118
excluded because of factors contraindicating anticoagulant therapy (a history of haemorrhagic diathesis or peptic ulcer disease, or, in a few cases, strong belief in the prophylactic value of aspirin). 156 patients were excluded because the referring physicians thought they required antiooagulant therapy, and this group is, of course, of particular importance in this context. We have gone through the records of all these patients: 101 were given warfarin because the physicians at one of the hospitals believed in the prophylactic value of warfarin after anterior wall myocardial infarction (n = 32) or after streptokinase therapy for myocardial infarction (n 69); other reasons were atrial fibrillation (n = 30), arterial embolism (n = 8), venous thrombosis (n = 6), valvular heart disease (n=4), and miscellaneous (n=7). The male/female ratio was 3-9 to 1 in these excluded patients and 3to 1 in our study group; the mean age was 615and 616, respectively. Of the patients excluded because of anticoagulant therapy, none had a known aPL syndrome.3 Thus, no patient populations at high risk for the end points were excluded. One might argue that the patients with anterior wall infarction and atrial fibrillation were at high risk for cerebral embolism; however, involvement of aPL in the pathogenesis of this condition is not suspected. Of the 1214 patients remaining after the exclusions, 607 were randomised to placebo and constitute our cohort. Our belief that no high-risk population has been removed is borne out by the high mortality (19-9%) and occurrence of reinfarction (20-1%) and cerebrovascular disease (7-4%) during the study period. We had measured aCEPHA and aCL in the entire cohort of 1200 patients. There was no effect of the antibodies on the end points in the warfarin group-as we found for the placebo group. Thus, the patient population studied was an unselected group of patients who had survived an AMI. Of course, our results do not exclude the possibility that high aPL values might be an independent risk factor for thrombo-embolic events in patients with other disorders--eg, patients with the aPL syndromethe existence of which we do not doubt. =
Haematological Research Laboratory, Department of Internal Medicine, Ullevål University Hospital, N 0407 Oslo, Norway
K. E. SLETNES P. SMITH M. ABDELNOOR H. ARNESEN F. WISLØFF
1. Smith
P, Amesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 1990; 323: 147-52. 2. Smith P, Arnesen H. Mortality in non-consenters in a post-myocardial infarction trial. J Intern Med 1990; 228: 253-56. 3. Harris EN. Antiphospholipid antibodies. Br J Haematol 1990; 74: 1-9.
readily auto-oxidise, generating free radicals and other compounds that disrupt cellular function and damage cell membranes. Increased intake of highly polyunsaturated fats increases the nutritional requirement for vitamin E, but by how and
much is not known. Contamination with toxic residues is also a concern. Lead and mercury in the commonly occurring methylated form are lipophilic, as are organochlorides such as DDT, and preferentially accumulate in the lipid stores of fish living in contaminated waters. These difficulties are surmountable by careful control of production conditions. Oxidation can be kept to a minimum by refrigeration, addition of anti-oxidants such as vitamin E, and the use of packaging that excludes light and air; and toxic residues are largely removed by efficient processing. However, such manoeuvres and the stringent quality control needed to ensure consumer safety add considerably to the cost of the final product. An alternative approach might be to encourage regular fish consumption in pregnant women. As Olsen et al point out, the differences between those who received and did not receive fish oil supplements were considerably reduced when individuals who habitually ate a lot of fish were compared, suggesting that the effect of fish oil on gestation length and birthweight has a limit. In the Aarhus study seven out of ten of the fish oil group had belching; unpleasant taste and nausea were also common. Despite these effects, compliance rates of 75% were achieved, which bespeaks participant motivation and researcher persuasiveness unlikely to be found outside the context of a clinical trial. Consuming fish rather than fish oil capsules might have the added benefit of displacing other saturated and n-6 fats from the diet. Since the effects of n-3 fatty acids are much affected by the total amount and proportions of other dietary fats, this might further potentiate their effects, leading to a reduction in the amount needed. Fred Hutchinson Cancer Research Center, Gastroenterology/Hepatology Section SC-111, Seattle, WA 98104, USA
ANNE TOBIN
Neuringer M, Connor WE. n-3 fatty adds in the brain and retina: evidence for their essentiality. Nutr Rev 1986; 44: 285-94. 2. Neuringer M, Connor WE, Lin DS, Baistad L, Luck F. Biochemical and functional effects of prenatal and postnatal n-3 fatty acid deficiency on retina and brain in rhesus monkeys. Proc Natl Acad Sci USA 1986; 83: 4021-25. 3. Thomgren M, Gustafson A. Effects of 11 week increase in dietary eicosapentaonoic acid on bleeding time, lipids and platelet aggregation. Lancet 1981; ii: 1190-93. 4. Goodnight SH, Harris WS, Connor WE. The effects of dietary w-3 fatty acids on platelet composition and function in man: a prospective study. Blood 1981; 58: 1.
