Acta Paediatr Scand Suppl 363: 58-65, 1989

Relation between Essential Fatty Acid Metabolism and

Gastrointestinal Symptoms in Cystic Fibrosis

B. STRANDVIK
From the Departments of Paediatrics and Research Centre, Karolinska Jnstillltet,
Huddinge University Hospital, Stockholm. Sweden

ABSTRACT. Strandvlk, B. (Departments of Paediatrics and Research Centre, Karolinska

lnstitutet, Huddlnge University Hospital, Stockholm, Sweden). Relation between essential
fatty acid metabolism and gastrointestinal symptoms In cystic fibrosis. Acta Paediatr Scand
Suppl 363: 58, 1989.
Studies in our laboratory have supported the hypothesis, that the basic defect in cystic fibrosis
increases the metabolism of essential fatty acids and thereby gradually gives rise to essential
fatty acid deficiency, which Is a well documented finding in most cases with this disease. Both
the increased metabolism-giving high liberation of arachidonic acid and its metabolic
products, i.e. different elcosanolds--and the subsequent essential fatty acid deficiency will
cause gastrointestinal symptoms and the sequence of this development will mirror the natural
history of the disease. Clinical data and results from animal research are discussed in relation
to gastrointestinal symptoms and signs of cystic fibrosis. Key words: arachidonic acid, linoleic
acid, liver, pancreas, intestine, eicosanoids.

ESSENTIAL FATTY ACID DEFICIENCY IN CYSTIC FIBROSIS

Essential fatty acid (EFA) deficiency has been a known complication in cystic fibrosis
(CF) since nearly 30 years ( 1). Many later studies have confirmed this observation (for a
review see 2) and shown that the EFA deficiency is not restricted to cases with pancreatic
insufficiency (3-5). Indicators of an increased turnover of essential fatty acids in CF (6-8),
and the finding of increased amounts of arachidonic acid in phospholipids of bronchial
secretions in EFA deficient patients with CF (9), delivered a hypothesis about the basic
defect including an increased turnover of EFA and thereby giving rise to EFA deficiency
(10). This hypothesis was strongly supported by the finding of impaired inhibition of
arachidonic acid release by dexamethasone in lymphocytes from patients with CF (II).
Symptoms would thus be expected to develop both from the overproduction of substrate
for eicosanoid synthesis and from the gradually developing EFA deficiency (12).

GASTROINTESTINAL SYMPTOMS IN CF
The gastrointestinal tract is one of the major organ systems involved in CF. The most
common initial symptom is steatorrhoea, mainly due to pancreatic insufficiency. Recent
observations show that both bicarbonate and chloride secretion are impaired in the pan-
creas, probably explaining the low water content of the secretion also in cases with high
enzyme concentration. An extensive review of the gastrointestinal symptoms are given
elsewhere in this issue (13). Impaired chloride transport has been shown also in intestinal
cells (14) and relation between abnormal potential difference over the colonic mucosa and
amiloride sensitive sodium transport has been shown ( 15).
Many complications have been reported from the liver and biliary system. Steatosis is a
much more common finding than fibrosis and cirrhosis and might sometimes be so heavy
that it is revealed on standard roentgenological examinations (16-19). The cirrhosis is focal
and therefore liver function is usually well preserved for a tong time·and clinical signs of
Acta Paediatr Scand Suppl 363 Relation EFA-CF 59

portal hypertension are generally rare (19). Liver disease may present as neonatal choles-
tasis, sclerosing cholangitis, cholelithiasis or other biliary disturbances as recently re-
viewed (20).
Generally most of the gastrointestinal symptoms in CF are related to the increased
mucus production and the low water content, making all secretions more viscous and
sticky. The steatorrhoea is another probJem, which although persistent (21), becomes
clinically less prominent with age when a tendency to constipation may predominate.
Unspecific colitis has been a finding in about 3% of our patients. Early in life an increased
appetite is a common sign, which corresponds to the increased caloric demand and might
give a normal growth until an infection spoil the trend and reveal the malabsorption. In
more severe disease poor appetite is a more general symptom, giving difficulties to obtain
enough calories without special supplementation.

