Yiming Xia. Cambridge World History of Food. Editor: Kenneth F Kiple & Kriemhild Conee Ornelas, Volume 1, Cambridge University Press, 2000.
Discovery and Characteristics of the Disease
Keshan disease (KD) is a unique endemic cardiomyopathy in China with high incidence and mortality. Its etiology and pathogenesis are not as yet completely clear.
In the winter of 1935, an outbreak of an unknown disease with sudden onset of precardial oppression, pain, nausea, vomiting (yellowish fluid), and fatal termination in severe cases occurred in Keshan County, in Heilongjiang Province of northern China. Because its cause was not known, it was named after the place of outbreak by a Japanese military surgeon (Apei 1937).
Later, Keshan disease was also reported from other parts of China and, in fact, research now indicates that the condition has been prevalent in that country for close to 200 years. The earliest-known account of the disease was found in an inscription on a stone pillar at Jinling Temple, Xiaosi village, Huang-long County, Shaanxi Province, in 1812 (Shan and Xue 1987).
Epidemiological Characteristics
There are three major epidemiological characteristics of Keshan disease. The first is its regional distribution. Keshan disease areas are focally distributed in a belt extending from northeast to southwest China and usually located in hilly land. There are isolated spots known as “safety islands” surrounded by affected areas. The second is population susceptibility. Children below 15 years of age and women of childbearing age in northern China, and children below 10 years of age in southern China, constitute the most susceptible populations. They all live in rural areas and in farm families. The third characteristic is seasonal prevalence. The peak season of Keshan disease in northern China is in winter, but in the south it is in summer. There is also a natural fluctuation of prevalence from year to year.
The annual incidence, mortality, and case fatality of Keshan disease in China are shown in Figure IV.D.3.1. The peak years of 1959, 1964, and 1970 had incidences of 6.02, 4.17, and 4.04 per 10,000, respectively, and the mortality was 1.996, 0.978, and 0.676 per 10,000 (Sun et al. 1982; Sun 1987; The Ministry of Public Health of China 1987-95).
Clinical Manifestations
There are no specific symptoms and signs that clearly identify Keshan disease. But according to the degree of heart function insufficiency and of compensative status, Keshan disease is classified into four clinical types: acute, subacute, chronic, and latent (Ge et al. 1983).
Acute cases usually occur suddenly, with acute heart function insufficiency such as cardiogenic shock, severe arrhythmia, and pulmonary edema. The prominent characteristic of the chronic type is chronic congestive heart failure, which is the consequence of acute or subacute types or a result of a long-standing cardiac disorder of an insidious onset.Moderate or severe heart enlargement is always seen in chronic cases.
Subacute cases occur primarily in children. The onset is less sudden and the insidious period is about one or two weeks.The clinical manifestations of the subacute type are mainly cardiogenic shock and/or chronic congestive heart failure, and most patients have facial edema and galloping rhythm of the heart. Latent cases may be discovered as only an incidental finding upon routine physical examination.They usually show a mildly enlarged heart with normal heart function, abnormal electrocardiogram changes of the right bundle branch block, and infrequent premature ventricular contractions.
Pathological Observations
A large number of autopsies have been carried out since the recognition of Keshan disease in 1935. More than 3,600 autopsy cases were collected in the 1950s, when there was a heavy prevalence of the disease in northern China. Later, an endemic cardiomyopathy that was prevalent in children in southern China was studied and in 1965 identified as Keshan disease. Since then, large amounts of epidemiological, clinical, and pathological data have been accumulated in the south.
Multifocal necrosis and fibrous replacement of the myocardium are the principal pathological features of Keshan disease (Ge et al. 1983). Two patterns of myocardial necrosis are distinguishable by light microscopy. One is myocytolysis; the other is contraction band necrosis. Myocytolysis exists in the majority of cases and is regarded as a representative lesion of Keshan disease. It seems to be initiated by mitochondrial disorganization and results in the final disappearance of the myofibers. Contraction band necrosis is characterized by myofibril segmentation and has been considered to be the consequence of the severe circulatory disorders predominantly observed in acute cases.
