807

than normal, but in those cases where thrombocytopenia is associated with alcoholic cirrhosis the count will remain low. Alcoholics with normal platelet-counts may show a rise above normal (up to 800 000/µl) after alcohol withdrawal13—a phenomenon which must be saying something to us about the mechanisms whereby circulating platelet numbers are controlled. Patients with these changes are severe alcoholics, most of whom have chronic liver disease and will go into delirium tremens when alcohol is withdrawn. What of the less severely affected but alcohol-dependent subjects without serious liver damage? If these blood changes are a direct effect of alcohol poisoning rather than a secondary effect due to liver damage then one might expect the same changes to be present but to a lesser degree. A report from the Karolinska Institute"now shows that this is so. Men drinking an average of 244_+102 g of alcohol 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-sedimentation rate and haptoglobin levels rose. These changes are not great and they need confirmation by more detailed individual studies (the report gives only mean values in 34 men); but alcohol must now be counted a possible cause of otherwise obscure changes in the blood of a patient recently admitted to hospital.

PLASMAPHERESIS IN MACROGLOBULINÆMIA PRIMARY

macroglobulinaemia (Waldenstrom’s macroglobulinxmia, W.M.) is a neoplastic disorder of B lymphocytes and their progenyl which produce a monoclonal gammaglobulin having the special physical and chemical properties of the macroglobulins. These include high intrinsic viscosity, precipitation on cooling, and the propensity to participate in protein/protein reactions.2 Like other chronic lymphoproliferative diseases, w.M. is associated with lymph-node enlargement, marrow infiltration, hepatosplenomegaly, and invasion of organs such as the kidney and central nervous system. However, in some cases, the underlying neoplastic disorder runs an indolent course,3 and in many the clinical picture is dominated by the hyperviscosity syndrome.4-6 The IgM molecule has a high molecular weight and a characteristic spiky shape; when present in large numbers these molecules increase serum viscosity, an effect exaggerated by the tendency of IgM molecules to stick together; moreover, by coating red cells and causing rouleaux formation, the abnormal protein increases whole-blood viscosity itself. This leads, in turn, to circulatory disturbances largely responsible for the ocular, neurological, and cardiovascular manifestations of the svndrome. 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, 1 Siegal, F P., Good, R. A. Clins Hœmat. 1977, 6, 395. 2. Wintrobe, M. M. (editor) in Clinical Hætmatology; p. 1625.

11.

Philadelphia,

1974. 3

Cohen,

The treatment of w.M., therefore, usually resolves itself into that of the underlying lymphoma and--often more urgently-that of the hyperviscosity syndrome. Chemotherapy and corticosteroids will help control the first and, eventually, reduce the concentration of circulating paraprotein, but plasma exchange by continuousflow centrifugation is now established as the most efficient way of dealing with the hyperviscosity syndrome .7,8 In w.M. as much as 95% of the abnormal protein is in the intravascular space, and some say that up to 80% can be removed by a single 5-litre plasma exchange;9 moreover, since plasma viscosity rises steeply with increasing IgM concentration, even a small reduction in serum-IgM will improve tissue perfusion when much paraprotein is present. Additional bonuses are reduction of the dilutional anaemia which occurs in w.M. because of plasma volume expansion1O,1l and the improvement in bleeding tendency which is due in part to the interaction of the abnormal protein with clotting factors and platelets. 12 Plasma exchange can be used as an emergency measure, like venesection in fulminating polycythaemia vera,

long-term policy designed to supplement, or even occasionally replace, chemotherapy. Russell et al.8 have reported striking clinical and biochemical improvements in 12 patients with w.M. treated by plasma exchange, while Buskard et awl. were able to control the hyperviscosity syndrome, with this therapy alone, in 2 elderly patients whose disease had become refractory to chemotherapy ; plasmapheresis was performed at roughly monthly intervals for up to 3 years, exchanging 5-6 litres of plasma each time. The fluid removed can be replaced, according to the patient’s requirements, with whole blood, freeze-dried plasma, or fresh-frozen plasma. However, Buskard et al. found that a mixture of plasma-protein fraction, dextran 150, and saline usually gave satisfactory results.9 Although the procedure is safe in experienced hands, over half the patients have adverse reactions: these are usually minor allergic episodes, controlled by hydrocortisone or antihistamines. Particular care is required in patients with ischaemic heart-disease, in whom angina, dyspnoea, or arrhythmia may occur; however, congestive cardiac failure related to hypervolsemia may be dramatically improved by plasmapheresis. Inevitably the procedure removes some platelets, so that platelet infusions may be required in patients with thrombocytopneia, but in practice this is usually outweighed by the beneficial effects on hamostasis. Occasionally, electrolyte depletion may require correction. Since at least 50% of the residual normal immunoglobulin lies in the extravascular space, it is less depleted than the paraprotein during plasmapheresis. Once controlled by vigorous plasmapheresis, the serum viscosity should be monitored at weekly or longer intervals: symptoms usually appear when it approaches or as a

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. R

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

274 4 Lancet, 1973,i, 359. 5 Bloch, K. J., Maki, D. G. Semin Hœmat. 6 Somer. TAdv. Microcirc. 1975, 6, 1.

1973, 10, 113.

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.

808 5 times normal." An occasional patient may be adequately controlled by plasmapheresis alone, but most require chemotherapy to delay the reaccumulation of paraprotein. Plasmapheresis has greatly improved the quality of life in patients with this uncommon disorder.

