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Lipoprotein(A) Thrombotic and Atherogenic

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Lipoprotein(A) Thrombotic and Atherogenic replace existing systems for collecting data. Part of its remit is Health-for example, how dangerous is long term exposure to assess these data critically and to collate them in a useful to low doses of pesticides?-will remain unanswered by the form. The pilot scheme should identify deficiencies in the new scheme. But the increase in information on the effects of existing mechanisms and improve reporting rates of sus- pesticides on health should be substantial. No room for pected adverse reactions to exposure to pesticides; current complacency exists while our knowledge is so incomplete: as BMJ: first published as 10.1136/bmj.303.6804.663 on 21 September 1991. Downloaded from levels of underreporting were noted with concern by the chief Geoffrey Rose said in a recent lecture on environmental medical officer in a circular earlier this year." The benefits of health to the Royal College of Physicians' regional conference the green card scheme will be strengthened by clinical and (Bristol, 1990), "Important effects on health could easily be toxicological support provided by the poisons unit. Detailed missed, and 'have not noticed' must never be mistaken for 'is clinical audit of reported cases is planned for the second and not there."' third years of the pilot scheme, which should help distinguish CHRISTOPHER BOOTH confirmed cases of pesticide poisoning from reported inci- Chairman, BMA Working Partv on Pesticides dents that are not confirmed by clinical follow up. DAV7ID MORGAN The green card, which requests information on the sus- Assistant Head, Professional and Scientific Division the patient, TARA LAMONT pected pesticide and the reactions and details of Secretary, Board of Science and Education has been designed to be as user friendly as possible. Since the British Medical Association, scheme was launched in June cards have been sent to 5000 London WC1H 9JP general practitioners and 50 accident and emergency depart- ALLISTER VALE ments in the West Midlands and Trent regions. Doctors Director, Pesticide Monitoring Unit, returning green cards will be contacted by staff at the poisons West Midlands Poisons Unit, unit, who will provide guidance about symptoms and their Dudley Road Hospital, possible connection with exposure to a pesticide. In addition Birmingham B18 7QH to providing immediate specialist advice by telephone (the 1 British Medical Association. Ilcsuiidcs, chenilcals anpid ctililti. Lonidoni: Edward Arnold, 1991. "pesticide hotline") on diagnosing and managing pesticide 2 World Healthi Organiisationi. Public lialth itmpact of pesticides used inl agriculntine. Genera: WHOT/N poisoning, the new scheme offers general practitioners back- Environment Programme, 1990. 3 HonLse of Commosns Agrictiltinre Committee. Annual report, aippenidix 11. Londoti: HMSO, 19X9. ground information on specific chemicals and reactions when 5 British Agrocheinicals Association. Annual revitew taitl handbook. PetcrboroLgh, Britishl Agrocllhini- appropriate. cals Association, 1989/90. 6 Department of Health. Reporting, of pesticidcs inclidnts. Londoni: I)eparnnentr ot Ifealth, 1991. P1)'1 Some questions raised by Pesticides, Chemicals and CMOF 91)5. Lipoprotein(a) Thrombotic and atherogenic In 1963 Berg described a lipoprotein antigen, which he called for more than 40% of the variability in Lp(a) concentrations.1' lipoprotein(a) (Lp(a)).' Numerous studies since then have Other sequence differences in the apo(a) gene, which presum- http://www.bmj.com/ found that plasma Lp(a) concentrations above 0 3 g/l (of total ably change mRNA or protein processing, may also substan- Lp(a) mass), which are present in one in five people, are tially alter Lp(a) plasma concentrations." associated with an increased risk of coronary heart disease2 1 Lp(a) is produced in the liver,' where it is presumably and stroke.4 Important milestones in Lp(a) research were the linked to apo BIO in the endoplasmic reticulum. In the elucidation of the primary structure of apo(a) and of apo endoplasmic reticulum and later in the Golgi apparatus apo B100, the two protein components of Lp(a).56 A flurry of B100 is loaded with triglyceride for secretion as very low recent research has contributed greatly to understanding the density lipoprotein. Although the density of most Lp(a) falls on 26 September 2021 by guest. Protected copyright. biosynthesis and degradation ofLp(a) and its role in thrombo- between the densities of low and high density lipoproteins, genesis and atherogenesis. Two studies in this week's issue Lp(a) can circulate with triglyceride rich lipoproteins and is add to this knowledge (pp 675, 694). presumably secreted as such.9" Lp(a) contains one (or two) molecules of apo(a) linked to