ESSENTIAL FATIY ~CID METABOLISM IN THE

GASTROINTESTINAL TRACT
The metabolism of EFA in the normal human gastrointestinal tract has not been the
subject of any extensive research. Most knowledge is based on animal studies. Products of
arachidonic acid as the prostaglandins and leukotrienes, are synthesized in the gastrointes-
tinal mucosa and the smooth muscle and are potent stimulators of mucus production (22,
23). Metabolites of leukotriene LTC 4 are mainly excreted in the bile and ha~e been shown
to be related to both severe liver damage and pancreatitis (24, 25). Prostaglandins have
been shown to be involved in the duodenal mucosal bicarbonate secretion (26). The role of
eicosanoids in colitis has been more discussed in recent years, and although mainly
thought to be secondary to the inflammation the pathophysiological events are yet poorly
understood (27). In EFA deficiency diarrhoea is a symptom, which in animals has been
shown to be related to an impaired fat absorption due to a decreased intestinal mucosal
transport of fat (28-30).
The jejunal mucosal cells seem to have an increased turnover, emerging crypt cells on
villi, which ultimately will change intestinal function (31). Mice and rats with EFA
deficiency have been shown to have steatosis (32, 33) and impaired growth and increased
caloric demand are early signs in EFA deficiency in animals (34). Although the pancreatic
amylase secretion is less sensitive to EFA deficiency (35), the early insulin response to a
glucose load is impaired in perfusion studies (36).

RELATION BETWEEN ESSENTIAL FATIY ACID METABOLISM AND CF

In what way could a disturbed EFA metabolism then be related to the symptoms in CF?
Obviously this is not a simple question, but according to the initially presented hypothesis
about EFA metabolism and the pathophysiology of CF, an increased release of arachi-
donic acid ( 11) will give several biochemical effects (Fig. 1). These effects could be divided
in two parts, firstly symptoms related to overproduction of arachidonic acid and its
metabolites, the eicosanoids (fig. I. left part), and secondly symptoms related to the
progressive EFA deficiency (fig. I, right part). The physiological results of the biochemi-
cal disturbances and the following clinical symptoms are briefly summarised in the figure.

Effects of increased eico.wnoid synthesis

It is well known that phospholipase Az, which releases arachidonic acid, is the rate-limit-
ing enzyme in the eicosanoid synthesis (37). An increased release of arachidonic acid will
therefore give rise to increased production of prostaglandins (PG's), tromboxanes (TX),
60 B. Strandvik Acta Paediatr Scand Suppl 363

lat level of
blacbe•lcol
effects

zn•laval
blacbemlcal
effects

I at level of
pllgstolotiCII
effects

2ad level of
pllgslologlcol
effocta
Saltt sveat Poocreotltla
Viscous secretin Liver cell
Pancreas tnsafflct ..cg •ecresla Moltgnoacg(?)
SYMPTOMS

""
Neonatal bepotltil
Sclerosing cboluattts
Meculum tleu (eqv.)

Fig. I. Approach to review the existing knowledge (in 1989) and the hypothesis about the basic
defect(s) of CF (2, 10-12) related to the gastrointestinal symptoms of the disease.

leukotrienes (LT's) and hydroxyeicosatetraenoic acids (HETE's), the so-called arachi·

donie acid cascade. Interestingly, most of these highly active substances. usually acting as
"local hormones", participate in both the regulation of chloride and sodium transport
-some counteracting each other-indicating that a balance between these substances are
of outmost importance for normal cellular function (for ref. see 2 and 12). The prostaglan-
dins and hydroxyeicosatetraenoic acids have been shown to be potent stimulators of
mucin production in the biliary system (for ref. see 2 and 12) and leukotrienes have a
similar effect in the respiratory system (38). The leukotrienes, which are mainly excreted
in the bile (39), have been shown to be mediators of inflammation in liver disease and
pancreatitis (25, 40). The leukotrienes are potent provokers of chemokinesis. chemotaxis.
aggregation and adherence of leukocytes. and in higher concentrations they may act as
complete secretagogues, causing degranulation. mobilisation of Ca~+. superoxide anion
generation as well as increased intracellular levels of cAMP (for review see 41 ). The
cysteinyl leukotrienes increase the permeability in the postcapillary venules, leading to
extravasation of plasma (42) and promote immature enterocytes (43), which lead to
disturbed mucosal transport. Thus many of the presenting symptoms in CF would be
explained by an imbalanced overproduction of eicosanoids; an extensive mucus-produc-
tion causing neonatal hepatitis (inspissated bile syndrome). sclerosing cholangitis. micro-
gallbladder and meconium ileus. The pancreas insufficiency might be due to a combination
of factors. and the known intestinal transport disturbances (44) have to be restudied in
view of the possibility of being a sign of immature enterocytes.
If this hypothesis should be valid, there will certainly develop a feed back regulation
which in some way (interaction between the eicosanoids or influence on arachidonic acid
release) stabilise and down-regulate the symptoms. This can be seen clinically in those
patients, who present with symptoms mimicking Hartter's syndrome (45). It might also be
Acta Paediatr Scand Suppl 363 Relation EFA-CF 61

illustrated by the fact that most patients after diagnosis have several years with very mild
symptoms. It is also known that EFA deficiency may down-regulate the eicosanoid
synthesis (46).

