- Email: [email protected]
LOW CHOLESTEROL AND INCREASED RISK
163 medical care there is no easy measure of aggregate but the efficacy of cervical cytology can be more easily evaluated by measuring changes in age-specific mortality rates and stage-specific registration rates. We know what should happen if an effective system is made available, comprising efficient provision of all aspects of record keeping, call and recall, smear taking, and
For
most
success
cytology. If, in five years time, the predicted benefit fails to happen, who will be held responsible?1 If mortality from this disease is considerably reduced despite increasing incidence, it will be the
general practitioners, laboratories, family practitioner committees, and administrators, and the women themselves, who will, deservedly, take the credit but nobody will want to take the responsibility for any failure. The CGC would have done so, but it cannot now that it has been disbanded. Districts can blame their own failure on insufficient funds and on policy guidelines which have neither the direct financial backing of the Department nor necessarily the scientific backing of anybody. To rely on the ad hoc advice of professional organisations with other interests (such as the Faculty of Community Medicine or Royal College of General Practitioners) is to invite no action. Many policy questions have direct financial implications, but such bodies can play them down in formulating scientific policy and the Department can implicitly ignore their advice on the grounds that other strategies take priority. This is a recipe for no action and no responsibility. The abandonment of a realistic line of responsibility will have predictable consequences. Highly stretched districts can save on services, the outcome of which is not, in the end, their responsibility. Meanwhile inadequate cervical screening provision and organisation will ensure high death rates. Will the Health Minister alone be responsible or will it be the NHS Management Board? White Paper or not, the responsibility must lie somewhere. We are told that Sir Roy Griffiths oversees the provision of services and that Dr Muir Gray has a role in linking together those involved in managing them. Is this widely known? Is such responsibility properly funded? Department of Community Medicine and General Practice, University of Oxford, Gibson Laboratories Building, Radcliffe Infirmary,
KLIM MCPHERSON
Oxford OX2 6HE 1. Editorial. Cancer of the
cervix:
death by incompetence. Lancet 1982; ii: 363-64.
LOW CHOLESTEROL AND INCREASED RISK
SIR,-Your June 24 editorial refers to the WHO Cooperative Trial, which used clofibrate to study the effect on coronary heart disease (CHD) of reducing high plasma cholesterol concentrations. The reassuring data you cite are, unfortunately, only one way of
assessing this study. The final follow-up report,l which you do not mention, showed that the ratio of events in the intervention and comparable high cholesterol control group was 1-65 (p < 0-05) for all cancers during the 5-3 years of the trial and 0-94 during the 7-9 year follow-up. This has been interpreted as an unexplained adverse effect of clofibrate or a chance effect. But it might also be a consequence of cholesterol lowering. Some reassurance about the last interpretation comes from the Helsinki Heart Trialwhich
showed no overall excess of cancer with cholesterol reduction. But in the Lipid Research Clinics trial4 there were 21 incident cases (8 deaths) from gastrointestinal cancer in the cholestyramine group compared with 11cases (1 death) in the control group, although there was no difference in all cancers between the groups. The possibility of an increase in cancer with cholesterol lowering was first raised by the Los Angeles Veterans’ Administration StudyS of the effect of a high polyunsaturated fat diet on cholesterol lowering and CHD. You stated that this fmding "was not corroborated in a larger series". This is inaccurate, since our subsequent report6merely added the negative results of four small trials, which were less rigorous in conduct, to those of the Veterans’ Administration study, thereby diluting the increased incidence of cancer found in that study. Normal cell activity depends inter alia on membrane function and permeability. This is partly dependent on the balance in the bilayer
between cholesterol and saturated and polyunsaturated fatty acids. The possibility that normal membrane function is impaired when there is a disproportionate decrease in cholesterol, with resulting loss of resistance to cancerous change, has to remain on the agenda of the risk/benefits of lowering plasma cholesterol. The ongoing trials of the effects of hydroxymethylglutaryl coenzyme A reductase inhibitors should provide a clearer answer, since plasma cholesterol concentrations are likely to be more profoundly reduced than in any previous trial. Monitoring of non-cardiovascular events in these trials is especially important. Cardiovascular Research Unit, Hugh Robson Building,
George Square, Edinburgh EH8 9XF
M. F. OLIVER
Report of the Committee of Principal Investigators. WHO cooperative trial in primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Lancet 1984; ii: 600-04. 2. Oliver M. Serum cholesterol-the knave of hearts and the joker. Lancet 1981; ii: 1.