880-85. 5.
Thomgren M, Shafi S, Born GVR Delay in primary haemostasis produced by a fish diet without change in local thromboxane A2 production. Br J Haematol 1984; 58: 567-78.
Fish oil
supplementation
in pregnancy
Medical audit of the investigation of toxoplasmosis associated with pregnancy
SIR,-Dr Olsen and colleagues (April 25, p 1003) report evidence that
dietary fish oil supplements prolong gestation and increase birthweight. The fetus may benefit from maternal supplementation in other ways; the n-3 fatty acids abundant in fish oil are major components of neuronal and retinal tissue and may be involved in learning and visual acuity. 1;z.Studies of rhesus monkeys suggest that a supply of these fatty acids is especially important in the last trimester and first three months of life when membranes high in n-3 3 fatty acids are being formed? Several studies have examined the effect of large doses of fish or fish oil on coagulation. Modest reductions in platelet count and aggregation and lengthening of mean bleeding times by up to 50%3,4 have been reported. In one study whose participants ate a diet high in fish, prolongation of bleeding time was highly variable, ranging from 2 to 93%, and persisted for three weeks after supplementation.5 It is therefore not surprising that in the group of Danish women taking fish oil there was a trend towards increased blood loss at delivery. This trend was apparent despite the group’s very low caesarean section (< 9%) and assisted delivery rates. In other obstetrical populations with higher rates of surgical
intervention, bleeding complications could be substantially higher. If these promising findings are duplicated by other studies, fish oil might be offered to large numbers of healthy pregnant women. The safety of fish oil supplements warrants consideration. By virtue of their high degree of polyunsaturation, n- 3 fatty acids are unstable
SIR,-Increased awareness of toxoplasmosis in pregnancy has led demands for serotesting and for routine screening. However, the study of toxoplasmosis associated with pregnancy may be problematic and in 141 cases, we found that 98 (70%) received non-ideal investigation.1 Thus we introduced a programme of enhanced communication between reference centre and clinician and monitored the effect on patient’s care. All cases of acute toxoplasmosis associated with pregnancy first investigated during 1990 were included. Letters were sent to all responsible clinicians when laboratory records indicated ideal investigation had not been achieved. Further details of the case were requested in a questionnaire and educational material was provided. Reminders were sent to non-responders and a quarterly analysis of the findings was given to all participants. 130 cases of acute toxoplasmosis associated with pregnancy were studied. In addition to standard laboratory results, a further 170 letters and 60 h of administrative time were devoted to these cases. 6 cases of congenital toxoplasmosis were confirmed and 50 children were shown to be free of infection. A definite diagnosis was not made in 62 cases. A further 12 pregnancies did not proceed to term (5 spontaneous abortions, 1 intrauterine death, 6 terminations). 5 products of conception showed no histological evidence of toxoplasma infection and the parasite was not isolated from fetal to
119
tissues. In the
remaining
7 cases, tissues
were not
available for