Effects of proKressive linoleic acid deficiency

Since linoleic acid and its metabolite arachidonic acid are important constituents of the
phospholipids in membranes. EFA deficiency leads to disturbances in membrane function,
including the regulation of membrane-bound enzymes (47). The effect of EFA deficiency
on different organ systems have mainly been studied in animals (for review see 34). An
increased sodium transport has been demonstrated and a decreased intestinal fat trans-
port, leading to steatorrhoea. both factors which might contribute to the intestinal symp-
toms in CF. The observation of an increased intestinal mucosal cell turnover (31) might as
well contribute to disturbances caused by overproduction of leukotrienes (43), and is
especially interesting in view of the discussions of increased risk of malignancy in the older
patients (48). The cause of development of cirrhosis in CF is probably multifactorial, but
steatosis might be one factor as has been shown in other diseases (49). The relation
between the disturbed insulin release and the high frequency of impaired glucose tolerance
and diabetes in CF is unclear and not exclusively related to the atrophy of pancreas-the
EFA deficiency might here have a role with implications also in other diabetic conditions.

CONCLUSION
Supports in clinical observations for the presented hypothesis and its implications have
been found. Already in the first report about EFA deficiency in CF it was pointed out that
this was not related to malabsorption and malnutrition ( 1) and later authors have con-
firmed that EFA deficiency also occurs in patients with normal pancreatic function (3-5).
In our series of patients supplied with EFA for 3 years by regular administration of
Intralipid®, the progression of steatosis was prevented compared with an unsupplied
control group (Strandvik et at., to be published), and we were also able to influence renal
sodium transport (50). Furthermore, we have found high levels of both prostaglandin
metabolites in urine (51) and leukotrienes in white blood cells after ionofore stimulation in ·
samples from patients with CF without clinical symptoms or signs of infection (Strandvik
& Lindgren, unpublished observation). However, much more clinical work and controlled
studies have to be performed to test the present hypothesis (cf. 2, I0-12). The strength of it
relies on its capacity to explain all the symptoms in CF from all different organs by one
single basic defective regulation, the progressive character of the disease and variable
speed of progression. as well as the highly varying age at debut of symptoms.

ACKNOWLEDGEMENTS
This work was supported by grants from the Swedish Medical Research Council (8558), the National
Association of Heart and Lung Diseases and the Swedish Association of Cystic Fibrosis. Prof. S. 0.
Gunnarsson is gratefully acknowledged for his patient help to construct the figure.

REFERENCES
t. 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.
2. Strandvik B. Bronnegard M. Carlstedt-Duke J. Arachidonic acid release in CF. In: Mastella G.
Quinton PM. eds. Cellular and molecular basis of cystic fibrosis. San Francisco: San Francisco
Press, 1988: 445-50.
62 B. Strandvik Acta Paediatr Scand Suppl 363

