipid (Elliott & Robinson, 1975, above). On alternate weeks for a year 10 children received either intravenous Intralipid or a similar number of calories as 10% glucose. The Intralipid-treated group were marginally better re. height but the numbers were small and the differences were not significant. The authors thought the differences may have been obscured by the response of all patients to the increased attention they received during the trial. The authors suggested multicentre studies from an early age and also that all should be screened annually for low linoleic acid levels and supplementing those with levels below 2SD of normal.


This was perhaps the first double blind study of a nutritional intervention in cystic fibrosis. Unfortunately the present findings did not confirm Elliot & Robinson’s 1975 observation and did not seem to have a significant impact on CF management at the time. The questions surrounding the importance of fatty acid deficiency in CF would persist for many decades and the subject is still an area of uncertainty and investigation.

 

1999 Freedman SD Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG. A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr-/-mice. PNAS 1999; 96:13995-14000.[PubMed]
A deficiency in essential fatty acid metabolism has been reported previously in plasma from patients with cystic fibrosis. The objective of this present study was to determine whether alterations in fatty acid metabolism were specific to CF-regulated organs and whether they played a role in the expression of disease. A membrane lipid imbalance was found in ileum, pancreas, and lung from cftr(-/-) mice characterized by an increase in phospholipid-bound arachidonic acid and a decrease in phospholipid-bound docosahexaenoic acid (DHA). This lipid imbalance was observed in organs pathologically affected by CF including lung, pancreas, and ileum and was not secondary to impaired intestinal absorption or hepatic biosynthesis of DHA. As proof of concept, oral administration of DHA to cftr (-/-) mice corrected this lipid imbalance and reversed the observed pathological manifestations in the pancreas. The authors considered these results strongly suggest that certain phenotypic manifestations of CF may result from remediable alterations in phospholipid-bound arachidonic acid and DHA levels (figure 1).


This paper, caused considerable interest in medical circles and in the media at the 1999 North American CF Conference in Seattle, as Dr Freedman of the Beth Israel Deaconess Medical Centre Boston, suggested that essential fatty acid imbalance, affected the phenotypic expression of the CF defect and hence implied that the CF phenotype could be modified by correction of the imbalance. This latest revival in interest in essential fatty acids was made possible by the availability of CF mice and the opportunity to examine their pancreatic tissue.
Unfortunately subsequent studies by this group failed to confirm the fundamental importance of these findings (Beharry et al, 2007 below) but did suggest that DHA therapy may release endogenous inhibitors of inflammation (below) although it is fair to say that the initial enthusiasm has waned (Freedman SD et al, 2004; Beharry et al, 2007 both described out of chronological order for convenience below).

Fig. 1: Pancreatic sections. Left - wild type mice. Centre - cftr-/- mice. Right - cftr -/- mice on DHA. (Shown at the 1999 North American CF Conference).

 

2004 Freedman SD, Blanco PG, Zaman MM, Shea JC, Ollero M, Hopper IK, Weed DA, Gelrud A, Regan MM, Laposata M, Alvarez JG, O'Sullivan BP. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Eng J Med 2004; 350:560-569. [PubMed]
The authors previously demonstrated that arachidonic acid levels are increased and docosahexaenoic acid levels are decreased in affected tissues from cystic fibrosis-knockout mice (Freedman et al, 1999 above). In this present study of fatty acids from nasal- and rectal-biopsy specimens, nasal epithelial scrapings, and plasma were analyzed from 38 subjects with CF and compared with results in 13 obligate heterozygotes, 24 healthy controls, 11 subjects with inflammatory bowel disease, 9 subjects with upper respiratory tract infection, and 16 subjects with asthma. The ratio of arachidonic to docosahexaenoic acid was increased in mucosal and submucosal nasal-biopsy specimens (P<0.001) and rectal-biopsy specimens (P=0.009) from subjects with CF compared with the healthy control subjects. In nasal tissue, this change reflected an increase in arachidonic acid levels and a decrease in docosahexaenoic acid levels. In cells from nasal mucosa, the ratio of arachidonic to docosahexaenoic acid was increased in subjects with cystic fibrosis (P<0.001), as compared with healthy controls, with values in obligate heterozygotes intermediate between these two groups (P<0.001). The authors concluded that these data indicated that alterations in fatty acids similar to those in cystic fibrosis-knockout mice are present in CFTR-expressing tissue from subjects with cystic fibrosis.


