FATTY ACIDS

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.
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 14).
This paper, caused considerable interest in medical circles and in the media at the 1999 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).

Figure 14: 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.

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. 22: Professor Birgitta Strandvik

 
Birgitta Strandvik, MD, PhD, (figure 22) 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. 47: Dr John Lloyd-Still

Dr John Lloyd Still (figure 47) 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 W/H%, 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.

Recent review by Professor Strandvik, an expert in this field -

2010 Strandvik B. Fatty acid metabolism in cystic fibrosis. Prostaglandins Leukot Essent Fatty Acids. 2010; 83:121-129. [PubMed]
Despite identification twenty years ago of the gene responsible for cystic fibrosis transmembrane conductance regulator (CFTR), the protein defective in cystic fibrosis (CF), 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.

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