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 cells.2 2h Lp(a) is not for those people with substantially raised cholesterol concen- apparently a fibrinolytic enzyme like plasmin.2" Thus, Lp(a) trations, in whom high Lp(a) greatly increases the risk of could impede the access of plasminogen to endothelial cell coronary heart disease,2' or those with premature coronary tissue plasminogen activator and produce a prothrombotic heart disease in the absence of other risk factors. How should state by suppressing local fibrinolysis. Induction by Lp(a) of a raised concentration be treated? For lack of other treat- plasminogen activator inhibitor 1 in endothelial cells could ments, the best measure is to dramatically reduce blood total also contribute to thrombogenesis.2 cholesterol concentration and to minimise all other risk To date no effective treatment has been found for reducing factors. With time, drugs that safely reduce plasma Lp(a) raised blood Lp(a) concentrations. HMG CoA reductase concentration should become available. inhibitors, bile acid sequestrants, fibric acid derivatives, JAMES SCOTT probucol, and diet have little effect on Lp(a) concentra- Division of Molecular Medicine, tions.2 482' Nicotinic acid alone or in combination with MRC Clinical Research Centre, neomycin reduces Lp(a), but flushing and hepatic toxicity Harrow HAI 3UJ

Berg K. A new scrtim tpe systcm in man: thc Lp system. .Acia PaholAllicrobtlIScand 1963;59:369- 16 'I'akegoshi 'I', Haba '', Hirai J-I, Kitoh C, Saga F, Yamazaki ci ala. Altcrations oi' lipoprotcin:a in 82. patients with diabetic nephropathy. Atherosclerosis 1990;83:99-1(00. http://www.bmj.com/ 2 UtermaniiG. he mnsteries ol Iipoproteinka). Sciettce 1989;246:904-10. 17 IParra HJ, MIezdouir H, Cachera C, l)racon M, 'I'acquLet A, Fruchiart JC. Lpla) lipoprotciti i 3 Scaiuil AMI, Fless (iM. Lipoprotein(a). Heterogeneity and biological relevance. 7 Clin Invcst patients with chronic renial failure treated by hemodialysis. Clin Clhenm 1987;33:721. 1990;85: 1709-15. 18 Karadi 1, Romica L, I'alos G, D)oman J, Kaszas 1, Hesz A. it ttl. Lptas lipoprotcin coniccntrattion in 4 Woo J, Lani , l.am (CWK, Kay R, [Ieoh R, Wong HY, e atl. Hvpertension, lipoprotein(a), and sertum of patients with heavy proteinuria ot different origin. C/tn Cthern 1989;35:2121-3. apolipoprotein A-I as risk factors for stroke in the Chinese. Stroke 1991;22:203-8. 19 Grundv SMI, Mok HYI, Zech L, Berman M. Influence of nicotinic acid oni metabolism of' 5 Knott TJ, IPease RJ, Powell LM, Wallis SC, Rall SC Jr, Innerarity IL, et al. Complete protein cholesterol and triglvceridcs in man. 7 Lipid Re.s 1981;22:24-36. sequence and ideintificationl ol structural domains of human apolipoprotein B. Nature 1986;323: 20 Scott J. Regulation otf the biosynthesis of apolipoprotein BI()( and apolipoiprotein B48. Curreit 734-8. )pitniotu itt Lipido/gv 1990;1 :96-103. 6 McLean JW, I omlinson JE, Kuiatig W-J. c)NA sequience of human apolipoprotein(a) is 21 Seed AM, Hoppichler F, Reaveley D, McCarthy 'S'hompsonS, GR, Boerwitklec E, et al. Relation of homologous to plasminogeit. N'ature 1987;300: 132-7. sertim lipoproteitt(a) conicenitration and apolipoprotcin(a) phenotype to coronary heart disease in Med 1990;3221494-9. 7 Farish E, Rolton HA, Barncs JF, Hart I)M Reduction of lipoprttein(a) levels in postmenopausal patienits with familial hyperchoIlesterolemia. IEtnglJ on 26 September 2021 by guest. Protected copyright. women beinig treated with niorcthistcrottc. 1/ 117 1991;303:694. 