35

inefficiency-which, in medical work, implies lessthan the best treatment.

Requests for reprints should be addressed to C. I. P., EyePavilion, Chalmers Street, Edinburgh EH3 9HA.

REFERENCES

1. Br. med. J. 1973, i, 166.2. Med. J. Aust. 1971, ii, 1291.3. See Brown, J. A. C. The Social Psychology of Industry; p. 69.

Harmondsworth, 1954.4. Hlth Trends, 1972, 4, 48; Hlth Bull., Scotland, 1972, 31, 294.5. Br. med. J. 1972, iii, 696.

Occasional Survey

ILEAL BYPASS IN THE TREATMENT OF

HYPERLIPOPROTEINÆMIA

GILBERT R. THOMPSON* ANTONIO M. GOTTO, JR.Division of Atherosclerosis and Lipoprotein Research,Department of Medicine, Baylor College of Medicine,Methodist Hospital, Houston, Texas 77025, U.S.A.

INTRODUCTION

IT is now over ten years since Buchwald and Varco

performed the first ileal bypass for the purpose oflowering the serum-cholesterol of a patient with hyper-cholesterolaemia.1 Buchwald and his colleagues have

, subsequently carried out more than 100 similar

operations and have claimed that this procedure repre-sents the single most effective form of therapy forpatients with various forms of hyperlipoprotein2emia 2

including those with type-n disorder in the originalclassification of Fredrickson et al. 3 Although the ilealbypass procedure has now been utilised by other

workers, 4- the published experiences of the Minnesotagroup exceed those from all other sources com-

bined. 2, 9-12 We attempt here to evaluate ileal bypassfrom the point of view of the physician involved in themanagement of patients with hyperlipoproteinaemia.

RATIONALE AND RESULTS

In the operative procedure devised by Buchwaldand Varco, 10 the distal third or terminal 200 cm. of thesmall intestine is excluded from continuity with theproximal small bowel, and the proximal cut-end of thesmall bowel is implanted into the caecum. In theirhands this operation has resulted in an average decreasein serum-cholesterol to 60% of the preoperative value,both preoperative and postoperative determinationsbeing obtained with patients on a diet low in cholesteroland saturated fat and high in polyunsaturated fat.9 Thisdecrease has been maintained in some patients through-out a 5-year period of postoperative observation.2 Thefall in serum-cholesterol is usually accompanied by amarked reduction in the absorption of both exogenousand endogenous cholesterol. 8,10,13The rationale for the ileal bypass procedure was

initially based on the hypothesis that cholesterol isabsorbed preferentially in the ileum/’" as originallysuggested by Byers et al.14 However, subsequentmore physiologically designed studies have shown that* On leave of absence from the Royal Postgraduate Medical School,

London.

cholesterol is absorbed maximally in the jejunum, bothin the rat 15 and in man.16 Further studies by Gebhardand Buchwald 17 failed to confirm that the ileum hasany specific role in this respect. It is therefore probablethat the reduced absorption of cholesterol which followsileal bypass is due not to exclusion of absorptivearea but to the increased speed of intestinal transit 18 aand reduced reabsorption of bile acids which resultfrom the procedure. 8, 13, 19 Interference with bile-acidabsorption not only impairs cholesterol absorption, byreducing the supply of bile acids available for micelleformation, but also leads to an increased rate of turn-over of cholesterol into bile acids.13, Zo The net effectis usually a fall in the serum-cholesterol, although thefall is sometimes counterbalanced by a compensatoryincrease in cholesterol synthesis. 20, 21

ILEAL BYPASS VERSUS CHOLESTYRAMINE

The metabolic consequences of ileal bypass are verysimilar to those achieved by the administration ofcholestyramine resin, which interferes with bile-acidabsorption by virtue of its anion-binding properties.The comparative merits of these two methods oflowering the serum-cholesterol have been reviewed byGrundy.22 There is some suggestion that ileal bypassreduces the serum-cholesterol to a greater extent thandoes cholestyramine administration, 19,22 2 althoughGrundy et al. considered that there was no essentialdifference between the actions of ileal exclusion and ofcholestyramine on bile-acid excretion in man. However,it seems likely that intestinal transit would be morerapid after ileal bypass, and, if so, this would tend toadversely influence cholesterol absorption and thuscause an additional drain on cholesterol synthesis. Thecommonest side-effect of cholestyramine is constipation,whereas ileal bypass tends to cause diarrhoea, which issometimes persistent and severe, 7,8 as well as malab-sorption of vitamin B12. In addition to its effect on bileacids, cholestyramine also interferes with the absorp-tion of therapeutic agents such as thyroxine 23 anddigitoxin,24 probably by non-specific binding. 25 Ontheoretical grounds it is to be expected that both theoperation and the drug might predispose to the