Treatment
There is no specific therapy for Keshan disease. However, the method of administering a megadose of ascorbic acid (vitamin C) in cases of acute and sub-acute Keshan disease was discovered by Xian Medical College in 1961 (Research Laboratory of Keshan Disease of Xian Medical College 1961). It was a breakthrough in the treatment of Keshan disease and particularly effective in patients with cardiogenic shock. Since then, the case fatality of the acute type of Keshan disease has decreased significantly from 80 percent to less than 20 percent. Patients with congestive heart failure require prompt and optimal digitalization, although the response in some cases is poor. Other treatments (antibiotics, oral diuretics, and moderate restriction of salt) are used for the control of congestive heart failure (Yang et al. 1984).
The Relation Between Selenium and Keshan Disease
In the 1960s, it was found that white muscle disease (WMD) in young ruminants caused by selenium (Se) deficiency often occurred in areas affected by Keshan disease, and some similarities in clinical symptoms and pathological features between Keshan disease and white muscle disease were found. The scientists in the Institute of Shaanxi Veterinary Medicine suggested that both Keshan disease and white muscle disease could be responsive to selenium. Small-scale human intervention studies were carried out by several research groups, and some encouraging results were obtained; however, the effectiveness of Se supplementation was demonstrated only by a large-scale selenium intervention study in Mianning County, Sichuan Province, in southwestern China. This study was carried out from 1974 to 1976 by the Keshan Disease Research Group, Chinese Academy of Medical Sciences (Keshan Disease Research Group, Chinese Academy of Medical Sciences 1979).
Sodium Selenite Intervention
In 1974, 119 production teams observed children of susceptible age (1 to 9 years) in three villages of Mianning County. In 1975, the study was extended to include 169 teams in four villages. One-half of the children were given sodium selenite tablets and the other half a placebo. The assignment to one of these groups was made randomly and remained unchanged during the two years of the investigation. The subjects took sodium selenite once a week, with a dosage of 0.5 milligrams (mg) for those aged 1 to 5 years and a dose of 1.0 mg for those 6 to 9 years old. Because of the convincing results obtained in 1974 and 1975 (to be discussed shortly), the control groups were abandoned and all subjects were given sodium selenite in 1976 and 1977.
A Keshan disease hospital was established in the area under investigation; there, diagnosis and subtyping of the disease were carried out according to the criteria set up in 1974 by the National Seminar of the Etiology of Keshan Disease. Electrocardiograms, heart roentgenograms, and physical examinations were performed on patients admitted to the hospital for observation. In some cases, blood Se content, glutathione peroxidase (GPX), serum glutamic oxalacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT) activity were determined. Patients receiving treatment at other medical units were transferred to the hospital after the improvement of their general condition. Follow-up examinations were carried out each year to study the progress of individual patients.
The incidence and prognosis of the subjects investigated are shown in Table IV.D.3.1. In 1974, among the 3,985 children in the control group, there were 54 cases of Keshan disease (13.55 per 1,000), whereas only 10 of the 4,510 Se-supplemented subjects fell ill (2.22 per 1,000). The difference between the incidence of the two groups was highly significant (P < 0.01). A similar difference was found in 1975. In 1976, when all subjects were given selenite, only 4 cases out of 12,579 subjects occurred, which further lowered the incidence to 0.32 per 1,000. There was 1 case of the typical subacute type among 212 children who failed to take selenite. In 1977, there were no new cases among the 12,747 supplemented subjects. These results indicated that sodium selenite intervention had a significant effect in reducing incidence of Keshan disease.The Se-supplemented subjects had not only a lower incidence but also lower mortality and better prognosis.
In 1976 and 1977, liver function tests and general physical examinations were given to 100 subjects who had taken Se tablets weekly for three to four years.The results were not significantly different from those for the unsupplemented children and indicated that selenium-supplementation produced no untoward side effects.
Table IV.D.3.1. Keshan disease inciidence and prognosis of selenium-supplemented and control children (1-9 years old) in Mianning County, Sichuan Province, China, during 1974-7a
| Prognosis | ||||||||
| Groups | Year | Subjects | New cases | Incidence (0/00) | Turned chronic | Turned latent | Improved | Death |
| Se-supplemented | 1974 | 4,510 | 10 | 2.22 | 1 | 9 | 0 | 0 |
| 1975 | 6,767 | 7 | 1.03 | 0 | 6 | 0 | 1 | |
| 1976 | 12,579 | 4 | 0.32 | 0 | 2 | 0 | 2 | |
| 1977 | 12,747 | 0 | 0.32 | 0 | 0 | 0 | 0 | |
| (Total) | 36,603 | 21 | 0.57 | 1 | 17 | 0 | 3 | |
| Control | 1974 | 3,985 | 54 | 13.55 | 2 | 16 | 9 | 27 |
| 1975 | 5,445 | 52 | 9.55 | 3 | 13 | 10 | 26 | |
| 1976 | 212 | 1 | 4.72 | 1 | 0 | 0 | 0 | |
| (Total) | 9,642 | 107 | 11.10 | 6 | 29 | 19 | 53 | |
a There are significant differences of incidence between the two groups in each year and in total (P < 0.01).