3. Galabert C. Filliat M. Chazalette JP. Fatty acid composition of serum-lecithins in cystic fibrosis
patients without steatorrhoea. Lancet 1978: i: 903.
4. Rogiers V. Dab I, Crokaert R. Vis HL. Long chain non-esterified fatty acid pattern in plasma of
cystic fibrosis patients and their parents. Pediatr Res 1980; 14: 1088-91.
5. Rogiers V, Vercruysse A. Dab I. Baran D. Abnormal fatty acid pattern of the plasma cholesterol
ester fraction in cystic fibrosis patients with and without pancreatic insufficiency. Eur J Pediatr
1983: 141: 39-42.
6. Chase HP. Dabiere CS. Elliott RB. Fibroblast fatty acids in cystic fibrosis. Metabolism 1980; 29:
36.5-68.
7. Rogiers V, Mandelbaum I, Mozes N et al. In vitro study of the incorporation and transport of
non-esterified fatty acids into the phospholipids of the red blood cell membranes in cystic fibrosis.
Pediatr Res 1982; 16: 761-68.
8. Roscher AA, Hadorn B. Regulation of beta-receptor-mediated biological signals on the cellular
level. In: Kaiser D, ed. Approaches to cystic fibrosis research. Berlin: Maizena Diat, 1981:61-67.
9. Gilljam H, Strandvik B, Ellin A, Wiman LG. Increased mole fraction of arachidonic acid in
bronchial phospholipids in patients with cystic fibrosis. Scand J Clin Lab Invest 1986:46: 511-18.
10. Strandvik B, Ellin A, Gilljam H, Kallner A, Wiman LG. Fatty acid metabolism in cystic fibrosis.
In: Warwick W, ed. I 000 years of cystic fibrosis. Minneapolis: University of Minnesota, 1981:
3()4....{}5.
II. Carlstedt-Duke J, Bronnegard M, Strandvik B. Pathological regulation of arachidonic acid release
in cystic fibrosis: the putative basic defect. Proc Natl Acad Sci USA 1986: 83: 9202-06.
12. Strandvik B. Bronnegard M, Gilljam H. Carlstedt-Duke J. Relation between defective regulation
of arachidonic acid release and symptoms in cystic fibrosis. Scand J Gastroenterol 1988; 23 (Suppl
143): 1-4.
13. Durie PR. The pathophysiology of the pancreatic defect in cystic fibrosis. Acta Paediatr Scand
1989: Suppl 363: 41-44.
14. Taylor CJ, Baxter PS, Hardcastle J, Hardcastle PT. Failure to induce secretion in jejunal biopsies
from children with cystic fibrosis. Gut 1988; 29: 957-62.
15. Patton CJ, Jenkins MQ, Briggman JV, Spicer SS. Effect of amiloride on potential difference
across rectal mucosa in cystic fibrosis patients. Pediatr Res 1982: 16: 1035-36.
16. di Sant'Agnese P, Blanc W. A distinctive type of biliary cirrhosis of the liver associated with
cystic fibrosis of the pancreas. Pediatrics 1956; 3: 387-409.
17. Tanner MS. Current clinical management of hepatic problems in cystic fibrosis. J R Soc Med
1986; 79 (Suppl 12): 38-43.
18. Koepp P. Winkler P, Schafer JH, Moncayo F. Massive steatosis in an infant with cystic fibrosis.
Monatsschr Kinderheilkd 1987; 135: 655-57.
19. Stern RC, Stevens DP, Boat TF et al. Symptomatic hepatic disease in cystic fibrosis: incidence,
course and outcome of portal systemic shunting. Gastroenterology 1976; 70: 645-49.
20. Sinaasappel M. Hepatobiliary pathology in patients with cystic fibrosis. Acta Paediatr Scand
1989; Suppl 363: 45-51.
21. Strandvik B, Norman A, Eklund A. Bile acid excretion in cystic fibrosis. In: Paumgartner G,
Stiehl A, eds. Bile acid metabolism in health and disease. Lancaster: MTP Press, 1977: 241-46.
22. Aly A, Johansson C, Slezak P, Gr~en K. Bioconversion of arachidonic acid in the human
gastrointestinal tract .. Biochem Med 1984; 31: 319-31.
23. Dreyling KW, Hoppe U, Peskar BA, Morgenroth K, Kozuschek W, Peskar BM. Leukotriene
synthesis by human gastrointestinal tissues. Biochim Biophys Acta 1986: 878: 184-93.
24. Hagmann W, Keppler D. Leukotrienes and other eicosanoids in liver pathophysiology. In: Arias
IM, Jakoby WB, Popper H, eds. The liver: biology and pathobiology, 2nd ed. New York: Raven
Press, 1988: 793-806.
25. Keppler D. Stoffwechsel und Analyse von Leukotrienen in vivo. Klin Wochenschr 1988; 66:
997-1005.
26. Selling JA. Hogan DL, Aly A, Koss MA. Isenberg Jl. Indomethacin inhibits duodenal mucosal
bicarbonate secretion and endogenous prostaglandin E2 output in human subjects. Ann Intern
Med 1987: 106: 368-71.
27. Donowitz M. Arachidonic acid metabolites and their role in inflammatory bowel disease. An
update requiring addition of a pathway. Gastroenterology 1985; 88: 58(}..87.
28. Barnes RH, Miller ES, Gurr GO. Fat absorption in essential fatty acid deficiency. J Bioi Chern
1941; 140: 77.
29. Clark SB, Ekkers TE, Singh A, Balint JA, Holt PR. Rodgers Jr JB. Fat absorption in essential
fatty acid deficiency: a model experimental approach to studies of the mechanism of fat malab-
sorption of unknown etiology. J Lipid Res 1973; 14: 581-88.
Acta Paediatr Scand Suppl 363 Relation EFA-CF 63

30. Hjelte L. Melin T. Nilsson A. Strandvik B. Absorption and metabolism of JH-arachidonic and
14 C-Iinoleic acid in essential fatty acid deficient rats. Am J Physiol (submitted).