development of gallstones by increasing the litho-

genicity of bile, but so far there is no evidence of this. 22 z

SELECTION OF PATIENTS

The Minnesota workers have used ileal bypass inthe treatment of various forms ofhyperlipoproteinsemia,including patients with the type II, III, and IV disordersdescribed by Fredrickson et al. 3 However, in view ofthe numerous effective dietary and drug regimens fortreating the type III and IV disorders, most physicianswould not contemplate use of ileal bypass in themanagement of patients in these two categories.Similarly, many patients with the non-familial varietyof the type-II disorder will respond to dietary measuresalone. However, patients with familial type-ll hyper-lipoproteinaemia pose a more difficult problem. Wenow wish to consider in some detail whether there is

any evidence that ileal bypass has any advantage overcombined diet and drug therapy in this particularsituation.

First and foremost, it seems clear that the rare but

36

lethal homozygous form of type-ll hyperlipoprotein-semia is as resistant to ileal bypass as to all other forms oftreatment. Evidence pointing to this conclusion comesfrom three quite separate sources. 2, 4. 8 In two in-stances, both cholestyramine and ileal bypass resultednot in a fall but in a rise in serum-cholesterol. 8 own theother hand, heterozygous patients with the type-lldisorder vary considerably in their response to hypo-cholesterolxmic agents. Clofibrate generally producesno more than a 10% fall in plasma-cholesterol in typelia, although some investigators have found a greaterdecrease in type lib. (Type lia refers to an increase inlow-density lipoprotein alone, while type lib is definedas an increase in both low-density and very-low-densitylipoprotein.26) Many type-ll patients will respondto cholestyramine, nicotinic acid, neomycin, or D-

thyroxine, although some are unable to take chole-styramine or nicotinic acid because of side-effects. Neo-mycin carries potential renal and otic toxicity and D-thyroxine is probably contraindicated in patients withcoronary-artery disease." There are reports that ilealbypass may lower the serum-cholesterol where drugshave failed.7,28 However, even then the operation mayhave to be supplemented by the administration of anagent designed to suppress cholesterol synthesis, suchas nicotinic acid, if the serum-cholesterol and low-

density-lipoprotein levels are to be kept within trulynormal limits. 28 Although ileal bypass is undoubtedlyan effective way of lowering the serum-cholesterol inhyperlipoproteinaemic patients, so also is diet in con-junction with cholestyramine. We therefore agree withGrundy et al. that in most cases the choice betweenthe two will depend upon factors such as cost, toleranceof medication, the risks of surgery, and the personalpreference of the patient. Yet it is clearly importantto establish whether there are some patients withheterozygous forms of familial type-ll hyperlipo-proteinaemia who genuinely do respond better to ilealbypass. A carefully documented preoperative trial ofcholestyramine in all patients undergoing ileal bypassin the future would be of considerable value in deter-mining whether the operation does indeed confersome special metabolic advantage over the drug. Sucha trial might also provide information which will en-able the clinician to predict which patients will respondwell to the surgical form of therapy.

We are not convinced that a prophylactic ileal bypassoperation is the method of choice for controlling hyper-lipoproteinsemia in growing children 12 or in otherindividuals with the type-ll disorder. While the lipidhypothesis of arteriosclerosis is a plausible one, it hasnot yet been unequivocally proven that lowering theserum-cholesterol will protect against the developmentof ischaemic heart-disease. Nor is there any evidencethat ileal bypass is beneficial in the management ofhomozygous type-ll subjects with established atheroma,who continue to remain a formidable therapeuticchallenge. At the present time, it would seem prudentto limit consideration of the use of this operation toyoung adult patients with severe heterozygous type-nhyperlipoproteinasmia which has proven refractory todrugs, as advocated by Strisower and his colleagues, 7or who are unable to tolerate an effective drug regimen.As more data become available it should be possible to

J

decide whether ileal bypass is simply a surgical alter.native to life-long cholestyramine therapy, or whetherit has a unique role to play in the management ofhyperlipoproteinaemia.