testing. All cases lacking a definite diagnosis were analysed in detail. In 26 patient was classified as lost to follow-up by the responsible clinician. Of these, 5 women had returned to their country of origin for delivery, 2 failed to keep appointments, and 3 were subject to administrative errors. 1 mother had refused further medical care and 1 child had been discharged, erroneously, on the basis of a normal clinical appearance. Details of the other 14 cases were not stated. The clinicians responsible for the other 36 cases without a definite diagnosis but with continued medical contact were sent further literature describing the recommended investigation of toxoplasmosis in pregnancy and asked to provide information about outcome of the patient. 25 recipients did not reply; 5 children were subsequently shown to be free of infection; 3 cases failed to keep further appointments; and in 2 cases the clinician decided further investigation of the child would result in unacceptable parental anxiety.1 child was mistakenly discharged after the parasite had not cases the
been isolated at cordocentesis before delivery. Our intervention resulted in 61 of 130 cases (47%) achieving a substantiated final diagnosis compared with 30% of cases before instigation of the programmed The resolution of additional cases involved an average of 2-7 h administrative work per patient. These findings illustrate the influence of patient’s and physician’s compliance on the optimal investigation of toxoplasmosis in pregnancy. These limitations should be included in any cost-benefit analysis of antenatal screening for toxoplasmosis. This work was
supported by
a
grant from Birthright.
Toxoplasma Reference Laboratory, Public Health Laboratory Service, St George’s Hospital, London SW170QT, UK 1. Hartup C, Johnson JD, Holliman RE. 317-18.
C. HARTUP J. D. JOHNSON R. E. HOLLIMAN Toxoplasma and pregnancy. Lancet 1991; 338:
Aflatoxin biomarkers SIR,-Dr Hall and C. P. Wild (June 6, p 1413) in their comments about our report (April 18, p 943) provide a thoughtful assessment of several important issues related to the interaction between chronic hepatitis B virus infection and urinary biomarkers of aflatoxin exposure and liver cancer risk. We, too, were initially surprised at the strength of this relation and have considered several points they raise. As Hall and Wild suggest, it is feasible that aflatoxin exposure is fairly constant among individuals in Shanghai over time, but only repeated sampling in the same individuals can fully assess this possibility. After additional analysis of our data, we have found further evidence that aflatoxin-guanine adduct concentrations in urine, and not those of the parent compound or other metabolites, are the critical biomarker of risk. This not only lends further biological credibility to our findings but also supports the idea that individual metabolism of aflatoxins might be as critical, if not more so, than exposure itself in determining risk. We have also considered the possibility that aflatoxin-guanine adducts in urine might be a better measure of long-term exposure than other urinary biomarkers. Still, one is left with the strong possibility that misclassification may have occurred and that the true association and interaction might be substantially larger than observed. We chose to report our findings after a short follow-up because of the widespread interest in this topic. To assess the possibility of the tumour affecting diet and/or hepatic metabolism, we examined the aflatoxin and liver cancer association among cases diagnosed within 24 months offollow-up separately from those diagnosed after longer follow-up. Stronger associations between aflatoxin biomarkers and liver cancer risk were actually seen for the longer than for the shorter follow-up interval (for the parent compound, aflatoxin B1 for example, 6 of 7 cases identified after 24 months of follow-up vs 15 of 35 controls were positive, yielding a relative risk of 7-4). Moreover, as we note in our paper, associations were observed for three separate metabolic endpoints of aflatoxin Bp suggesting a strong relation between urinary markers and liver cancer risk that is independent of latent disease effects.