THE FUTURE IN LIPID DISEASES THE disappointing results of past epidemiological studies of the effects of anti-hyperlipidaemic drugs meant that the Sixth International Symposium on Drugs Affecting Lipid Metabolism (Philadelphia, August-September) was largely a search for new directions. There was no lack of candidate drugs for the therapy of hyperlipidaemia. Over thirty new agents were proposed for treatment, but many had not been assessed in man. Although some were analogues of existing treatments, such as clofibrate or nicotinic acid, there were several

apparently unique agents.



E. H. Ahrens reminded symposiasts that, although the theory of the relationship of disordered lipid metabolism and atheroma is well established, the usefulness of alteration of abnormalities is a hypothesis which has still not been properly tested. The answer was unlikely to come from expensive population trials, and there was much talk throughout the symposium about the possible usefulness of serial angiography to demonstrate arrested progression or actual regression of atheroma. One of the features of previous lipoprotein research has been the emphasis on total serum cholesterol and low-density lipoprotein as a risk factor for ischxmic heart disease. Yet evidence of the, protective effect of high-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 mechanisms, proposing H.D.L. as either a scavenger of arterial wall lipid or an antagonist to its deposition. At a subsequent symposium in Cambridge W. P. Castelli, of the Framingham Study, remarked on the simplicity of measuring H.D.L. lipids and illustrated the powerful predictive value of the ratio of H.D.L. cholesterol to total cholesterol. H.D.L. levels are proportional to exercise and inversely proportional to obesity, cigarette smoking, and very-low-density lipoproteins. The next generation of drugs may well be aimed at increasing H.D.L. rather than lowering serum cholesterol and triglycerides. The importance of platelets in the process of atheroma was emphasised, and the complex role of prostaglandins in aggregation has been partly elucidated. Evidently the arterial wall may have a protective effect by inhibiting platelet aggregation. M. A. Packham discussed the drugs which alter platelet adherence; whether these will be useful in therapy remains to be seen. The long and chequered history of anticoagulants in ischaemic 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 may partly explain their failure to show benefit. This is not true of the W.H.O. trial of clofibrate to be reported next year. Preliminary results from this trial were presented 13. Franklin, E. C., Buxbaum, J. Clins Hœmat. 1977, 6, 504.

M. F. Oliver. There were important differences in risk factors for ischxmic heart-disease between Sweden and Scotland, which may explain the high prevalence of coronary thrombosis in Scotland. Though Scots had serum-cholesterol levels similar to those of Swedes, they had higher serum-triglycerides, systolic and diastolic blood-pressures, and alcohol and cigarette consumption; and lower H.D.L. levels, height, physical activity, and polyunsaturated fats in the diet. From Australia R. B. Blacket reported a trial of diet in secondary prevention of ischxmic heart-disease. The only factor which seemed to influence survival after symptomatic heart disease

by

was

physical activity. Dietary manipulation

may

even

have been harmful. The side-effects of therapy received some further attention. L. A. Carlson and other speakers mentioned the metabolic effects of various drugs used in therapy. Clofibrate seemed to improve glucose tolerance and nicotinic acid to worsen it -a theoretical advantage for the former drug. A combination of the two agents left glucose metabolism unaltered. A troublesome feature of medication in hyperlipidaemia is gallstone induction. This has been amply demonstrated with clofibrate treatment, but there is only scanty information about the effects of other drugs on bile. B. Leijd reported that nicotinic acid increases cholesterol in bile, but to a lesser extent than clofibrate. Cholestyramine abolishes the deterioration caused by clofibrate; thus combination therapy may be desirable in hypercholesterolaemia. B. Angelin stated that chenodeoxycholic acid suppresses triglyceride synthesis and commended the drug in hypertriglyceridxmia because of its low toxicity and salutary effects on bile. Others suggested that chenodeoxycholic acid might be just as effective as clofibrate. Many of the agents discussed were derivatives of nicotinic acid, and it was a sad reflection of attitudes in clinical research that the half-dozen new analogues had not been properly compared with those currently in wide use. Some interesting new drugs were proposed for therapy. Bezafibrate is a powerful analogue of clofibrate ; gemfibrozil is a potent agent for lowering triglycerides and also raising H.D.L. (which is at best an uncertain attribute of clofibrate); probucol is a compound of unknown pharmacodynamics which lowers only serumcholesterol 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 colestipol none showed it to be superior to cholestyramine, and an effective, well-tolerated bile-acid-binding agent is yet to be found. The need now is for drugs which, as well as influencing H.D.L. levels, will be acceptable for long-term treatment. There was little enthusiasm for the use of jejunoileal anastomosis, portacaval shunts, or plasmapheresis in hypercholesterolxmia, and the sideeffects of the surgical procedures together with the heavy requirement for medical technology of plasmapheresis make these procedures doubtful candidates for wide application. Agents to raise H.D.L. levels, and proof of efficacy by serial angiography, seem the likely path of advance in management of atheroma by manipulation of lipid metabolism. Pessimism caused by poor results of previous studies may now be replaced by cautious optimism based on deeper understanding of the mechanisms of vascular disease and the desirable effects of drug therapy.

Plasmapheresis in macroglobulinaemia.

807 than normal, but in those cases where thrombocytopenia is associated with alcoholic cirrhosis the count will remain low. Alcoholics with normal p...
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