REFERENCES

1. Buchwald, H. Circulation, 1964, 29, 713.2. Moore, R. B., Varco, R. L., Buchwald, H. Am. J. Cardiol. 1973,

31, 148.3. Fredrickson, D. S., Levy, R. I., Lees, R. S. New Engl. J. Med. 1967,

276, 148.4. Davis, J. A., Johnston, I. D. A., Moutafis, C. D., Myant, N. B.

Lancet, 1966, ii, 971.5. Fritz, S. H., Walker, W. J. Am. Surg. 1966, 32, 691.6. Swan, D. M., McGowan, J. M. Am. J. Surg. 1968, 116, 22.7. Strisower, E. H., Kradjian, R. M., Nichols, A. V., Coggiola, E.,

Tsai, J. J. Atheroscler. Res. 1968, 8, 525.8. Grundy, S. M., Ahrens, E. H., Salen, G. J. Lab. clin. Med. 1971, 78,

94.9. Buchwald, H., Varco, R. L. J. Am. med. Ass. 1966, 196, 119.

10. Buchwald, H., Varco, R. L. Surgery Gynec. Obstet. 1967, 124, 1231.11. Buchwald, H., Moore, R. B., Lee, G. B., Frantz, I. D., Varco, R. L.

Archs Surg., Chicago, 1968, 97, 275.12. Buchwald, H., Moore, R. B., Krantz, I. D., Varco, R. L. Surgery,

St. Louis, 1970, 68, 1101.13. Moore, R. B., Frantz, I. D., Buchwald, H. ibid. 1969, 65, 98.14. Byers, S. O., Friedman, M., Gunning, B. Am. J. Physiol. 1955,

175, 375.15. Swell, L., Trout, E. C., Hopper, J. R., Field, H., Treadwell, C. R.

J. biol. Chem. 1958, 233, 49.16. Borgstrom, B. J. clin. Invest. 1960, 39, 809.17. Gebhard, R. L., Buchwald, H. Surgery, St. Louis, 1970, 67, 474.18. Gump, F. E., Barker, H. G. ibid. 1968, 64, 509.19. Miettinen, T. A. Scand. J. clin. Lab. Invest. 1969, 110, suppl. p. 48.20. Moutafis, C. D., Myant, N. B., Tabaqchali, S. Clin. Sci. 1968, 35, 537.21. Moutafis, C. D., Myant, N. B. ibid. 1968, 34, 541.22. Grundy, S. M. Archs intern. Med. 1972, 130, 638.23. Northcutt, R. C., Stiel, J. N., Hollifield, J. W., Stant, E. G. J. Am.

med. Ass. 1968, 208, 1857.24. Caldwell, J. H., Greenberger, N. J. J. clin. Invest. 1971, 50, 2638.25. Gallo, D. G., Bailey, K. R., Sheffner, A. L. Proc. Soc. exp. Biol. Med.

1965, 120, 60.26. Bull. Wld Hlth Org. 1970, 43, 891.27. J. Am. med. Ass. 1973, 220, 996.28. Miettinen, T. A., Lempinen, M. Scand. J. clin. Lab. Invest. 1970,

113, suppl. p. 55.

In England Now

THE CHIEF’S BASIC RULES

Rule 1.-The Chief is right.Rule 2.-In the impossible hypothesis that a subordinate

may be right, rule 1 becomes immediately operative.Rule 3.-The Chief does not sleep: he rests.Rule 4.-The Chief is never late: he is delayed elsewhere.Rule 5.-The Chief never leaves his work: his presence

is required elsewhere.Rule 6.-The Chief never reads the paper in his office:

he studies.Rule 7.-The Chief never takes liberties with his

secretary: he educates her.Rule 8.-Whoever may enter the Chief’s office with an

idea of his own must leave the office with his Chief’s ideas.Rule 9.-The Chief is always Chief even in bathing togs.

* ’" *

I hear that a consultant has just concluded a rathervitriolic book review with the following charmingly mixedmetaphor: " I also am an editor and can sniff out humbugwhen I see it ".

* * *

" A 95 m.p.h. tornado ripped the roof off the wind unitof the Electrical Research Association at Cranfield, Bed-fordshire. The unit conducts research into the effect ofhigh winds on buildings. Mr Ian Harris, the head of theunit, said yesterday as he helped to tidy up: ’ I suppose hewho lives by the wind shall perish by the wind. We

certainly learned something from it. Our building wasn’tstrong enough ’."-Guardian, June 28, 1973.