In the Melting Pot

1061

the nature of the relationship between dietary-fat intake and serum-cholesterol. Although cholesterol levels may be altered by dietary manipulation," it seems that the variation in serumcholesterol from one individual to another cannot be explained by their different consumption of fat. Community-based surveys, including the Framingham Study in the U.S.A., have shown that the serum-cholesterol of different individuals within a population is unrelated to current dietary-fat intake. 12-11 Various reasons for this "missing link" have been proposed. For example, it has been suggested that the methods of estimating dietary fat, which were usually based on a 24-hour dietary history, are unsatisfactory; and that variations in fat intake from one individual to another were too small to permit the detection of an existing difference in serum-cholesterol. But the explanations seem inadequate. If dietary fat is an important determinant of serum-cholesterol in an individual, it is surprising that no relationship was detected, even though the measurements were crude. How would the lack of association between fat intake and total serum-cholesterol relate to the cholesterol fractions? Does the protective role of H.D.L. cholesterol threaten the dietary-fat hypothesis? Until we know more about the relationships between diet and each cholesterol fraction we can only speculate about their implications. It is possible to envisage certain findings which would strengthen the dietary-fat hypothesis: if a high-fat diet were found to be negatively related to H.D.L. cholesterol but positively related to L.D.L. cholesterol, this might explain the absence of an association between dietary-fat intake and total serum-cholesterol. In addition, since H.D.L. cholesterol is inversely related to the risk of coronary heart-disease, a negative association between dietary-fat intake and H.D.L. cholesterol would lend further support to the hypothesis. At present there is little to suggest that dietary surveys will yield such straightforward results. Small studies in selected patients indicate that under certain dietary conditions the cholesterol fractions are reciprocally related, but that under other conditions they change in parallel.l6-18 Furthermore, population surveys have found no association between an individual’s H.D.L. cholesterol and his L.D.L. cholesterol,but the average H.D.L. cholesterol and L.D.L. cholesterol in different population groups seem to be reciprocally related.19 concerns

THE LANCET In the

Melting Pot

THE controversy over the dietary origin of coronary heart-disease has been rekindled by the find-

ings of the Troms0 study.

It is

now

clear that

cer-

tain fractions of serum-cholesterol have separate and apparently contrary relationships to coronary heart-disease. In the early 1950s there were many reports that patients with coronary heart-disease had lower levels of high-density-lipoprotein (H.D.L.) cholesterol, and higher levels of low-density-lipoprotein (L.D.L.) cholesterol, than did controls. 2-1 The relevance of these observations was questioned at the times and, unfortunately, this line of inquiry fell into disrepute. Now, more than twenty years later, the findings of GOFMAN and NIKKILA and their colleagues are being rediscovered. 1,6. Notable among the recent reports, the Troms0 study claims not only that H.D.L. cholesterol protects against coronary heart-disease, but also that H.D.L. level is a better predictor of heart-disease than total serumcholesterol itself. Cholesterol is central to the dietary-fat hypothesis. Diets rich in fat and cholesterol are said to increase total serum-cholesterol and, in turn, to increase the risk of coronary heart-disease. That H.D.L. cholesterol may be a better predictor of heart-disease than total cholesterol has led MANN8 to suggest that we are approaching "the end of an era" dominated by the notion that coronary heartdisease was caused by excessive consumption of fat and cholesterol. The implications of H.D.L. cholesterol and L.D.L. cholesterol for the dietary-fat hypothesis must be considered together with other evidence relating to it. A large body of data supports the hypothesis. The average consumption of fat in different countries is closely correlated with the average serum-cholesterol and with the level of coronary heart-disease in that country.9 Moreover, it has been shown repeatedly that an individual’s risk of acquiring coronary heart-disease increases progressively as total serum-cholesterol increases. 10 Nevertheless, certain observations do not accord with the hypothesis. The most serious discrepancy 1 2

Miller, N. E., Farde, O. H., Thelle, D. S., Mjøs, O. D. Lancet, 1977, i, 965. Gofman, J. W., Jones, H. B., Lindgren, F. T., Lyon, T. B., Elliott, H. A., Strisower,B Circulation, 1950, 2, 161. 3 Barr, D. P., Russ, E. M., Eder, H. A.Am. J. Med. 1950, 11, 480. 4 Nikkilä,E Scand. J. clin. Lab. Invest. 1953, 5, suppl. 8.

5. Keys, A. J. Am. med. Ass. 1951, 147, 1514. 6. Medalie, J. H., Kahn, H. A., Neufeld, H. N., Riss, E., Goldbourt, U. J.chron. Dis. 1973, 26, 329. 7 Rhoads, G. G., Gulbrandsen, C. L., Kagan, A. New Engl. J. Med. 1976, 294, 293.

8. Mann, G.V. ibid 1977, 297, 644. 9 Keys, A. Coronary Heart Disease in Seven Countries. American Heart Association monograph no. 29, 1970. 10 Intersociety Commission for Heart Disease Resources. Circulation, 1970, 42.

11 The National Diet-Heart

Study Final Report. American Heart Association monograph no. 18, 1968. 12. Morris, J N, Marr, J. W., Heady, J. A., Mills, G. L., Pilkington, T. R. E. Br. med. J. 1971, i, 573. 13. Kannel, W. B. Med Clins N. Am. 1974, 58, 363. 14. Epstein, F H. Atherosclerosis, 1971, 14, 1. 15. Shaper. A G., Marr, J W. Br. med J 1977, i, 867 16. Levy, R I., Lees, R S., Fredrickson, D. S. J clin. Invest. 1966, 45, 63. 17. Lees, R S, Wilson, E. D. ibid. 1972, 51, 1051. 18 Schonfeld, G., Weidman, S. W.,Witztum, J. L, Bowen, R. M. Metabolism, 1976, 25, 261. 19 Miller, G J., Miller, N E. Lancet, 1975, i, 16.