31. Snipes RL. The effects of essential fatty acid deficiency on the ultrastructure and functional
capacity of the jejunal epithelium. Lab Invest 1968; 18: 179-89.
32. Sinclair AJ, Collins FO. Fatty livers in rats deficient in essential fatty acids. Biochim Biophys
Acta 1968: 152: 498-510.
33. Altmann DW, Gibson DM. Fatty acid synthesis during early linoleic acid deficiency in the mouse.
J Lipid Res 1%5; 6: 51-62.
34. Holman RT. Essential fatty acid deficiency. Prog Med Chern 1971; 9: 279-348.
35. Marshall PJ, Dixon JF. Hokin LE. Evidence that phosphatidylinositol breakdown releases
arachidonic acid. forming prostaglandins which are involved in stimulus-secretion coupling in the
exocrine pancreas. Prog Lipid Res 1981; 20: 229-32.
36. Akpan JO, Hurley MC, Lands WEM. Insulin and glucagon secretion in essential fatty acid
deficient rats. Acta Diabetol Lab 1981; 18: 147-56.
37. Bergstrom S, Danielsson H. Samuelsson B. The enzymatic formation of prostaglandin E 2 from
arachidonic acid. Biochim Biophys Acta 1964; 90: 207-10.
38. Peatfield AC, Piper PJ, Richardson PS. The effect of leukotriene C4 on mucin release into the cat
trachea in vivo and in. vitro. Br J Pharmacol 1982: 77: 391-93.
39. Keppler D, Huber M, Hagmann W, Ball HA, Guhlmann A, Kastner S. Metabolism and analysis
of endogenous cysteinylleukotrienes. Ann NY Acad Sci 1988; 524: 68-74.
40. Keppler D. Huber M, Baumert T. Leukotrienes as mediators in diseases of the liver. Semin Liver
Dis 1988; 8: 357-61.
41. Samuelsson B, Dahl~n S-E, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins:
structures, biosynthesis, and biological effects. Science 1987; 237: 1171-76.
42. Dahlen S-E, Bjork J, Hedqvist P et al. Leukotrienes promote plasma leakage and leukocyte
adhesion in postcapillary venules: In vivo effects with relevance to the acute inflammatory
response. Proc Nat! Acad Sci USA 1981; 78: 3887-91.
43. Lewis RA, Austen KF. The biologically active leukotrienes. Biosynthesis, metabolism, receptors,
functions, and pharmacology. J Clin Invest 1984; 73: 889-97.
44. Morin Cl, Roy CC, LaSalle R. BovinA. Small bowel mucosal dysfunction in patients with cystic
fibrosis. J Pediatr 1976; 88: 213-16.
45. Davison AG, Snodgrass GJA. Cystic fibrosis mimicking Hartter's syndrome. Acta Paediatr Scand
1983; 72: 781-83.
46. Dunham EW, Balasingam M, Privett OS, Nickell EC. Effects of essential fatty acid deficiency on
prostaglandin synthesis and fatty acid composition in rat renal medulla. Lipids 1976; 13: 892-97.
47. Sandermann Jr H. Regulation of membrane enzymes by lipids. Biochim Biophys Acta 1978; 515:
209-37.
48. Siraganian PA, Miller RW, Swender PT. Cystic fibrosis and ileal carcinoma. Lancet 1987; ii: 1158.
49. Thaler H. Relation of steatosis to cirrhosis. J Clin Gastroenterol 1975; 4: 273-80.
50. Strandvik B, Berg U, Kallner A, Kusoffsky E. The effect on renal function of essential fatty acid
supplementation in cystic fibrosis. J Pediatr 1989; 115: 242-48.
51. Strandvik 8, Seyberth HJ. Prostanoid metabolites in urine of patients with cystic fibrosis. Taipei
Conference on Prostaglandin and Leukotriene Research. Taipei, Taiwan 1988: 166.

