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than normal, but in those cases where thrombocytopeniais associated with alcoholic cirrhosis the count willremain low. Alcoholics with normal platelet-counts mayshow a rise above normal (up to 800 000/µl) after alco-hol withdrawal13—a phenomenon which must be sayingsomething to us about the mechanisms whereby circulat-ing platelet numbers are controlled.

Patients with these changes are severe alcoholics,most of whom have chronic liver disease and will go intodelirium tremens when alcohol is withdrawn. What ofthe less severely affected but alcohol-dependent subjectswithout serious liver damage? If these blood changes area direct effect of alcohol poisoning rather than a second-ary effect due to liver damage then one might expect thesame changes to be present but to a lesser degree. Areport from the Karolinska Institute"now shows thatthis is so. Men drinking an average of 244_+102 g ofalcohol a day (4-10 single measures of gin or whisky)had a small reticulocyte response, a fall in serum-iron,and a rise in white-cell count after alcohol withdrawal.Platelet-counts were unchanged but erythrocyte-sedi-mentation rate and haptoglobin levels rose. These

changes are not great and they need confirmation bymore detailed individual studies (the report gives onlymean values in 34 men); but alcohol must now becounted a possible cause of otherwise obscure changes inthe blood of a patient recently admitted to hospital.

PLASMAPHERESIS IN MACROGLOBULINÆMIA

PRIMARY macroglobulinaemia (Waldenstrom’s macro-globulinxmia, W.M.) is a neoplastic disorder of B lympho-cytes and their progenyl which produce a monoclonal gam-maglobulin having the special physical and chemicalproperties of the macroglobulins. These include high in-trinsic viscosity, precipitation on cooling, and the pro-pensity to participate in protein/protein reactions.2

Like other chronic lymphoproliferative diseases, w.M.is associated with lymph-node enlargement, marrow in-filtration, hepatosplenomegaly, and invasion of organssuch as the kidney and central nervous system. How-ever, in some cases, the underlying neoplastic disorderruns an indolent course,3 and in many the clinical pic-ture is dominated by the hyperviscosity syndrome.4-6The IgM molecule has a high molecular weight and acharacteristic spiky shape; when present in largenumbers these molecules increase serum viscosity, aneffect exaggerated by the tendency of IgM molecules tostick together; moreover, by coating red cells and caus-ing rouleaux formation, the abnormal protein increaseswhole-blood viscosity itself. This leads, in turn, to circu-latory disturbances largely responsible for the ocular,neurological, and cardiovascular manifestations of thesvndrome.

13 Lindenbaum, J., Hargrove, R.L. Ann. intern Med. 1968, 68, 256.14. Myrhed, M., Berglund, L., Böttiger, L. E. Acta med. scand. 1977, 202, 11.1 Siegal, F P., Good, R. A. Clins Hœmat. 1977, 6, 395.2. Wintrobe, M. M. (editor) in Clinical Hætmatology; p. 1625. Philadelphia,

1974.3 Cohen, R J, Bohannon, R. A., Wallerstein, R. O. Am. J. Med. 1966, 41,

2744 Lancet, 1973, i, 359.5 Bloch, K. J., Maki, D. G. Semin Hœmat. 1973, 10, 113.6 Somer. T Adv. Microcirc. 1975, 6, 1.

The treatment of w.M., therefore, usually resolvesitself into that of the underlying lymphoma and--oftenmore urgently-that of the hyperviscosity syndrome.Chemotherapy and corticosteroids will help control thefirst and, eventually, reduce the concentration of circu-lating paraprotein, but plasma exchange by continuous-flow centrifugation is now established as the most effi-cient way of dealing with the hyperviscositysyndrome .7,8 In w.M. as much as 95% of the abnormalprotein is in the intravascular space, and some say thatup to 80% can be removed by a single 5-litre plasmaexchange;9 moreover, since plasma viscosity rises steeplywith increasing IgM concentration, even a small reduc-tion in serum-IgM will improve tissue perfusion whenmuch paraprotein is present. Additional bonuses arereduction of the dilutional anaemia which occurs in w.M.because of plasma volume expansion1O,1l and the im-provement in bleeding tendency which is due in part tothe interaction of the abnormal protein with clottingfactors and platelets. 12