A self-reported history of cirrhosis of the liver was a strong risk factor for liver cancer in our study (3 of 22 cases vs 2 of 140 controls, relative risk 75), as was a history of any chronic liver disease (8 of 22 cases vs 19 of 140 controls, relative risk 3-3). The association with aflatoxin biomarkers was similarly strong when we excluded all subjects with a history of self-reported chronic liver disease from the
analysis. We agree strongly with Hall and Wild about the importance of understanding the precise nature of the interaction between
hepatitis B virus infection and aflatoxin exposure in hepatocellular carcinogenesis, especially the relative timing of these two exposures. In Chongming Island, a high-risk region for liver cancer near Shanghai, there has been a substantial reduction in consumption of maize, the principal source of dietary aflatoxins, since the 1960s. A subsequent gradual reduction in liver cancer mortality seems to have occurred.2 Although very indirect, these observations support the possibility that liver cancer rates might be reduced reasonably quickly by systematic removal of major sources of aflatoxin from the diet. Kenneth Norns Jr Comprehensive Cancer Center, University of Southern California School of Medicine, Los Angeles, 90033 California, USA
RONALD K. Ross MIMI C. YU BRIAN E. HENDERSON
JIAN-MIN YUAN GENG-SUN QIAN
JI-TAO Tu
Shanghai Cancer Institute, Shanghai, People’s Republic of China
YU-TANG GAO
Division of Toxicology, Massachusetts Institute of Technology, Boston
Division of Environmental Chemistry and Johns Hopkins University, Baltimore
GERALD N. WOGAN Biology,
JOHN D. GROOPMAN
Qian G-S, Yu MC, Ross RK, et al. Aflatoxin exposure and hepatocellular carcinoma in Shanghai, People’s Republic of China. Cancer Epidemiol Biomarkers Prev (in press). 2. Tu J-T, Gao R-N, Zhang D-H, Gu B-C. Hepatitis B virus and primary liver cancer on Chongming Island, People’s Republic of China. Natl Cancer Inst Monograph 1985; 1.
69: 213-15.
Chest
pain and the oesophagus
SIR,-In response to your March 7 editorial (p 583), Professor Cheng writes (April 25, p 1049) that mitral valve prolapse (MVP) with its associated cryptic chest pain should be considered in such patients. As Cheng notes, oesophageal dysmotility has been amply demonstrated in patients with MVP. However, I do not believe that this should be regarded as an isolated gut disorder in these patients. In 1985 I reported an increased frequency of irritable bowel syndrome (IBS) in patients with MVP.1 I suggested that the disordered oesophageal motility that is seen in such patients1 might also account for the cryptic chest pain of MVP. Both MVP and IBS symptoms arise more frequently in women. Because neurohorinonal3 ’ and associated psychiatric abnonnalitiess,6 have been described in both disorders, perhaps there is a common pathogenesis for the two entities. In addition to oesophageal dysmotility, patients with MVP commonly have other gut complaints that should not be overlooked. As a practising community gastroenterologist I believe that IBS would best explain the gut symptoms of patients with MVP. 366 South Main Steet, Connecticut 06410, USA 1. Sataline L. Irritable bowel
LEE SATALINE
syndrome and mitral valve prolapse syndrome. JAMA 1985; 253: 41. 2 Whorwell FJ, Clouter C, Smith CL. Oesophageal motility in irritable bowel syndrome. BMJ 1981; 282: 1101-02. 3. Kellow JE, Phillips SF. Altered small bowel motility in irritable bowel syndrome is correlated with symptoms. Gastroenterology 1987; 92: 1885-93. 4. Abrahamsson H. Gastrointestinal motility in patients with the irritable bowel syndrome. Scand J Gastroenterol 1987; 130 (suppl): 21-26. 5. Devereux RB, Kramer-Fox R, Kligfield P. Mitral valve prolapse: causes, clinical manifestations and management. Ann Intern Med 1989; 111: 305-17. 6. Drossman DA, McKee DC, Sandler RS, et al. Psychological factors in the irritable bowel syndrome: a multivariate study of patients and non-patients with irritable bowel syndrome. Gastroenterology 1988; 95: 701-08.