1062

With the revival of interest in cholesterol fractions, we may indeed be approaching the end of an era in our thinking about fats and coronary heartdisease. But it will not necessarily be marked by a rejection of the dietary-fat hypothesis, as MANN8 and others20,21 have suggested. Instead, the central role previously ascribed to total cholesterol may be transferred to the cholesterol fractions. A shift in emphasis from total cholesterol to its fractions would overcome the discrepancies in the old hypothesis, without changing the underlying assertion that diets rich in fat cause coronary heart-disease. One exciting prospect for those interested in the way hypotheses about heart-disease are evaluated by the scientific community22 is that the stagnant arguments between the proponents and critics of the dietary-fat hypothesis may now progress to different issues. New questions can be asked: how does diet affect each fraction? How do these fractions relate to coronary heart-disease and other factors? But if diets rich in fat prove to have no clear association either with low H.D.L. cholesterol or with high L.D.L. cholesterol, then the dietaryfat hypothesis will look fragile indeed.

Factors in Ovarian Cancer

Aetiological

THE mortality-rates for ovarian cancer have risen since 1950 in both the United Kingdom and the United States of America, particularly in older women. The reasons are obscure, but the increase provides a disagreeable reminder that our knowledge of the aetiology of ovarian cancer is scanty.! One factor which has attracted attention is an alleged link between the disease and marital status and parity. An increased incidence of ovarian cancer in unmarried women and in women with no or few children has been described2,3 (and also disputed4,5). Two surveys6,7have now confirmed such an association, and the combined evidence is con-

vincing. British investigators6 examined a large number of possible xtiological factors with a questionnaire in three groups of women-300 index cases, drawn from 17 centres, in whom ovarian cancer was diagnosed at laparotomy, and two sets of age-matched control cases The controls were postoperative 20. Cole, T J ibid 1977, i, 1199. 21. Evans, E. J. ibid. p. 1200. 22. Marmot, M. Am. J Epidem 1976, 103, 519. 1. Lingeman, C. H. J natn. Cancer Inst. 1974, 53, 1603. 2. Dorn, H. J., Cutler, S. Morbidity from Cancer in the United States (Publ. Hlth Monogr. no 56). Washington, D.C., 1959. 3. Joly, D. J., Lilienfeld, A. M., Diamond, E. L., Bross, I D. J. Am. J. Epidem.

with

gynxcological

ovarian

tumours or

cinoma,

serous

with clear-cell

cystadenocarcinoma combined

adenocarcinoma, endometrial

car-

cinoma, and mucinous cystadenocarcinoma), accounted for 90% of the cases; the fifth category consisted of non-epithelial tumours such as mesonephroma, dysgerminoma, and granulosa-cell neoplasms. The results of the questionnaire were first examined in the index cases alone, by comparison of the five tumour groups. No significant differences emerged. But when the results were compared between the index cases, considered as a whole, and the two control series, certain differences in obstetric history became clear. Fewer of the index cases had married, fewer had become pregnant, and their mean numbers of pregnancies were lower. This difference was equally clear when comparison was made with the postoperative control group and with the control cases from the G.P.s’lists. Another study,based on the National Cancer Institute’s Third National Cancer Survey,8 produced broadly concordant results. A group of 4468 newly diagnosed cases of ovarian cancer, aged at least 25, was examined. It was concluded that the incidence of the disease was 60-70% higher in White and Black women who had never married than in those who had. The excess of cases in unmarried women was apparent at all ages covered by the survey, least impressive in the youngest patients (25-34) and most obvious in the oldest (65+). The relation between marital status and ovarian cancer was found to hold for epithelial-cell tumours but not for germ-cell or sex-cord/mesenchymal neoplasms, probably because many of the latter lesions occur in children and others below the age of 25. When the group of epithelial tumours was subdivided into various histological categories, the association between cancer and marital status appeared strongest for clear-cell and endometrioid

neoplasms. An association of the kind proposed between ovarian cancer and marital status and childbearing is difficult to evaluate; but it may well point to a common factor in cancers of ovary, breast, and endometrium.l,9 The analogies between these three cancers cannot be stretched too far, but there is certainly an increased incidence of ovarian carcinoma in patients with breast cancer and viceversa. Attention is inevitably focused on possible 7.

1974, 99, 190. 4. West, R. O. Cancer, 1966, 19, 1001. 5. Wynder, E. L., Dodo, H., Barber, H. R. K. ibid. 1959, 23, 352. 6. Newhouse, M. L., Pearson, R. M., Fullerton, J. M., Boesen, E. A. non, H. S. Br J. prev. soc. Med. 1977, 31, 148.

conditions other than and women from general cysts, practitioners’ lists living in the same neighbourhood as the index cases. The tumours were divided into five histological groups: four of them, originating from germinal epithelium (papillary cystadenocar-

patients

Weiss, N. W., Young, J. L., Jr., Roth, G. J. J.

natn.

Cancer Inst. 1977, 58,

913.

M., Shan-

8. Cutler, S. J., Young, J. L., Jr. Natn. Cancer Inst. Monogr 1975, 41, 1. 9. Henderson, B. E., Gerkins, V. R., Pike, M. C in Persons at High-Risk of Cancer (edited by J. F. Fraumeni, Jr.); p. 267. New York, 1975