Despite considerable published work, up to 2008, EFA therapy has not been established as beneficial in people with CF; nor has this work had a major impact on the understanding of or treatment of cystic fibrosis as was hoped when first reported in 1999.

 


Lloyd-Still JD, Powers CA, Hoffman DR, Boyd-Trull K, Lester LA, Benisek DC, Arterburn LM. Bioavailability and safety of a high dose of docosahexaenoic acid triacylglycerol of algal origin in cystic fibrosis patients: a randomized, controlled study. Nutrition 2006; 22:36-46. [PubMed]

Several studies have reported omega-3 and omega-6 fatty acid imbalances in patients with cystic fibrosis. Whether these imbalances contribute to, or are manifestations of, the pathophysiology of CF is unknown. This study by John Lloyd-Still and colleagues from Chicago was to determine bioavailability, tissue accretion, and safety of a large dose of an algal source of docosahexaenoic acid (DHA) triacylglycerol and to observe the effects on lung function in patients with CF. Twenty subjects with CF (8 to 20 yrs of age) were randomly assigned to receive algal oil providing 50 mg of DHA per kilogram per day (1 to 4.2 g of DHA per subject per day) or placebo for 6 months. The authors found that algal DHA triacylglycerol oil is readily absorbed well tolerated, and increases blood and tissue DHA levels in patients with CF. No adverse developments were associated with this large dose of DHA oil.
The authors concluded that larger studies of longer duration are needed to determine whether DHA supplementation results in any clinically significant benefits in patients with CF. Subsequently a report from Belgium failed to show any clinical improvement after a year's supplementation with a DHA rich algal oil (Van Biervliet S et al. Prostaglandins Leukot Essent Fatty Acids 2008; 78:109-115. [PubMed]).

Dr John Lloyd Still is one of the leading figures in CF care and research in N. America and has been involved in CF and paediatric gastroenterology for many years since he qualified at Guys Hospital in London in 1960. After qualifying he worked in London in paediatrics and eventually moved to Boston where he worked with Harry Shwachman. He is now in charge of the CF care at the Rush University Medical Center, Chicago. He edited a major textbook on CF in 1983 to which most of the leading authorities on CF in North America at the time contributed (Textbook of Cystic Fibrosis. Lloyd-Still J D. John Wright PSG Inc. 1983). He is particularly interested in, and has published widely on, the gastroenterological and nutritional aspects of CF.

 

 

2007 Beharry S, Ackerley C, Corey M, Kent G, Heng YM, Christensen H, Luk C, Yantiss RK, Nasser IA, Zaman M, Freedman SD, Durie PR. Long-term docosahexaenoic acid therapy in a congenic murine model of cystic fibrosis. Am J Physiol – Gastr L 2007; 292:G839-48. [PubMed]
A congenic C57Bl/6J cystic fibrosis transmembrane conductance regulator (Cftr)(-/-) mouse model, which develops cystic fibrosis (CF)-like pathology in all organs, was used to evaluate the short- and long-term therapeutic effects of dietary docosahexaenoic acid (DHA). Thirty-day-old Cftr (-/-) mice and wild-type littermates were randomized to receive a liquid diet with or without DHA (40 mg/day). Animals were killed for histological and lipid analysis after 7, 30, and 60 days of therapy. DHA had no significant therapeutic or harmful effect on the lung, pancreas, or ileum of the Cftr (-/-) mice or their wild-type littermates. In contrast, dietary DHA resulted in highly significant amelioration of the severity of liver disease in the Cftr (-/-) mice, primarily a reduction in the degree of peri-portal inflammation. The authors concluded that inhibition of cytokines and/or eicosanoid metabolism and release of endogenous inhibitors of inflammation by the DHA may account for the anti-inflammatory effects in the liver of this congenic murine model of CF. The potential therapeutic benefits of DHA in severe CF-associated liver disease remain to be explored.


So the EFA story continues and although dietary DHA supplements had no effect on many organs of the Cftr (-/-) mouse including the pancreas as had been suggested in 1999, there was considerably less hepatic inflammation in the treated mice.