excluded because of factors contraindicating anticoagulant therapy (a history of haemorrhagic diathesis or peptic ulcer disease, or, in a few cases, strong belief in the prophylactic value of aspirin). 156 patients were excluded because the referring physicians thought they required antiooagulant therapy, and this group is, of course, of particular importance in this context. We have gone through the records of all these patients: 101 were given warfarin because the physicians at one of the hospitals believed in the prophylactic value of warfarin after anterior wall myocardial infarction (n = 32) or after streptokinase therapy for myocardial infarction (n 69); other reasons were atrial fibrillation (n = 30), arterial embolism (n = 8), venous thrombosis (n = 6), valvular heart disease (n=4), and miscellaneous (n=7). The male/female ratio was 3-9 to 1 in these excluded patients and 3to 1 in our study group; the mean age was 615and 616, respectively. Of the patients excluded because of anticoagulant therapy, none had a known aPL syndrome.3 Thus, no patient populations at high risk for the end points were excluded. One might argue that the patients with anterior wall infarction and atrial fibrillation were at high risk for cerebral embolism; however, involvement of aPL in the pathogenesis of this condition is not suspected. Of the 1214 patients remaining after the exclusions, 607 were randomised to placebo and constitute our cohort. Our belief that no high-risk population has been removed is borne out by the high mortality (19-9%) and occurrence of reinfarction (20-1%) and cerebrovascular disease (7-4%) during the study period. We had measured aCEPHA and aCL in the entire cohort of 1200 patients. There was no effect of the antibodies on the end points in the warfarin group-as we found for the placebo group. Thus, the patient population studied was an unselected group of patients who had survived an AMI. Of course, our results do not exclude the possibility that high aPL values might be an independent risk factor for thrombo-embolic events in patients with other disorders--eg, patients with the aPL syndromethe existence of which we do not doubt. =
Haematological Research Laboratory, Department of Internal Medicine, Ullevål University Hospital, N 0407 Oslo, Norway
K. E. SLETNES P. SMITH M. ABDELNOOR H. ARNESEN F. WISLØFF
1. Smith
P, Amesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 1990; 323: 147-52. 2. Smith P, Arnesen H. Mortality in non-consenters in a post-myocardial infarction trial. J Intern Med 1990; 228: 253-56. 3. Harris EN. Antiphospholipid antibodies. Br J Haematol 1990; 74: 1-9.
readily auto-oxidise, generating free radicals and other compounds that disrupt cellular function and damage cell membranes. Increased intake of highly polyunsaturated fats increases the nutritional requirement for vitamin E, but by how and
much is not known. Contamination with toxic residues is also a concern. Lead and mercury in the commonly occurring methylated form are lipophilic, as are organochlorides such as DDT, and preferentially accumulate in the lipid stores of fish living in contaminated waters. These difficulties are surmountable by careful control of production conditions. Oxidation can be kept to a minimum by refrigeration, addition of anti-oxidants such as vitamin E, and the use of packaging that excludes light and air; and toxic residues are largely removed by efficient processing. However, such manoeuvres and the stringent quality control needed to ensure consumer safety add considerably to the cost of the final product. An alternative approach might be to encourage regular fish consumption in pregnant women. As Olsen et al point out, the differences between those who received and did not receive fish oil supplements were considerably reduced when individuals who habitually ate a lot of fish were compared, suggesting that the effect of fish oil on gestation length and birthweight has a limit. In the Aarhus study seven out of ten of the fish oil group had belching; unpleasant taste and nausea were also common. Despite these effects, compliance rates of 75% were achieved, which bespeaks participant motivation and researcher persuasiveness unlikely to be found outside the context of a clinical trial. Consuming fish rather than fish oil capsules might have the added benefit of displacing other saturated and n-6 fats from the diet. Since the effects of n-3 fatty acids are much affected by the total amount and proportions of other dietary fats, this might further potentiate their effects, leading to a reduction in the amount needed. Fred Hutchinson Cancer Research Center, Gastroenterology/Hepatology Section SC-111, Seattle, WA 98104, USA
ANNE TOBIN
Neuringer M, Connor WE. n-3 fatty adds in the brain and retina: evidence for their essentiality. Nutr Rev 1986; 44: 285-94. 2. Neuringer M, Connor WE, Lin DS, Baistad L, Luck F. Biochemical and functional effects of prenatal and postnatal n-3 fatty acid deficiency on retina and brain in rhesus monkeys. Proc Natl Acad Sci USA 1986; 83: 4021-25. 3. Thomgren M, Gustafson A. Effects of 11 week increase in dietary eicosapentaonoic acid on bleeding time, lipids and platelet aggregation. Lancet 1981; ii: 1190-93. 4. Goodnight SH, Harris WS, Connor WE. The effects of dietary w-3 fatty acids on platelet composition and function in man: a prospective study. Blood 1981; 58: 1.
