113 cetamol. The 4 h plasma-paracetamol concentration is not the best early guide to prognosis3 10 but we believe it is the most practical index by which to group patients for comparison of treatments. Cysteamine was the most consistently effective agent studied, but more extensive experience is clearly desirable. Whatever the treatment it must be started as soon as possible, and certainly within 10 h. Treatment with these or similar agents is unlikely to be effective after 12 h and may be harmful in patients who have already suffered severe liver damageY Much has been made of the toxicity of cysteamine. 10 18 20 So far we have not encountered serious or life-threatening complications and, although unpleasant, the treatment of severe paracetamol poisoning with cysteamine is undoubtedly preferable to death in hepatic failure. We thank the medical and nursing staff of the Regional Poisoning Treatment Centre; Mrs E. F. Watson of the Pharmacy of the Royal Infirmary for preparation of the cysteamine, methionine, and penicillamine ; and Mr 1. King and Mrs I. Darrien for technical assistance. This work was supported by grants from the Scottish Home and Health Department and McNeil Laboratories Inc., Fort Washington, Pa., U.S.A:
REFERENCE S 1. 2. 3. 4.
Davidson, D. G., Eastham, W. N. Br. med. J. 1966, ii, 497. Proudfoot, A. T., Wright, N. ibid. 1970, iv, 557. Prescott, L. F., Wright, N., Roscoe, P., Brown, S. S. Lancet, 1971, i, 519. Clark, R., Thompson, R. P. H., Borirakchanyavat, V., Widdop, B., Davidson, A. R., Goulding, R., Williams, R. ibid. 1973, i, 66. 5. Mitchell, J. R., Thorgeirsson, S. S., Potter, W. Z., Jollow, D. J., Keiser, H. Clin. Pharmac. Ther. 1974, 16, 676. 6. Mitchell, J. R., Jollow, D. J., Potter, W. Z., Gillette, J. R., Brodie, B. B. J. Pharmac. exp. Ther. 1973, 187, 211. 7. Gazzard, B. G., Hughes, R. D., Portmann, B., Dordoni, B., Williams, R. Br. J. exp. Path. 1974, 55, 601. 8. Strubelt, O., Siegers, C. P., Schutt, A. Archs. Toxicol. 1974, 33, 55. 9. McLean, A. E. M., Day, P. A. Biochem. Pharmac. 1975, 24, 37. 10. Prescott, L. F., Newton, R. W., Swainson, C. P., Wright, N., Forrest, A. R. W., Mathew, H. Lancet, 1974, i, 588. 11. Wright, N., Prescott, L. F. Scott. med. J. 1973, 18, 56. 12. Prescott, L. F., Matthew, H. Lancet, 1974, i, 998. 13. Routh, J. I., Shane, N. A., Arredondo, E. G., Paul, W. D. Clin. Chem., 1968, 14, 882. 14. Prescott, L. F. J. Pharm. Pharmac. 1971, 23, 807. 15. Prescott, L. F. ibid. p.111. 16. Davis, M., Simmons, C. J., Harrison, N. G., Williams, R.
Q. Jl. 45, 181. 17. Lancet, 1975, ii, 1189. 18. Douglas, A. P., Hamlyn, A. N., James, O. ibid. 1976, i, 111. 19. Scott, C. R., Stewart, M. J. ibid. 1975, i, 452. 20. Hughes, R. D., Trewby, P., Williams, R. ibid. 1976, i, 536.
Med.
1976,
DEATH FROM ISCHÆMIC HEART-DISEASE AND MALIGNANCY IN ADULT PATIENTS WITH CŒLIAC DISEASE P.