 

2000 Bhura-Bandali FN, Suh M, Man SF, Clandinin MT. The deltaF508 mutation in the cystic fibrosis transmembrane conductance regulator alters control of essential fatty acid utilization in epithelial cells. J Nutr 2000; 130:2870-2875. [PubMed]
Essential fatty acid (EFA) incorporation into phospholipid is influenced by chloride channels, suggesting that CFTR may exert a regulatory effect on EFA metabolism. The authors state that the observations in this paper suggest that CF results in a defect in the utilization of 18:2(n-6), which they attribute in part to the defective CFTR.

This is yet another twist to the EFA story in cystic fibrosis. Recently Freedman et al (1999 above) had shown a membrane lipid imbalance in the ileum, pancreas, and lung from cftr (-/-) mice characterized by an increase in phospholipid-bound arachidonic acid and a decrease in phospholipid-bound docosahexaenoic acid. This finding caused considerable interest at the 1999 North American CF Conference but unfortunately subsequent studies failed to confirm the fundamental importance of the findings. A later report from Freedman and colleagues in 2007 suggested that DHA therapy may release endogenous inhibitors of inflammation although the initial enthusiasm has waned (Freedman SD et al, 2004; Beharry et al, 2007 both below).

 

2001 Strandvik B, Gronowitz E, Enlund F, Martinsson T, Wahlstrom J. Essential fatty acid deficiency in relation to genotype in patients with cystic fibrosis. J Pediatr 2001; 139:650-655.[PubMed]
Serum concentrations of linoleic acid and docosahexaenoic acid were significantly lower in patients with severe cystic fibrosis transmembrane conductance regulator mutations, such as DF508, suggesting an association between the basic defect and abnormal essential fatty acid metabolism in CF patients. A relationship between these fatty acids and the basic defect had been suggested previously – most recently by Freeman et al, (1999 above).

 

Fig. 2: Birgitta Strandvik

 

Birgitta Strandvik, MD, PhD, (figure 2) is Professor Emeritus of Pediatrics at Goteborg University, Sweden. She has published more than 250 scientific papers and book chapters and made major contributions to the scientific and clinical aspects of both cystic fibrosis and paediatric gastroenterology. She has a particular interest in essential fatty acids but has always been obviously greatly concerned in the practical care of patients with CF.

 

2004 Freedman SD. Blanco PG. Zaman MM. Shea JC. Ollero M. Hopper IK. Weed DA. Gelrud A. Regan MM. Laposata M. Alvarez JG. O'Sullivan BP. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Eng J Med 2004; 350:560-569. [PubMed]
The ratio of arachidonic to docosahexaenoic acid was increased in mucosal and submucosal nasal-biopsy specimens (P<0.001) and rectal-biopsy specimens (P=0.009) from subjects with cystic fibrosis and pancreatic sufficiency and subjects with cystic fibrosis and pancreatic insufficiency, as compared with values in healthy control subjects. So alterations in fatty acids similar to those in cystic fibrosis-knockout mice are present in CFTR-expressing tissue from subjects with cystic fibrosis.

 

2006 Lloyd-Still JD, Powers CA, Hoffman DR, Boyd-Trull K, Lester LA, Benisek DC, Arterburn LM. Bioavailability and safety of a high dose of docosahexaenoic acid triacylglycerol of algal origin in cystic fibrosis patients: a randomized, controlled study. Nutrition 2006; 22:36-46. [PubMed]
Several studies have reported omega-3 and omega-6 fatty acid imbalances in patients with cystic fibrosis. Whether these imbalances contribute to, or are manifestations of, the pathophysiology of CF is unknown. This study by John Lloyd-Still and colleagues from Chicago was to determine bioavailability, tissue accretion, and safety of a large dose of an algal source of docosahexaenoic acid (DHA) triacylglycerol and to observe the effects on lung function in patients with CF.