(8. S.) Department of Pediatrics

Huddinge University Hospital
S-14186 Huddinge
Sweden

DISCUSSION
Question de Jongste: If we administer leukotrienes into the lungs by aerosol a considerable
amount of degradation products will be excreted in the urine. Is there any correlation
between disease severity of CF and the excretion of leukotriene degradation products in
the urine?
Answer Mrs Strandvik: We are studying this and have to wait for the answers. As I
presented there is a much higher release of leukotrienes. But these are mainly metabolised
64 B. Strandvik Acta Paediatr Scand Suppl 363

in the liver, the metabolites are excreted in the bile and make an intrahepatic circulation.
Only a small part is excreted in the urine. Therefore, looking only at urinary excretion is
not enough.
Question Sinaasappel: You presented evidence that prostaglandin levels are raised in
CF patients. You showed that prostaglandins influence the chloride channel and chloride
excretion. Chloride channels are impermeable in CF. How could you explain that with an
increased prostaglandin level you will have an impaired chloride channel?
Answer Mrs Strandvik: It is much more complicated than stated. The leukotriene C4
also increases chloride transport, though leukotriene B4 inhibits it. There is a balance
between the influences of these different eicosanoids on the chloride transport. So, if one
receptor is defect, it is difficult to foresee the outcome, since all the eicosanoids interfere
with each other in feedback system. We need more knowledge than the only fact that there
is an increased level of arachidonic acid and prostaglandins.
Question Kuyper: Is it possible to correct the essential fatty acid deficiency by transcu-
taneous application of linoleic acid in the form of sunflower oil?
Answer Mrs Strandvik: It has been shown in elderly people that transcutaneous
application raised the level of essential fatty acids. At present one of our co-workers is
studying the fat absorption in essential fatty acid deficient rats, what kind of effects are
due to eicosanoids and which are due to essential fatty acids. Are there similarities to CF?
At the moment the opinion is that if you have already an essential fatty acid deficiency of
some extent, it does not help to supply them by oral route because of the fat malabsorp-
tion. It is worthwhile studying transcutaneous application from an early phase on.
Question Bakker: You hypothesize a central role for essential fatty acid deficiency. Do
you know any other intestinal disease in which essential fatty acid deficiency occurs, e.g.
malabsorption syndromes, and which causes pulmonary changes like CF in the long run?
Answer Mrs Strandvik: Not to our knowledge. There is evidence that some patients with
colitis and with liver disease have bronchopulmonary disease in some respects similar to
CF. But the role of prostaglandins and leukotrienes in colitis is not determined yet. About
3% of our CF patients have an unspecific colitis, sometimes rather complicated notwith-
standing their mild CF.
Question de Jonge: According to some recent Nature publications some arachidonic
acid metabolites, e.g. leukotriene B4 and C4, exert a direct stimulatory effect on potas-
sium channels in the heart, whereas there is no indication at all that there would be any
disturbances at the level of heart function in CF patients. How do you integrate this in your
hypothesis?
Answer Mrs Strandv.ik: That question is difficult to answer. In Eastern Europe however
heart disease in CF is often described; but this is really not an answer to your question.
Question de Jonge: Ttie consequences of your hypothesis are unlikely to remain
restricted to epithelial tissues. Since most tissues produce arachidonic acid by a lipocortin-
sensitive form of phospholipase A2, in my opinion one would expect severe complications
in almost all tissues and not just in epithelial tissues.
Answer Mrs Strandvik: In principle I agree; however, I do not think the lack of
complications in most other tissues proves that our hypothesis is incorrect. The body may
find ways to compensate for a disturbance of phospholipid metabolism in some tissues but
not in others.
Question Smith: Could you comment on the use of lipoxygenase inhibitors as potential
treatment modalities in CF?
Answer Mrs Strandvik: Specific leukotriene inhibitors have not been studied yet. More
directed inhibitors might cure a part of the pulmonary symptoms in CF by influencing the
feedback regulation.
Acta Paediatr Scand Suppl 363 Relation EFA-CF 65

Question Van Haren: After all the debate, should we treat essential fatty acid deficiency
aggressively'?
Answer Mrs Strandvik: Since I think that essential fatty acid deficiency contributes to
the progress of the disease we treat our CF patients rather aggressively with lntralipid.®
Patients are in a much better shape. The mean survival rate in our centre is 29 years. We
think this high rate is partly due to the regular Intralipid® infusions.
Question Sinaasappel: Your results of the release of arachidonic acid are derived from
lymphocytes. We tried to study the same effects in fibroblasts and could not find similar
results.
Answer Mrs Stranduik: We also studied fibroblasts and these results were more varying
than from our lymphocyte studies. Differences in metabolism between fibroblasts and
leukocytes might be one of the reasons of these varying results.

S-898314