J. WHORWELL
M. R. ALDERSON*
K. J. FOSTER RALPH WRIGHT
Southampton University Hospitals The cause of death was obtained for 77 members of the Cœliac Society resident in England and Wales. Proportional mortality analysis revealed a significant deficiency in deaths from ischæmic heart-disease in males and a non-significant deficiency in females. It is suggested that this apparent protective effect of cœliac disease might result from malabsorption of dietary lipids. The study also confirmed findings of an
Summary
*Present address: Institute of Cancer Research, Sutton,
Surrey.
excess
tinal
of deaths from
lymphoma
and upper
gastrointes-
neoplasms. Introduction
UNTREATED coeliac disease is associated with defective
absorption or intestinal loss of several nutrients, including fats, carbohydrates, and proteins. Malabsorption of fat and its loss into the intestine results in clinical steatorrhoea. Since an increased dietary intake of lipids is considered to play an important role in the aetiology of atherosclerosis and ischaemic heart-disease,1-3 we have speculated on the possibility that malabsorption of lipids in untreated coeliac disease might result in protection from ischxmic heart-disease. It has also been our clinical impression that ischaemic heart-disease is seen less commonly in patients with adult coeliac disease than would be expected. To test this hypothesis, we studied the records of the deceased patients who had been members of the Coeliac Society to determine whether the proportion of deaths from ischaemic heart-disease differed from that in the general population. We also examined the proportion of deaths from lymphoma and other malignant disorders in view of their reported increase in coeliac disease.4-6
Subjects
and Methods
The Cceliac Society maintains a current mailing list of its members (approximately 5000 adults), which is used for a twice-yearly mail-out. The subjects on this mailing list are identified by surname, forename or initial, and usually age, date of birth, marital status for females, and postal address. It was thought that most members who joined the society inform it of changes in their addresses, and that relatives or other agents might inform the society when the patient died. Inevitably, some of the subjects were lost to postal contact, some of whom would have died. Though adequate information was not available on all the patients who died, an attempt was made to trace them through the Office of Population Censuses and Surveys (O.P.C.S.) to obtain the cause of death. Where possible, the death data were traced and the relevant information forwarded to one of us (M.R.A.). Without details of the population at risk, it was only feasible to carry out a proportional mortality analysis; using this technique, the distribution of observed deaths is compared with the expected proportional distribution of deaths from different causes, taking age, sex, and calendar period of death into account.7 The identification particulars available for tracing the cause of death were relatively limited compared with those desirable for this activity. This created some problems in tracing an adequate proportion; this had to be taken into account when interpreting the data.
Results 141 members resident in England and Wales were thought to have died; 77 (54.6%) were traced and the relevant particulars were available of the deaths of 42 men and 35 women. The method of analysis used allowed examination of the observed distribution of deaths within the total number of deaths. The accompanying table shows the distribution of deaths by cause for ischxmic heart-disease, all malignancies, and those malignancies of special interest. There is a major reduction in the observed, compared with the expected number of deaths from ischaemic heart-disease, and this reaches significant levels for the male group and the group as a whole; the number of females available for
114 DISTRIBUTION OF OBSERVED AND EXPECTED CAUSE OF DEATH
analysis was small, but the trend was in the same direction. There is a moderate excess of observed deaths from all malignancy and from upper alimentary tract malignancy, but the numbers are small and the differences do not reach statistical significance. There is a highly significant excess of observed deaths from lymphoma over expected deaths, confirming earlier reports.4-6 Discussion In the present
study we have confirmed earlier increased incidence of death from lymphoma in patients with coeliac disease. We also found a significant decrease in expected deaths from ischmmic heart-disease. The study depended on identifying the cause of death occurring in a specific group of subjects, that is, former members of the Coeliac Society, and comparing this with the expected distribution of deaths by cause. Such a study is a relatively crude one and important points need to be taken into account when considering whether it is a true reflection of deaths from these disorders in patients with coeliac disease compared to the normal population. Patients joining the Coeliac Society are required to sign an application form stating that there has been a hospital diagnosis of coeliac disease, but this has not always been proven by the currently accepted criterion of biopsy response to a gluten-free diet. If our data included patients who did not have creliac disease, any association being sought might be expected to be weakened. There is an obvious pitfall when examining the association with intestinal lymphomas; patients in the early stages of the disease might be diagnosed as having caeliac disease, join the society, and die from their primary intestinal lymphoma without having pre-existing cceliac disease. We therefore examined the hospital records where available, and in 6 of the 8 records examined there was a long history of coeliac disease (greater than 4 years) suggesting that the lymphoma arose as a complication of the coeliac disease. This still leaves a highly significant difference between the observed and expected number of deaths from lymphoma (P
REFERENCE S 1. 2. 3. 4.