Twenty subjects with CF (8 to 20 yrs of age) were randomly assigned to receive algal oil providing 50 mg of DHA per kilogram per day (1 to 4.2 g of DHA per subject per day) or placebo for 6 months. The authors found that algal DHA triacylglycerol oil is readily absorbed well tolerated, and increases blood and tissue DHA levels in patients with CF. No adverse developments were associated with this large dose of DHA oil.
The authors concluded that larger studies of longer duration are needed to determine whether DHA supplementation results in any clinically significant benefits in patients with CF. Subsequently a report from Belgium failed to show any clinical improvement after a year's supplementation with a DHA rich algal oil (Van Biervliet S et al. Prostaglandins Leukot Essent Fatty Acids 2008; 78:109-115. [PubMed]).

 

 

Fig. 3:John Lloyd-Still

 

Dr John Lloyd Still (figure 3) is one of the leading figures in CF care and research in N. America and has been involved in CF and paediatric gastroenterology for many years since he qualified at Guys Hospital in London in 1960. After qualifying he worked in London in paediatrics and eventually moved to Boston where he worked with Harry Shwachman. He is now in charge of the CF care at the Rush University Medical Center, Chicago. He edited a major textbook on CF in 1983 to which most of the leading authorities on CF in North America at the time contributed (Textbook of Cystic Fibrosis. Lloyd-Still J D. John Wright PSG Inc. 1983). He is particularly interested in, and has published widely on, the gastroenterological and nutritional aspects of CF

 

2008 Van Biervliet S, Devos M, Delhaye T, Van Biervliet JP, Robberecht E, Christophe A. Oral DHA supplementation in DeltaF508 homozygous cystic fibrosis patients. Prostaglandins Leukotr Essent Fatty Acids 2008; 78:109-115. [PubMed]
The treatment group was supplemented with algal DHA-rich oil and the control group with sunflower seed oil. There was no difference between the control and treatment groups for percentage weight for height, caloric intake, FEV1% and FVC% at the start of the study and after 1 year of supplements.

So although DHA-rich oil shifted the serum phospholipid fatty acids to a less pro-inflammatory profile, no conclusive clinical improvement could be observed.

 

2010 Strandvik B. Fatty acid metabolism in cystic fibrosis. [Review] Prostag Leukotr Ess 2010; 83:121-129. [PubMed]
Twenty years ago the gene responsible for cystic fibrosis transmembrane conductance regulator (CFTR), the protein defective in cystic fibrosis (CF), was identified but research of this monogenetic disease has not provided an explanation for the divergent symptoms, and a treatment breakthrough is still awaited. This review discusses different aspects of disturbances in lipid metabolism seen in CF.

These include increased release of arachidonic acid (AA) from cell membrane phospholipids and a low status of linoleic and docosahexaenoic acids. Recent research has explored more complicated lipid associations. Disturbances in annexins and ceramides might act in concert to explain the impact on inflammation and AA release. The connections to CFTR and between the disturbances in essential fatty acid metabolism are reviewed. The metabolic interactions, some of which might be compensating, possibly explain the difficulties in understanding the fatty acid disturbances in relation to different symptoms and their relation to the defective CFTR.

Brigitta Strandvik (figure 2) has had a particular interest in fatty acid metabolism in CF for many years and in this article by an expert in the subject, brings together some of the existing knowledge; also there does seem to be some interesting and possibly significant associations such as that with ceramides.

 

2010 Zaman MM, Martin CR, Andersson C, Bhutta AQ, Cluette-Brown JE, Laposata M, Freedman SD. Linoleic acid supplementation results in increased arachidonic acid and eicosanoid production in CF airway cells and in cftr-/- transgenic mice. Am J Physiol - Lung C 2010; 299:L599-606. [PubMed]
Cystic fibrosis (CF) patients display a fatty acid imbalance characterized by low linoleic acid levels and variable changes in arachidonic acid. This led to the recommendation that CF patients consume a high-fat diet containing >6% linoleic acid. The authors hypothesized that increased conversion of linoleic acid to arachidonic acid in CF leads to increased levels of arachidonate-derived pro inflammatory metabolites and that this process is exacerbated by increasing linoleic acid levels in the diet. To test this hypothesis, they determined the effect of linoleic acid supplementation on downstream pro inflammatory biomarkers in two CF models: 1) in vitro cell culture model using 16HBE14o(-) sense [wild-type (WT)] and antisense (CF) human airway epithelial cells; and 2) in an in vivo model using cftr(-/-) transgenic mice. Fatty acids were analyzed by gas chromatography-mass spectrometry (GC/MS), and IL-8 and eicosanoids were measured by ELISA. Neutrophils were quantified in bronchoalveolar lavage fluid from knockout mice following linoleic acid supplementation and exposure to aerosolized Pseudomonas LPS. Linoleic acid supplementation increased arachidonic acid levels in CF but not WT cells. IL-8, PGE(2), and PGF(2alpha) secretion were increased in CF compared with WT cells, with a further increase following linoleic acid supplementation. cftr(-/-) Mice supplemented with 100 mg of linoleic acid had increased arachidonic acid levels in lung tissue associated with increased neutrophil infiltration into the airway compared with control mice. These findings support the hypothesis that increasing linoleic acid levels in the setting of loss of cystic fibrosis transmembrane conductance regulator (CFTR) function leads to increased arachidonic acid levels and pro inflammatory mediators.