880-85. 5.
Thomgren M, Shafi S, Born GVR Delay in primary haemostasis produced by a fish diet without change in local thromboxane A2 production. Br J Haematol 1984; 58: 567-78.
Fish oil
supplementation
in pregnancy
Medical audit of the investigation of toxoplasmosis associated with pregnancy
SIR,-Dr Olsen and colleagues (April 25, p 1003) report evidence that
dietary fish oil supplements prolong gestation and increase birthweight. The fetus may benefit from maternal supplementation in other ways; the n-3 fatty acids abundant in fish oil are major components of neuronal and retinal tissue and may be involved in learning and visual acuity. 1;z.Studies of rhesus monkeys suggest that a supply of these fatty acids is especially important in the last trimester and first three months of life when membranes high in n-3 3 fatty acids are being formed? Several studies have examined the effect of large doses of fish or fish oil on coagulation. Modest reductions in platelet count and aggregation and lengthening of mean bleeding times by up to 50%3,4 have been reported. In one study whose participants ate a diet high in fish, prolongation of bleeding time was highly variable, ranging from 2 to 93%, and persisted for three weeks after supplementation.5 It is therefore not surprising that in the group of Danish women taking fish oil there was a trend towards increased blood loss at delivery. This trend was apparent despite the group’s very low caesarean section (< 9%) and assisted delivery rates. In other obstetrical populations with higher rates of surgical
intervention, bleeding complications could be substantially higher. If these promising findings are duplicated by other studies, fish oil might be offered to large numbers of healthy pregnant women. The safety of fish oil supplements warrants consideration. By virtue of their high degree of polyunsaturation, n- 3 fatty acids are unstable
SIR,-Increased awareness of toxoplasmosis in pregnancy has led demands for serotesting and for routine screening. However, the study of toxoplasmosis associated with pregnancy may be problematic and in 141 cases, we found that 98 (70%) received non-ideal investigation.1 Thus we introduced a programme of enhanced communication between reference centre and clinician and monitored the effect on patient’s care. All cases of acute toxoplasmosis associated with pregnancy first investigated during 1990 were included. Letters were sent to all responsible clinicians when laboratory records indicated ideal investigation had not been achieved. Further details of the case were requested in a questionnaire and educational material was provided. Reminders were sent to non-responders and a quarterly analysis of the findings was given to all participants. 130 cases of acute toxoplasmosis associated with pregnancy were studied. In addition to standard laboratory results, a further 170 letters and 60 h of administrative time were devoted to these cases. 6 cases of congenital toxoplasmosis were confirmed and 50 children were shown to be free of infection. A definite diagnosis was not made in 62 cases. A further 12 pregnancies did not proceed to term (5 spontaneous abortions, 1 intrauterine death, 6 terminations). 5 products of conception showed no histological evidence of toxoplasma infection and the parasite was not isolated from fetal to
119
tissues. In the
remaining
7 cases, tissues
were not
available for