Davidson, D. G., Eastham, W. N. Br. med. J. 1966, ii, 497. Proudfoot, A. T., Wright, N. ibid. 1970, iv, 557. Prescott, L. F., Wright, N., Roscoe, P., Brown, S. S. Lancet, 1971, i, 519. Clark, R., Thompson, R. P. H., Borirakchanyavat, V., Widdop, B., Davidson, A. R., Goulding, R., Williams, R. ibid. 1973, i, 66. 5. Mitchell, J. R., Thorgeirsson, S. S., Potter, W. Z., Jollow, D. J., Keiser, H. Clin. Pharmac. Ther. 1974, 16, 676. 6. Mitchell, J. R., Jollow, D. J., Potter, W. Z., Gillette, J. R., Brodie, B. B. J. Pharmac. exp. Ther. 1973, 187, 211. 7. Gazzard, B. G., Hughes, R. D., Portmann, B., Dordoni, B., Williams, R. Br. J. exp. Path. 1974, 55, 601. 8. Strubelt, O., Siegers, C. P., Schutt, A. Archs. Toxicol. 1974, 33, 55. 9. McLean, A. E. M., Day, P. A. Biochem. Pharmac. 1975, 24, 37. 10. Prescott, L. F., Newton, R. W., Swainson, C. P., Wright, N., Forrest, A. R. W., Mathew, H. Lancet, 1974, i, 588. 11. Wright, N., Prescott, L. F. Scott. med. J. 1973, 18, 56. 12. Prescott, L. F., Matthew, H. Lancet, 1974, i, 998. 13. Routh, J. I., Shane, N. A., Arredondo, E. G., Paul, W. D. Clin. Chem., 1968, 14, 882. 14. Prescott, L. F. J. Pharm. Pharmac. 1971, 23, 807. 15. Prescott, L. F. ibid. p.111. 16. Davis, M., Simmons, C. J., Harrison, N. G., Williams, R.
Q. Jl. 45, 181. 17. Lancet, 1975, ii, 1189. 18. Douglas, A. P., Hamlyn, A. N., James, O. ibid. 1976, i, 111. 19. Scott, C. R., Stewart, M. J. ibid. 1975, i, 452. 20. Hughes, R. D., Trewby, P., Williams, R. ibid. 1976, i, 536.
Med.
1976,
DEATH FROM ISCHÆMIC HEART-DISEASE AND MALIGNANCY IN ADULT PATIENTS WITH CŒLIAC DISEASE P.
J. WHORWELL
M. R. ALDERSON*
K. J. FOSTER RALPH WRIGHT
Southampton University Hospitals The cause of death was obtained for 77 members of the Cœliac Society resident in England and Wales. Proportional mortality analysis revealed a significant deficiency in deaths from ischæmic heart-disease in males and a non-significant deficiency in females. It is suggested that this apparent protective effect of cœliac disease might result from malabsorption of dietary lipids. The study also confirmed findings of an
Summary
*Present address: Institute of Cancer Research, Sutton,
Surrey.