These findings are important as there was considerable interest in linoleic acid supplementation in people with CF - even a trial of intravenous linoleic acid in the Seventies. The situation regarding essential fatty acids remain unclear to this writer!

 

2010 Rhodes B, Nash EF, Tullis E, Pencharz PB, Brotherwood M, Dupuis A, Stephenson A. Prevalence of dyslipidemia in adults with cystic fibrosis. J Cyst Fibros 2010; 9:24-28. [PubMed]
A high fat high calorie diet is advocated for patients with cystic fibrosis (CF) however the lipid profiles of individuals with CF, including those with CF-related diabetes (CFRD), are not well studied. We conducted a retrospective review of adult CF patients attending St Michael's Hospital between January 2005 and December 2007. 334 patients (77% pancreatic insufficient (PI)) were included in the study. Mean HDL cholesterol was significantly lower in males (p<0. 0001) with 44% of males having HDL cholesterol <38. 7mg/dL(1mmol/L). Pancreatic sufficient patients were more likely than PI subjects to have total cholesterol >201mg/dL(5. 2mmol/L) (p<0. 01). 5% of subjects had triglyceride concentrations >195mg/dL(2. 2mmol/L). Diabetes was diagnosed in 23% of subjects. Lipid profiles were similar between diabetics and non-diabetics. Total cholesterol and triglycerides both increased with increasing age and increasing BMI (p<0. 01).


The authors concluded that dyslipidemia occurs in CF patients however no differences in lipid profiles were seen between those with diabetes and those without. Fasting lipids should be monitored in CF patients, particularly those with PS, older age, and high BMI. As survival in CF increases, the prevalence of dyslipidemia may increase resulting in clinically important complications.

 

2011 Becker KA. Henry B. Ziobro R. Riethmuller J. Gulbins E.  Lipids in cystic fibrosis. [Review] Exp Rev Respir Med 2011; 5:527-535.[PubMed]
Recent studies developed novel and exciting concepts regarding the pathogenesis and treatment of cystic fibrosis. In particular, several studies indicated a critical role of death receptors, caveolae proteins, membrane rafts, alterations of the ceramide metabolism with an accumulation of ceramide and a reduction of 15-keto-prostaglandin 2 in cystic fibrosis lungs. These alterations have been found to be critically involved in the pulmonary inflammation and infection susceptibility of cystic fibrosis patients. However, albeit these studies provided novel insights into molecular mechanisms causing inflammation and vulnerability to infection, the details of these processes are still unknown

 

2011 Oliver C, Jahnke N. Omego-3 fatty scids for cystic fibrosis. Cochrane Database Syst Rev 2011 aug10:(8): CD002201. [PubMed]

These reviewers concluded that the data, from the 4 studies they found acceptable of 13 previous studies, suggested that regular omega-3 studies may provide some benefits for people with cystic fibrosis with relatively few adverse effects. However, the evidence was not adequate to recommend their routine use. 

 

2013 Witters P. Dupont L. Vermeulen F. Proesmans M. Cassiman D. Wallemacq P. De Boeck K. Lung transplantation in cystic fibrosis normalizes essential fatty acid profiles. J Cyst Fibros 2023; 12:222-228. [PubMed]

Disorders in essential fatty acid state are increasingly reported and various supplementation trials have been performed in an attempt to improve outcomes. However, the mechanisms leading to these disturbances remain elusive. We wanted to investigate the role of the diseased CF lung on fatty acid profiles.