Plasma exchange can be used as an emergency mea-sure, like venesection in fulminating polycythaemia vera,or as a long-term policy designed to supplement, or evenoccasionally replace, chemotherapy. Russell et al.8 havereported striking clinical and biochemical improvementsin 12 patients with w.M. treated by plasma exchange,while Buskard et awl. were able to control the hypervis-cosity syndrome, with this therapy alone, in 2 elderly pa-tients whose disease had become refractory to chemo-therapy ; plasmapheresis was performed at roughlymonthly intervals for up to 3 years, exchanging 5-6litres of plasma each time. The fluid removed can be re-placed, according to the patient’s requirements, withwhole blood, freeze-dried plasma, or fresh-frozen

plasma. However, Buskard et al. found that a mixtureof plasma-protein fraction, dextran 150, and saline

usually gave satisfactory results.9 Although the proced-ure is safe in experienced hands, over half the patientshave adverse reactions: these are usually minor allergicepisodes, controlled by hydrocortisone or antihista-mines. Particular care is required in patients with ischae-mic heart-disease, in whom angina, dyspnoea, or

arrhythmia may occur; however, congestive cardiac fail-ure related to hypervolsemia may be dramatically im-proved by plasmapheresis. Inevitably the procedureremoves some platelets, so that platelet infusions may berequired in patients with thrombocytopneia, but in prac-tice this is usually outweighed by the beneficial effects onhamostasis. Occasionally, electrolyte depletion mayrequire correction. Since at least 50% of the residualnormal immunoglobulin lies in the extravascular space,it is less depleted than the paraprotein during plasma-pheresis.Once controlled by vigorous plasmapheresis, the

serum viscosity should be monitored at weekly or longerintervals: symptoms usually appear when it approaches

7. Solomon, A., Fahey, J. L. Ann. intern. Med. 1963, 58, 789.8. Russell, J. A., Toy, J. L., Powles, R. L. Exp. Hœmat 1977, 5, suppl. 1, p.

105.9. Buskard, N. A., Galton, D. A. G., Goldman, J. M., Kohner, E. M., Grindle,

C. F. J., Newman, D. L., Twinn, K. W., Lowenthal, R. M. Can. med Ass.J. 1977, 117, 135.

10. MacKenzie, M. R., Brown, E., Fudenberg, H. H., Goodenay, L. Blood,1970, 35, 394.

11. Alexanian, R. Blood, 1977, 49, 301.12. Godal, H. C., Borchgrevink, C. F. Scand. J. clin. Lab. Invest. 1965, 17,

suppl. 84, 54.

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5 times normal." An occasional patient may be adequa-tely controlled by plasmapheresis alone, but most

require chemotherapy to delay the reaccumulation ofparaprotein. Plasmapheresis has greatly improved thequality of life in patients with this uncommon disorder.

THE FUTURE IN LIPID DISEASES

THE disappointing results of past epidemiological stu-dies of the effects of anti-hyperlipidaemic drugs meantthat the Sixth International Symposium on DrugsAffecting Lipid Metabolism (Philadelphia, August-Sep-tember) was largely a search for new directions. Therewas no lack of candidate drugs for the therapy of hyper-lipidaemia. Over thirty new agents were proposed fortreatment, but many had not been assessed in man.

Although some were analogues of existing treatments,such as clofibrate or nicotinic acid, there were severalapparently unique agents.

E. H. Ahrens reminded symposiasts that, althoughthe theory of the relationship of disordered lipid metabo-lism and atheroma is well established, the usefulness ofalteration of abnormalities is a hypothesis which has still

’

not been properly tested. The answer was unlikely tocome from expensive population trials, and there wasmuch talk throughout the symposium about the possibleusefulness of serial angiography to demonstrate arrestedprogression or actual regression of atheroma.One of the features of previous lipoprotein research

has been the emphasis on total serum cholesterol andlow-density lipoprotein as a risk factor for ischxmicheart disease. Yet evidence of the, protective effect ofhigh-density lipoprotein (and the cholesterol it carries)has been available for 25 years. D. B. Zilversmit, G.Schlierf, and S. B. Hulley discussed the possible mech-anisms, proposing H.D.L. as either a scavenger of arterialwall lipid or an antagonist to its deposition. At a subse-quent symposium in Cambridge W. P. Castelli, of theFramingham Study, remarked on the simplicity of mea-suring H.D.L. lipids and illustrated the powerful predic-tive value of the ratio of H.D.L. cholesterol to total cho-lesterol. H.D.L. levels are proportional to exercise andinversely proportional to obesity, cigarette smoking, andvery-low-density lipoproteins. The next generation ofdrugs may well be aimed at increasing H.D.L. ratherthan lowering serum cholesterol and triglycerides.The importance of platelets in the process of ather-