2090-95. 3. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987; 317: 1237-45. 4. Lipid Research Clinics Coronary Primary Prevention Trial. I. Reduction in incidence of coronary heart disease. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984; 251: 351-74. 5. Dayton S, Pearce ML, Hashimoto S, Dixon WJ, Tomiyasu U. A controlled trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation 1969; 39/40 (suppl II): II-1-63. 6. Ederer F, Leren P, Turpeinen O, Frantz ID. Cancer among men on cholesterollowering diets: experience from five clinical trials. Lancet 1971; ii: 203-06.
HEART DISEASE IN TIBET
SIR,-I read with interest your note (June 10, p 1341) about why ischaemic heart disease (IHD) is uncommon among Tibetan highlanders, despite their high haematocrits and the lack of fish in the diet. Besides rarity of systolic hypertension and the low serum cholesterol, apolipoprotein B, and apoB/apo A-1 ratios I would like to propose a third explanation. Beall and colleagues! studied haemoglobin concentrations in a sample of 103 pastoral nomads who are lifelong residents of Phala, at 4850-5450 m, on the northern plateau of Tibet. This is the highest altitude of regular habitation in the world and these nomads are thus exposed to the most extreme chronic hypoxic stress. However, they do not exhibit the most pronounced physiological adaptations-ie, haemoglobin concentrations exceeding those found in all other high-altitude populations. Mean haemoglobin concentrations in male and female Phala adults of 18.2 and 16.7 mg/dl, respectively, were found, at least 37% lower than those predicted for data from the Andes. Thus even though polycythaemia appears to be a universal adaptive response to high altitude residence, there is obviously a quantitative population difference in haematological adaptation to high-altitude hypoxia between Tibetan highlanders and other high-altitude native populations. This genetic difference certainly may play a role also in the IHD differences. Department of Medicine, George Washington University Medical Center, Washington, DC 20037, USA
TSUNG O. CHENG
1. Beall CM, Goldstein MC. The Tibetan Academy of Social Sciences: hemoglobin concentration of pastoral nomads permanently resident at 4,850-5,450 meters in Tibet. Am J Phys Anthropol 1987; 73: 433-38.
TACRINE IN ALZHEIMER’S DISEASE
SiR,—Summers et aP reported significant improvement in psychological assessments after a double-blind crossover placebo-controlled trial of tacrine (tetraclinical and
hydroaminoacridine) and lecithin of 6 weeks’ duration in patients with Alzheimer’s disease. The fourteen patients in the trial had improved in a previous open evaluation. These results produced considerable interest. We have repeated the trial with clinical and psychological follow-up for a further 3 months of tacrine therapy.
For
most
success
cytology. If, in five years time, the predicted benefit fails to happen, who will be held responsible?1 If mortality from this disease is considerably reduced despite increasing incidence, it will be the
general practitioners, laboratories, family practitioner committees, and administrators, and the women themselves, who will, deservedly, take the credit but nobody will want to take the responsibility for any failure. The CGC would have done so, but it cannot now that it has been disbanded. Districts can blame their own failure on insufficient funds and on policy guidelines which have neither the direct financial backing of the Department nor necessarily the scientific backing of anybody. To rely on the ad hoc advice of professional organisations with other interests (such as the Faculty of Community Medicine or Royal College of General Practitioners) is to invite no action. Many policy questions have direct financial implications, but such bodies can play them down in formulating scientific policy and the Department can implicitly ignore their advice on the grounds that other strategies take priority. This is a recipe for no action and no responsibility. The abandonment of a realistic line of responsibility will have predictable consequences. Highly stretched districts can save on services, the outcome of which is not, in the end, their responsibility. Meanwhile inadequate cervical screening provision and organisation will ensure high death rates. Will the Health Minister alone be responsible or will it be the NHS Management Board? White Paper or not, the responsibility must lie somewhere. We are told that Sir Roy Griffiths oversees the provision of services and that Dr Muir Gray has a role in linking together those involved in managing them. Is this widely known? Is such responsibility properly funded? Department of Community Medicine and General Practice, University of Oxford, Gibson Laboratories Building, Radcliffe Infirmary,
KLIM MCPHERSON
Oxford OX2 6HE 1. Editorial. Cancer of the
cervix:
death by incompetence. Lancet 1982; ii: 363-64.