22 Zitonchcck IF, Itowell LMI, Rice GC, Eaton D)L, ILawni RAI. Interactioii oti recombinatit 8 Kapcirud H, Baitgstad H-13, I)ahl-Jorgensen K, Berg K, Hanlssen KF. Serum Lp(a) lipoprotein apolipoprotein(a) and lipoprotein(a) with macrophages. J Clitn Invest 1991;87:767-7 1. concentrations in instulin delpndent diabetic patients with microalbuminuria. BMJ 1991; 23 Rath M, Niendorf A, Reblin T, Manfred D, Krebbcr H-J, Beisiegel U. Detectioll and 303:675. qttatttihcation of lipoproteitt(a) in the arterial wall of 107 corotnarv bypass patieits. Arte'riosclerosis 9 Albers JJ, Alarcovina SM\, Lodge MS. 'I'hc uiniquLe lipoproteinka): properties and immunochemical 1989;9:579-92. measurement. Cin Ctlient 1990;36:2019-26. 24 Rotiv 1), Grailhe 1', Nigott F, Chapman J, Angles-Catno E. Lipoprotein:a) impairs gettcration of' Ill SuLndell IB, Nilsson rK, Halltmaans (i, Hellsten G, lDahlett GH. Interrelationships between plasma plasmin by finrin-botiiid tissue-type plasminogeti activator. A-rteriuscler IThromnh 1991;11:629-38. levels of plasminogenl actisvator itthibitor, tiSSuLe plasmiiloengl actisator, lipoprotein;a), and 25 Miles LA, Fless GMI, Levin EG, Scanu AM, Plow EF. A potential basis for the thrombotic risks established cardiovascuLlar risk factors itt a North Swedish ptpulation. Atherosclerosis 1989;80:9- associated with lipoprotein:a). Nature 1989;339:301-3. 16. 26 Hajjar KA, (Gavish 1), Breslow JL, Nachman RL. Lipotproteinta) modulatiott of cndothclial cell II l,acknerC, Boerwinkle l;, Lefert C(, Rahmig '', Hobbs HH. Molecular basis ol'ayptlipKprotein(a) sturfiace fibrinolysis and its potential role in atherosclerosis. Nature 1989;339:303-5. isotform sizc heterogencity as resealed by pulsed-fieli gel electrophoresis. .7 Clin Invest 27 Etingin OR, Hajjar D)P, Hajjar KA, Harpel PC, Nachman RL. Lipoprtotein(a) regulates 1991;87:2153-61. plasminogen activator inhibitor- exprcssion in endothelial cells.] Bitol C/tenm 1991;266:2459-65. 12 Boerwittklc E, Menzel HJ, Kraft H(G, Utermann G. Contrihbitioni of Lp;a) glycoprotein phenotype 28 Maeda S, Okuno Mi, Abe A, Noma A. Lack otf etfect otf probticol on serum lipoprotein(a) levels. to normal lipid variation. HuntnGenet 1989;8:73-8. .Atteroscleroisis 1989;79:267-9. 13 Bcrsot Pl, Inneraritv Fl, Iitas RE, Rall SC, Weisgraber KH, M\anley RW. Fat f'eeding in htumans 29 Albers JJ, raggart HMcA, Applebaum-Boowden D, Haffner S, Chestntut CH, Hazzard WiR. induces lipp)proteilns otf detsity less than 1-006 that are enrichcd in apoli-poprotein(a) and that Redttction of lecithin-cholestrirol acvl tratisferase, apilipoprotein B and the Lp(a) lipoproteins cattse lipid aCCLtmuliation in macrophagcs.j Clin Invest 1986;77:622. with the attabolic sterroid stanozolol. Bititt iips-s Acta 1984:795:293-6. 14 Mlarth E, Cazzolato G, Bittolo Bon G, Avogaro P. Seruim concentrations ot Lp(a) and other 30 Rijpkcma AHM, san der Satiden AA, RtliIs AHC. Elfccts oti ptist-menopattsal oestrogen- lipoprotcin parameters in heavy alcohol tonsumers. -Inn Nutrlfetab 1982;26:56. progestogeni replacement therapyton serum lipids atid liptoproteinis: a review. Mattrittas 15 Britkcrt F, D)avidtoff 1, (irimaldi A, 'Fruffert J, Giral P, Dourmith R, et at. Innrcased scruIm lCVCs 1990112:259-85. of lipoproteil(.a) itn diabctes mellittis and their redtuction with glvcemic control. jAMA 31 WCHO MONICA Ilroject. (IPrepared by TtLomilehto J, Kuulasmaas K.) Assessing CHI) mortalitV 199();263:35-6. and morbidity. Iit7 Epidentitol 1989;18:S38-45. 32 Ttinstall-Pedoe H. Heart discase mortalitv. BMJ 1989;298:751-2.

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