We compared fatty acid profiles in patients with CF after lung transplantation (n=11) to age-matched healthy controls and homozygous F508del patients (n=22 each). Compared to healthy controls, in patients with CF, there are decreased levels of docosahexaenoic, linoleic and arachidonic acid and increased levels of mead acid. In patients that underwent a lung transplantation, levels of docosahexaenoic, linoleic and arachidonic acid were normal. Mead acid did not decrease significantly.

The authors concluded that the diseased CFTR deficient lung is a major determinant in the disturbed fatty acid profile in CF.

 

2013 Alicandro G, Faelli N, Gagliardini R, Santini B, Magazzu G, Biffi A, Rise P, Galli C, Tirelli AS, Loi S, Valmarana L, Cirilli N, Palmas T, Vieni G, Bianchi ML, Agostoni C, Colombo C. A randomized placebo-controlled study on high-dose oral algal docosahexaenoic acid supplementation in children with cystic fibrosis. Prostag Leukotr Ess 2013; 88:163-169. [PubMed]

Low plasma concentrations of docosahexaenoic acid (DHA) are reported in unsupplemented cystic fibrosis (CF) patients. Forty-one CF patients aged from 6 to 12 years were randomized to receive high-dose DHA (100 mg/kg/day in the first month and 1g per day thereafter through a 12-month supplementation) or placebo (germ oil). Primary outcome was percentage change in plasma AA:DHA ratio. Secondary outcomes were changes in the number of pulmonary exacerbations compared to previous year, lung function, BMI, skinfold thicknesses, and body composition assessed by DXA and in serum concentrations of C-reactive protein, cytokines and vitamin (alpha-tocopherol and retinol).

Compared to the control group plasma AA:DHA ratio decreased in the intervention group after 6 months (median percentage changes: -73% in the intervention group vs. -10% in the control group, P=0.001). No differences were detected between groups for secondary outcomes.

Despite a decrease of the AA/DHA ratio, DHA supplementation for one year did not induce any significant biochemical and clinical improvement in CF patients. This is yet another study that failed to confirm the findings in mice of Beharry S et al. 2007. Long-term docosahexaenoic acid therapy in a congenic murine model of cystic fibrosis. Am J Physiol – Gastr L 2007; 292:G839-48.[PubMed]. See

Beharry et al, 2007 for more discussion.

 

2013 Witters P. Dupont L. Vermeulen F. Proesmans M. Cassiman D. Wallemacq P. De Boeck K. Lung transplantation in cystic fibrosis normalizes essential fatty acid profiles. J Cyst Fibros 2013; 12:222-228. [PubMed]

Disorders in essential fatty acid state are increasingly reported and various supplementation trials have been performed in an attempt to improve outcomes. However, the mechanisms leading to these disturbances remain elusive. The authors investigated the role of the diseased CF lung on fatty acid profiles.

They compared fatty acid profiles in patients with CF after lung transplantation (n=11) to age-matched healthy controls and homozygous F508del patients (n=22 each). They found that compared to healthy controls, in patients with CF, there are decreased levels of docosahexaenoic, linoleic and arachidonic acid and increased levels of mead acid. In patients that underwent lung transplantation, levels of docosahexaenoic, linoleic and arachidonic acid were normal. Mead acid did not decrease significantly.

The diseased CFTR deficient lung appeared to be a major determinant in the disturbed fatty acid profile in CF.

This is new and interesting data as abnormal fatty acid profiles have been reported in CF since the first paper by Kuo et al in 1962 and there is still confusion regarding the cause and significance. There is a clear and helpful discussion on this difficult subject at the end of this present paper.

The authors conclude that "the CF lung is an important player in the development of abnormal fatty acid profile. Rather than studying the effect of fatty acids on lung function (as in EFA supplementation trial) we did the reverse by documenting fatty acid profiles in a subset of patients who underwent lung transplantation. We showed that post-transplantation an evolution toward normal fatty acid profiles is to be exptected".