LOW CHOLESTEROL AND INCREASED RISK
SIR,-Your June 24 editorial refers to the WHO Cooperative Trial, which used clofibrate to study the effect on coronary heart disease (CHD) of reducing high plasma cholesterol concentrations. The reassuring data you cite are, unfortunately, only one way of
assessing this study. The final follow-up report,l which you do not mention, showed that the ratio of events in the intervention and comparable high cholesterol control group was 1-65 (p < 0-05) for all cancers during the 5-3 years of the trial and 0-94 during the 7-9 year follow-up. This has been interpreted as an unexplained adverse effect of clofibrate or a chance effect. But it might also be a consequence of cholesterol lowering. Some reassurance about the last interpretation comes from the Helsinki Heart Trialwhich
showed no overall excess of cancer with cholesterol reduction. But in the Lipid Research Clinics trial4 there were 21 incident cases (8 deaths) from gastrointestinal cancer in the cholestyramine group compared with 11cases (1 death) in the control group, although there was no difference in all cancers between the groups. The possibility of an increase in cancer with cholesterol lowering was first raised by the Los Angeles Veterans’ Administration StudyS of the effect of a high polyunsaturated fat diet on cholesterol lowering and CHD. You stated that this fmding "was not corroborated in a larger series". This is inaccurate, since our subsequent report6merely added the negative results of four small trials, which were less rigorous in conduct, to those of the Veterans’ Administration study, thereby diluting the increased incidence of cancer found in that study. Normal cell activity depends inter alia on membrane function and permeability. This is partly dependent on the balance in the bilayer
between cholesterol and saturated and polyunsaturated fatty acids. The possibility that normal membrane function is impaired when there is a disproportionate decrease in cholesterol, with resulting loss of resistance to cancerous change, has to remain on the agenda of the risk/benefits of lowering plasma cholesterol. The ongoing trials of the effects of hydroxymethylglutaryl coenzyme A reductase inhibitors should provide a clearer answer, since plasma cholesterol concentrations are likely to be more profoundly reduced than in any previous trial. Monitoring of non-cardiovascular events in these trials is especially important. Cardiovascular Research Unit, Hugh Robson Building,
George Square, Edinburgh EH8 9XF
M. F. OLIVER
Report of the Committee of Principal Investigators. WHO cooperative trial in primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Lancet 1984; ii: 600-04. 2. Oliver M. Serum cholesterol-the knave of hearts and the joker. Lancet 1981; ii: 1.
2090-95. 3. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987; 317: 1237-45. 4. Lipid Research Clinics Coronary Primary Prevention Trial. I. Reduction in incidence of coronary heart disease. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984; 251: 351-74. 5. Dayton S, Pearce ML, Hashimoto S, Dixon WJ, Tomiyasu U. A controlled trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation 1969; 39/40 (suppl II): II-1-63. 6. Ederer F, Leren P, Turpeinen O, Frantz ID. Cancer among men on cholesterollowering diets: experience from five clinical trials. Lancet 1971; ii: 203-06.
HEART DISEASE IN TIBET
SIR,-I read with interest your note (June 10, p 1341) about why ischaemic heart disease (IHD) is uncommon among Tibetan highlanders, despite their high haematocrits and the lack of fish in the diet. Besides rarity of systolic hypertension and the low serum cholesterol, apolipoprotein B, and apoB/apo A-1 ratios I would like to propose a third explanation. Beall and colleagues! studied haemoglobin concentrations in a sample of 103 pastoral nomads who are lifelong residents of Phala, at 4850-5450 m, on the northern plateau of Tibet. This is the highest altitude of regular habitation in the world and these nomads are thus exposed to the most extreme chronic hypoxic stress. However, they do not exhibit the most pronounced physiological adaptations-ie, haemoglobin concentrations exceeding those found in all other high-altitude populations. Mean haemoglobin concentrations in male and female Phala adults of 18.2 and 16.7 mg/dl, respectively, were found, at least 37% lower than those predicted for data from the Andes. Thus even though polycythaemia appears to be a universal adaptive response to high altitude residence, there is obviously a quantitative population difference in haematological adaptation to high-altitude hypoxia between Tibetan highlanders and other high-altitude native populations. This genetic difference certainly may play a role also in the IHD differences. Department of Medicine, George Washington University Medical Center, Washington, DC 20037, USA
TSUNG O. CHENG
1. Beall CM, Goldstein MC. The Tibetan Academy of Social Sciences: hemoglobin concentration of pastoral nomads permanently resident at 4,850-5,450 meters in Tibet. Am J Phys Anthropol 1987; 73: 433-38.
TACRINE IN ALZHEIMER’S DISEASE
SiR,—Summers et aP reported significant improvement in psychological assessments after a double-blind crossover placebo-controlled trial of tacrine (tetraclinical and
hydroaminoacridine) and lecithin of 6 weeks’ duration in patients with Alzheimer’s disease. The fourteen patients in the trial had improved in a previous open evaluation. These results produced considerable interest. We have repeated the trial with clinical and psychological follow-up for a further 3 months of tacrine therapy.