oma was emphasised, and the complex role of prosta-glandins in aggregation has been partly elucidated. Evi-dently the arterial wall may have a protective effect byinhibiting platelet aggregation. M. A. Packham dis-cussed the drugs which alter platelet adherence; whetherthese will be useful in therapy remains to be seen. Thelong and chequered history of anticoagulants in ischae-mic heart-disease warrants some reserve about these

agents.As Ahrens objected, the drug trials so far reported did

not select patients for hyperlipidaemia, and this maypartly explain their failure to show benefit. This is nottrue of the W.H.O. trial of clofibrate to be reported nextyear. Preliminary results from this trial were presented

13. Franklin, E. C., Buxbaum, J. Clins Hœmat. 1977, 6, 504.

by M. F. Oliver. There were important differences inrisk factors for ischxmic heart-disease between Swedenand Scotland, which may explain the high prevalence ofcoronary thrombosis in Scotland. Though Scots had ser-um-cholesterol levels similar to those of Swedes, theyhad higher serum-triglycerides, systolic and diastolic

blood-pressures, and alcohol and cigarette consumption;and lower H.D.L. levels, height, physical activity, andpolyunsaturated fats in the diet. From Australia R. B.Blacket reported a trial of diet in secondary preventionof ischxmic heart-disease. The only factor which seemedto influence survival after symptomatic heart diseasewas physical activity. Dietary manipulation may evenhave been harmful.

The side-effects of therapy received some furtherattention. L. A. Carlson and other speakers mentionedthe metabolic effects of various drugs used in therapy.Clofibrate seemed to improve glucose tolerance andnicotinic acid to worsen it -a theoretical advantage forthe former drug. A combination of the two agents leftglucose metabolism unaltered. A troublesome feature ofmedication in hyperlipidaemia is gallstone induction.This has been amply demonstrated with clofibrate treat-ment, but there is only scanty information about theeffects of other drugs on bile. B. Leijd reported thatnicotinic acid increases cholesterol in bile, but to a lesserextent than clofibrate. Cholestyramine abolishes thedeterioration caused by clofibrate; thus combination

therapy may be desirable in hypercholesterolaemia. B.Angelin stated that chenodeoxycholic acid suppressestriglyceride synthesis and commended the drug in hyper-triglyceridxmia because of its low toxicity and salutaryeffects on bile. Others suggested that chenodeoxycholicacid might be just as effective as clofibrate.Many of the agents discussed were derivatives of nico-

tinic acid, and it was a sad reflection of attitudes in clini-cal research that the half-dozen new analogues had notbeen properly compared with those currently in wideuse. Some interesting new drugs were proposed for ther-apy. Bezafibrate is a powerful analogue of clofibrate ;gemfibrozil is a potent agent for lowering triglyceridesand also raising H.D.L. (which is at best an uncertainattribute of clofibrate); probucol is a compound of un-known pharmacodynamics which lowers only serum-cholesterol but has a cumulative effect over some

months which may or may not be an advantage.Although there were several papers on the action of col-estipol none showed it to be superior to cholestyramine,and an effective, well-tolerated bile-acid-binding agent isyet to be found. The need now is for drugs which, aswell as influencing H.D.L. levels, will be acceptable forlong-term treatment. There was little enthusiasm for theuse of jejunoileal anastomosis, portacaval shunts, or

plasmapheresis in hypercholesterolxmia, and the side-effects of the surgical procedures together with the

heavy requirement for medical technology of plasma-pheresis make these procedures doubtful candidates forwide application. Agents to raise H.D.L. levels, and proofof efficacy by serial angiography, seem the likely path ofadvance in management of atheroma by manipulation oflipid metabolism. Pessimism caused by poor results ofprevious studies may now be replaced by cautious

optimism based on deeper understanding of themechanisms of vascular disease and the desirable effectsof drug therapy.