association with fibrinogen, even if it is real, can be of little practical importance. P C ELWOOD. MRC Epidemiology Unit,. Cardiff CF2 3AS. I Rogers S, James KS ...
CORRESPONDENCE * All letters must be typed with double spacing and signed by all authors.
* No letter should be more than 400 words. * For letters on scientific subjects we normally reserve our correspondence columns for those relating to issues discussed recently (within six weeks) in the BMJ.
* We do not routinely acknowledge letters. Please send a stamped addressed envelope ifyou would like an acknowledgment. * Because we receive many more letters than we can publish we may shorten those we do print, particularly when we receive several on the same subject.
Fish oil and plasma fibrinogen In a double blind trial Dr Arne T H0stmark and coworkers randomly assigned 64 men to receive either 14 g fish oil concentrate or 14 g olive oil (16 July, p 180). They found a significant decrease in mean plasma fibrinogen concentrations after three and six weeks of fish oil supplementation. We are studying the role offish oil in rheumatoid arthritis. In our double blind, placebo controlled, crossover trial with 12 week treatment periods 16 patients with active though stable rheumatoid arthritis (American Rheumatism Association criteria) were randomly allocated to receive either 12 fish oil capsules daily (eicosapentaenoic acid 2 04 g, decosahexaenoic acid 1-32 g, Intradal, Amersfoort, Holland) or 12 capsules of placebo (coconut oil). Complete data on 14 patients were obtained. The patient's usual diet was standardised and kept constant throughout the study. Current treatment with non-steroidal antiinflammatory or disease modifying drugs was continued. Clinical and biochemical evaluations were performed every two weeks and included a complete blood count and measurements of the erythrocyte sedimentation rate, serum amyloid A, C reactive protein, rheumatoid factor, and plasma fibrinogen concentrations (according to the method of Clauss'). Fish oil produced a statistically significant improvement in disease activity as measured by the joint swelling index and duration of morning stiffness compared with placebo, but the biochemical measures of inflammation remained unchanged. This result contrasts with that of Dr H0stmark and others. Although we used a lower dose of w3 fatty acids, fish oil seemed to have no influence on either the mean plasma fibrinogen concentration (table) or C reactive protein and serum amyloid A values. In spite of the lack of changes in the acute phase proteins the clinical benefits did correlate with significant changes in the mean neutrophil leukotriene production rate. A possible explanation for this discrepancy might be a difference in the measurement strategy Effects of fish oil supplementation on plasma fibrinogen and C reactive protein concentrations in 14 patients with rheumatoid arthritis. Results are means (SD) Weeks
-2 0 2 4 6
8 10 12
Fibrinogen (g/l)
C reactive protein (mg/I)
4-6 (1-0)
30 2 (2853)
4-6(1-0)
33-5(32-1) 30 4 (26 4) 33-8 (30 6) 33-3(35-1) 31-9(34 8) 31 5 (30-1) 30-8 (32 0)
4-6 (0 8) 4-6 (0 9)
43(09) 4-4(0 7) 4-1 (1 0)
4-2 (0 9)
Data were analysed with Student's t test.
BMJ
VOLUME 297
3 SEPTEMBER 1988
(separate measurements v measurements in all samples in the same run) or the use of different reference sera. Another explanation might be a dose dependent effect of fish oil on acute phase reaction, in particular on fibrinogen synthesis. The mechanism of action of fish oil remains to be determined as well as the optimum dose and duration of treatment. Long term, placebo controlled studies with different doses of fish oil are needed. J E TULLEKEN P LIMBURG M H VAN RIJSWIJK Department of Rheumatology, University Hospital, 9700 RB Groningen, The Netherlands 1 Clauss A. Gerinnungsphysiologische Shnellmethode zur Bestimmung des Fibrinogen. Acta Haematol (Basel) 1957;17:237-46.