testing. All cases lacking a definite diagnosis were analysed in detail. In 26 patient was classified as lost to follow-up by the responsible clinician. Of these, 5 women had returned to their country of origin for delivery, 2 failed to keep appointments, and 3 were subject to administrative errors. 1 mother had refused further medical care and 1 child had been discharged, erroneously, on the basis of a normal clinical appearance. Details of the other 14 cases were not stated. The clinicians responsible for the other 36 cases without a definite diagnosis but with continued medical contact were sent further literature describing the recommended investigation of toxoplasmosis in pregnancy and asked to provide information about outcome of the patient. 25 recipients did not reply; 5 children were subsequently shown to be free of infection; 3 cases failed to keep further appointments; and in 2 cases the clinician decided further investigation of the child would result in unacceptable parental anxiety.1 child was mistakenly discharged after the parasite had not cases the
been isolated at cordocentesis before delivery. Our intervention resulted in 61 of 130 cases (47%) achieving a substantiated final diagnosis compared with 30% of cases before instigation of the programmed The resolution of additional cases involved an average of 2-7 h administrative work per patient. These findings illustrate the influence of patient’s and physician’s compliance on the optimal investigation of toxoplasmosis in pregnancy. These limitations should be included in any cost-benefit analysis of antenatal screening for toxoplasmosis. This work was
supported by
a
grant from Birthright.
Toxoplasma Reference Laboratory, Public Health Laboratory Service, St George’s Hospital, London SW170QT, UK 1. Hartup C, Johnson JD, Holliman RE. 317-18.
C. HARTUP J. D. JOHNSON R. E. HOLLIMAN Toxoplasma and pregnancy. Lancet 1991; 338:
Aflatoxin biomarkers SIR,-Dr Hall and C. P. Wild (June 6, p 1413) in their comments about our report (April 18, p 943) provide a thoughtful assessment of several important issues related to the interaction between chronic hepatitis B virus infection and urinary biomarkers of aflatoxin exposure and liver cancer risk. We, too, were initially surprised at the strength of this relation and have considered several points they raise. As Hall and Wild suggest, it is feasible that aflatoxin exposure is fairly constant among individuals in Shanghai over time, but only repeated sampling in the same individuals can fully assess this possibility. After additional analysis of our data, we have found further evidence that aflatoxin-guanine adduct concentrations in urine, and not those of the parent compound or other metabolites, are the critical biomarker of risk. This not only lends further biological credibility to our findings but also supports the idea that individual metabolism of aflatoxins might be as critical, if not more so, than exposure itself in determining risk. We have also considered the possibility that aflatoxin-guanine adducts in urine might be a better measure of long-term exposure than other urinary biomarkers. Still, one is left with the strong possibility that misclassification may have occurred and that the true association and interaction might be substantially larger than observed. We chose to report our findings after a short follow-up because of the widespread interest in this topic. To assess the possibility of the tumour affecting diet and/or hepatic metabolism, we examined the aflatoxin and liver cancer association among cases diagnosed within 24 months offollow-up separately from those diagnosed after longer follow-up. Stronger associations between aflatoxin biomarkers and liver cancer risk were actually seen for the longer than for the shorter follow-up interval (for the parent compound, aflatoxin B1 for example, 6 of 7 cases identified after 24 months of follow-up vs 15 of 35 controls were positive, yielding a relative risk of 7-4). Moreover, as we note in our paper, associations were observed for three separate metabolic endpoints of aflatoxin Bp suggesting a strong relation between urinary markers and liver cancer risk that is independent of latent disease effects.