excess
tinal
of deaths from
lymphoma
and upper
gastrointes-
neoplasms. Introduction
UNTREATED coeliac disease is associated with defective
absorption or intestinal loss of several nutrients, including fats, carbohydrates, and proteins. Malabsorption of fat and its loss into the intestine results in clinical steatorrhoea. Since an increased dietary intake of lipids is considered to play an important role in the aetiology of atherosclerosis and ischaemic heart-disease,1-3 we have speculated on the possibility that malabsorption of lipids in untreated coeliac disease might result in protection from ischxmic heart-disease. It has also been our clinical impression that ischaemic heart-disease is seen less commonly in patients with adult coeliac disease than would be expected. To test this hypothesis, we studied the records of the deceased patients who had been members of the Coeliac Society to determine whether the proportion of deaths from ischaemic heart-disease differed from that in the general population. We also examined the proportion of deaths from lymphoma and other malignant disorders in view of their reported increase in coeliac disease.4-6
Subjects
and Methods
The Cceliac Society maintains a current mailing list of its members (approximately 5000 adults), which is used for a twice-yearly mail-out. The subjects on this mailing list are identified by surname, forename or initial, and usually age, date of birth, marital status for females, and postal address. It was thought that most members who joined the society inform it of changes in their addresses, and that relatives or other agents might inform the society when the patient died. Inevitably, some of the subjects were lost to postal contact, some of whom would have died. Though adequate information was not available on all the patients who died, an attempt was made to trace them through the Office of Population Censuses and Surveys (O.P.C.S.) to obtain the cause of death. Where possible, the death data were traced and the relevant information forwarded to one of us (M.R.A.). Without details of the population at risk, it was only feasible to carry out a proportional mortality analysis; using this technique, the distribution of observed deaths is compared with the expected proportional distribution of deaths from different causes, taking age, sex, and calendar period of death into account.7 The identification particulars available for tracing the cause of death were relatively limited compared with those desirable for this activity. This created some problems in tracing an adequate proportion; this had to be taken into account when interpreting the data.
Results 141 members resident in England and Wales were thought to have died; 77 (54.6%) were traced and the relevant particulars were available of the deaths of 42 men and 35 women. The method of analysis used allowed examination of the observed distribution of deaths within the total number of deaths. The accompanying table shows the distribution of deaths by cause for ischxmic heart-disease, all malignancies, and those malignancies of special interest. There is a major reduction in the observed, compared with the expected number of deaths from ischaemic heart-disease, and this reaches significant levels for the male group and the group as a whole; the number of females available for
114 DISTRIBUTION OF OBSERVED AND EXPECTED CAUSE OF DEATH
analysis was small, but the trend was in the same direction. There is a moderate excess of observed deaths from all malignancy and from upper alimentary tract malignancy, but the numbers are small and the differences do not reach statistical significance. There is a highly significant excess of observed deaths from lymphoma over expected deaths, confirming earlier reports.4-6 Discussion In the present
study we have confirmed earlier increased incidence of death from lymphoma in patients with coeliac disease. We also found a significant decrease in expected deaths from ischmmic heart-disease. The study depended on identifying the cause of death occurring in a specific group of subjects, that is, former members of the Coeliac Society, and comparing this with the expected distribution of deaths by cause. Such a study is a relatively crude one and important points need to be taken into account when considering whether it is a true reflection of deaths from these disorders in patients with coeliac disease compared to the normal population. Patients joining the Coeliac Society are required to sign an application form stating that there has been a hospital diagnosis of coeliac disease, but this has not always been proven by the currently accepted criterion of biopsy response to a gluten-free diet. If our data included patients who did not have creliac disease, any association being sought might be expected to be weakened. There is an obvious pitfall when examining the association with intestinal lymphomas; patients in the early stages of the disease might be diagnosed as having caeliac disease, join the society, and die from their primary intestinal lymphoma without having pre-existing cceliac disease. We therefore examined the hospital records where available, and in 6 of the 8 records examined there was a long history of coeliac disease (greater than 4 years) suggesting that the lymphoma arose as a complication of the coeliac disease. This still leaves a highly significant difference between the observed and expected number of deaths from lymphoma (P