The paper by Dr Arne T H0stmark and others (16 July, p 180) showed that a raised fibrinogen concentration, a well established risk factor for ischaemic heart disease, is significantly altered by supplementation with fish oil. This observation is an important addition to the evidence that fish oils have many effects that may be beneficial in preventing ischaemic heart disease.'2 These effects include actions on plasma triglycerides and high density lipoproteins, the coagulation system, platelet function, vascular reactivity, blood viscosity, and red cell deformability. Eskimos consume large amounts of fish, yet their plasma fibrinogen concentrations are higher than those of populations that take less fish in their diets.3 This suggests that ingestion of fish oil over prolonged periods may have a different effect from that of short term intake. Unfortunately, the authors do not report serum triglyceride concentrations. Hypertriglyceridaemia may be associated with increased plasma concentrations of fibrinogen, and this abnormality is corrected partially by successful treatment of the hyperlipidaemia.4 Fish oils also reduce plasma triglyceride concentrations, and a relation between triglyceride and fibrinogen should be considered. The activity of the inhibitor of tissue plasminogen activator is decreased by the administration of fish oil and correlates significantly with plasma triglyceride concentrations.5 D P MIKHAILIDIS M A BARRADAS P DANDONA
Metabolic Unit, Department of Chemical Pathology and Human Metabolism, Royal Free Hospital and School of Medicine, London NW3 2QG 1 Von Schacky C. Prophylaxis of atherosclerosis with marine omega-3 fatty acids. Ann Intern Med 1987;107:890-9.
2 Leaf A, Weber P. Cardiovascular effects of n-3 fatty acids. NEnglJMed 1988;318:549-57. 3 Dyerburg J, Bang HO. Lipid metabolism, atherogenesis, and haemostasis in eskimos: the role of the prostaglandin-3 family.
Haemostasis 1979;8:227-33. 4 Mikhailidis DP, Barradas MA, Dandona P. Cardiovascular risk in patients with treated familial hypercholesterolaemia and patients with severe hypertriglyceridaemia. J R Soc Med 1987;80:61. 5 Mehta J, Lawson D, Saldeen T. Reduction in tissue plasminogen activator inhibitor with omega-3 PUFA intake. J Am Coil Cardiol 1988;11:8.
Dr Arne T H0stmark and others reported a fall in plasma fibrinogen concentrations in halfofa group of men given fish oil and compared this with the changes in men given olive oil (16 July, p 180). More than a year ago we reported the results of an almost identical study in which there was no evidence of any change in fibrinogen concentrations.' The amount of eicosapentaenoic acid, the fatty acid of greatest interest in relation to lipid concentrations and thrombotic mechanisms, was higher in the authors' study than in ours, in which 272 g was taken daily for one week and then 156 g daily. All these doses, however, represent dietary intakes of fatty fish that are so high that an association with fibrinogen, even if it is real, can be of little practical importance. P C ELWOOD
MRC Epidemiology Unit, Cardiff CF2 3AS I Rogers S, James KS, Butland BK, Etherington MD, O'Brien JR, Jones JG. Effects of a fish oil supplement on serum lipids, blood pressure, bleeding time, haemostatic and rheological variables: a double blind randomised controlled trial in healthy
volunteers. Atherosckrosis 1987;63:13743.
The paper by Dr Arne T H0stmark and others (16 July, p 180), showing that the long chain n-3 essential fatty acids of fish oils lower plasma fibrinogen, supplies an important link in a chain. Meade et all and the Framingham study2 have shown that the risk of coronary heart disease is positively correlated with plasma fibrinogen values, and both groups attributed the increased risk of coronary heart disease in smokers to raised plasma fibrinogen concentrations, which Dr Hostmark and colleagues have confirmed. Smoking liberates fatty acids from adipose tissue, and in the United Kingdom these will be relatively saturated since adipose tissue contains only about 9%/o of linoleic acid (C18:2n-6) and very little docosahexaenoic acid (C22:6n-3); it is not surprising therefore that people smoking more than 20 cigarettes daily have a high ratio in plasma of saturated fatty acids to essential fatty acids,3 and this may be the cause of the rise in plasma concentrations of fibrinogen and apolipoprotein B.4' But on their traditional diet the Japanese and Eskimos smoke extensively and have relatively little coronary heart disease; the Japanese have 615