A self-reported history of cirrhosis of the liver was a strong risk factor for liver cancer in our study (3 of 22 cases vs 2 of 140 controls, relative risk 75), as was a history of any chronic liver disease (8 of 22 cases vs 19 of 140 controls, relative risk 3-3). The association with aflatoxin biomarkers was similarly strong when we excluded all subjects with a history of self-reported chronic liver disease from the
analysis. We agree strongly with Hall and Wild about the importance of understanding the precise nature of the interaction between
hepatitis B virus infection and aflatoxin exposure in hepatocellular carcinogenesis, especially the relative timing of these two exposures. In Chongming Island, a high-risk region for liver cancer near Shanghai, there has been a substantial reduction in consumption of maize, the principal source of dietary aflatoxins, since the 1960s. A subsequent gradual reduction in liver cancer mortality seems to have occurred.2 Although very indirect, these observations support the possibility that liver cancer rates might be reduced reasonably quickly by systematic removal of major sources of aflatoxin from the diet. Kenneth Norns Jr Comprehensive Cancer Center, University of Southern California School of Medicine, Los Angeles, 90033 California, USA
RONALD K. Ross MIMI C. YU BRIAN E. HENDERSON
JIAN-MIN YUAN GENG-SUN QIAN
JI-TAO Tu
Shanghai Cancer Institute, Shanghai, People’s Republic of China
YU-TANG GAO
Division of Toxicology, Massachusetts Institute of Technology, Boston
Division of Environmental Chemistry and Johns Hopkins University, Baltimore
GERALD N. WOGAN Biology,
JOHN D. GROOPMAN
Qian G-S, Yu MC, Ross RK, et al. Aflatoxin exposure and hepatocellular carcinoma in Shanghai, People’s Republic of China. Cancer Epidemiol Biomarkers Prev (in press). 2. Tu J-T, Gao R-N, Zhang D-H, Gu B-C. Hepatitis B virus and primary liver cancer on Chongming Island, People’s Republic of China. Natl Cancer Inst Monograph 1985; 1.
69: 213-15.
Chest
pain and the oesophagus
SIR,-In response to your March 7 editorial (p 583), Professor Cheng writes (April 25, p 1049) that mitral valve prolapse (MVP) with its associated cryptic chest pain should be considered in such patients. As Cheng notes, oesophageal dysmotility has been amply demonstrated in patients with MVP. However, I do not believe that this should be regarded as an isolated gut disorder in these patients. In 1985 I reported an increased frequency of irritable bowel syndrome (IBS) in patients with MVP.1 I suggested that the disordered oesophageal motility that is seen in such patients1 might also account for the cryptic chest pain of MVP. Both MVP and IBS symptoms arise more frequently in women. Because neurohorinonal3 ’ and associated psychiatric abnonnalitiess,6 have been described in both disorders, perhaps there is a common pathogenesis for the two entities. In addition to oesophageal dysmotility, patients with MVP commonly have other gut complaints that should not be overlooked. As a practising community gastroenterologist I believe that IBS would best explain the gut symptoms of patients with MVP. 366 South Main Steet, Connecticut 06410, USA 1. Sataline L. Irritable bowel
LEE SATALINE
syndrome and mitral valve prolapse syndrome. JAMA 1985; 253: 41. 2 Whorwell FJ, Clouter C, Smith CL. Oesophageal motility in irritable bowel syndrome. BMJ 1981; 282: 1101-02. 3. Kellow JE, Phillips SF. Altered small bowel motility in irritable bowel syndrome is correlated with symptoms. Gastroenterology 1987; 92: 1885-93. 4. Abrahamsson H. Gastrointestinal motility in patients with the irritable bowel syndrome. Scand J Gastroenterol 1987; 130 (suppl): 21-26. 5. Devereux RB, Kramer-Fox R, Kligfield P. Mitral valve prolapse: causes, clinical manifestations and management. Ann Intern Med 1989; 111: 305-17. 6. Drossman DA, McKee DC, Sandler RS, et al. Psychological factors in the irritable bowel syndrome: a multivariate study of patients and non-patients with irritable bowel syndrome. Gastroenterology 1988; 95: 701-08.