Plasma Lp(a) concentrations are influenced by metabolic apo B100 by a disulphide bridge.2 6 Apo(a) is related to and endocrine factors and by drugs that affect hepatic plasminogen, from which the enzyme plasmin that hydrolyses production of very low density lipoprotein in the same fibrin blood clots is released by tissue plasminogen activator. direction. Hepatic disease and excessive alcohol consumption The apo(a) molecule is composed of an N-terminal variable decrease Lp(a) concentrations.'4 Lp(a) is increased in diabetics repeat of plasminogen kringle (a disulphide bonded domain with proteinuria' and in albuminuric renal disease. '"" It is shaped like a Danish cake) IV, a single kringle V, and the decreased by treatment with nicotinic acid, which blocks the plasminogen protease domain. supply of non-esterified fatty acids to the liver. '9 Fish oil also Plasma Lp(a) concentration varies from almost undetect- appears to lower Lp(a) plasma concentrations, and fish oil able to over l0 g/l, but differs little with sex, body mass decreases secretion of very low density lipoprotein.' "' The index, or age in adults.2 "' Concentrations are, however, production of very low density lipoprotein is regulated reported to increase during infancy.9 Black people have entirely by post-translational mechanisms, partly by sorting substantially higher levels than white people, surprisingly apo B1O0 between intracellular degradation and secretion.2" without increased coronary heart disease.2'9 The size of apo(a) Most probably the production of Lp(a) is similarly controlled varies between about 280 and 830 kD.23 The 20 or more size once apo(a) and apo B become linked in the endoplasmic isoforms are inherited in Mendelian codominant fashion and reticulum. result from variation in the number of kringle IV repeats in The pathways of Lp(a) clearance from the circulation are the gene."' The Lp(a) plasma concentration is inversely uncertain. Studies, particularly with transgenic mice that correlated with allele size2; the size polymorphism accounts overexpress the low density lipoprotein receptor, suggest that BMJ VOLUME 303 21 SEPTEMBER 1991 663 the low density lipoprotein receptor is involved. 9 In support and ototoxicity militate against the long term use of these of this, in low density lipoprotein receptor defective familial drugs. 2 The anabolic steroid stanozolol9 and the androgenic hypercholesterolaemia the concentration of Lp(a) is substan- progestogens7 used in hormone replacement therapy reduce tially increased, and this greatly compounds the risk of Lp(a) concentration, thus ameliorating the otherwise adverse coronary heart disease.2' The low density lipoprotein receptor effect of these drugs on plasma lipids.30 Perhaps the best news BMJ: first published as 10.1136/bmj.303.6804.663 on 21 September 1991. Downloaded from cannot be wholly responsible for Lp(a) clearance: hydroxy- is that fish oil seems to reduce Lp(a) concentration, though methylglutaryl coenzyme A (HMG CoA) reductase inhibitors more work is certainly needed to confirm this.' and bile acid sequestrants, which increase the activity of the Why measure plasma Lp(a), and how should raised receptor, do not reduce Lp(a).2 The consensus must be concentrations be treated? Along with high total cholesterol, that the low density lipoprotein receptor is involved in Lp(a) reduced high density lipoprotein cholesterol, hypertension, clearance but that other mechanisms may also operate. and cigarette smoking an Lp(a) concentration above 0 3 g/l is Although the function of Lp(a) is not established, it has emerging as a major determinant of coronary heart disease. thrombotic and atherogenic properties. The presence of Unfortunately, Lp(a) cannot yet be recommended as a apo(a) with apo B100 in atherosclerotic plaques and the avid general screening test because a standard immunochemical binding of kringle IV to fibrin has lead to the suggestion that assay or means of expressing values is lacking."' Who then Lp(a) delivers cholesterol to proliferating cells by binding should be tested, in a country that has largely ignored fibrin at sites of vascular injury.222- Excess local Lp(a) at cholesterol as a risk factor and where coronary heart disease is injury sites may be oxidatively modified, taken up by more prevalent than in most of the rest of the modern macrophages, and contribute to foam cell formation within world?3' 32 Eventually Lp(a) must join total cholesterol plaques.24 An alternative function of Lp(a) is suggested by in and high density lipoprotein measurements in the routine vitro studies, which show that Lp(a) competes in equimolar evaluation of the risk of heart disease. In the interim, the concentrations with plasminogen for binding to plasminogen measurement of Lp(a) is best left to the specialist lipid clinic receptors on vascular endothelial
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