In 1976, observations on the effects of sodium selenite were extended beyond Mianning County to include Dechang, Xichang, Yuexi, and Puge Counties. All children (1 to 12 years old) in some of the most severely affected areas were supplemented with selenite as just described, whereas the children in the nearby areas served as unsupplemented controls. The results, summarized in Table IV.D.3.2, show that in each year the incidence of Keshan disease among the Se-supplemented children of the five counties was significantly lower than that among the unsupplemented children. Similar results were obtained by Xian Medical College in a study in Huanglong County, Shaanxi Province, from 1975 to 1977 (Research Laboratory of Keshan Disease of Xian Medical College 1979).
Because of the convincing evidence of the efficacy of sodium selenite in preventing Keshan disease, it has been widely used since 1976 in tablet form, as an addition to table salt, and as a fertilizer. Concomitantly, the incidence and mortality of Keshan disease decreased to 0.17 and 0.04 per 10,000, respectively.
Occurrence in Selenium-Deficient Areas
Since regional distribution is the first epidemiological characteristic of Keshan disease, the discovery of environmental differences between areas that are affected by Keshan disease and those that are not has been an important goal in the study of its etiology.
A fluorometric method for determining Se content and another method for determining glutathione peroxidase (GPX) activity were adapted and set up by the Keshan Disease Research Group of the Chinese Academy of Medical Sciences in 1972 and 1975. Sampling techniques indicated that blood and hair Se content and blood GPX activity of residents in Keshan disease-affected areas were lower than those of people in nonaffected areas (see Table IV.D.3.3). However, after the oral administration of sodium selenite for 1 year, the blood GPX activity of children in Keshan disease-affected areas had increased to levels comparable to those of children in nonaffected areas (see Table IV.D.3.4).
Table IV.D.3.2. Keshan disease incidence in selenium-supplemented and control children (1-12 years old) in five counties of Sichuan Province, China, during 1976-80a
| Se-supplemented | Control | ||||||
| Year | Subjects | New cases | Incidence (0/00) | Subjects | New cases | Incindence (0/00) | |
| 1976 | 45,515 | 8 | 0.17 | 243,649 | 488 | 2.00 | |
| 1977 | 67,754 | 15 | 0.22 | 222,944 | 350 | 1.57 | |
| 1978 | 65,953 | 10 | 0.15 | 220,599 | 373 | 1.69 | |
| 1979 | 69,910 | 33 | 0.47 | 223,280 | 300 | 1.34 | |
| 1980 | 74,740 | 22 | 0.29 | 197,096 | 202 | 1.02 | |
| Total | 323,872 | 88 | 0.27 | 1,107,568 | 1,713 | 1.55 | |
aThere are significant differences of incidence between the two groups in each year and in total (P < 0.01).
Table IV.D.3.3. Selenium levels in human blood and hair from residents in Keshan disease-affected and nonaffected areas in 1972-3
| Subjectsa | Blood Se (ng/g)b | Hair Se (ng/g)b |
| KD-affected areas | ||
| KD patients | 18 ± 9 (42)a | 107 ± 53 (21)f |
| Farmers | 21 ± 7 (24)a | |
| Nonaffected areas (near KD areas) | ||
| Farmers | 32 ± 4 (20)b | 187 ± 51 (20)g |
| Staff members in town | 41 ± 21 (10)c | |
| Nonaffected areas (far from KD areas) | ||
| Staff members (A) in city | 173 ± 44 (16)d | 712 ± 97 (13)h |
| Staff members (B) in city | 255 ± 38 (17)e | 834 ± 156 (11)k |
aStaff members (A) were the members of a KD research group of the Chinese Academy of Medical Sciences and had been in KD areas for less than one year; staff members (B) had never been in KD areas.
bValues are means ± SD; number of samples is in parentheses; values not sharing a common superscript in a vertical column are significantly different (P < 0.05) by the t-test.
It was assumed that the low-selenium status of people living in Keshan disease-affected areas was caused by a low dietary selenium intake. Therefore, large samples of cereals, soil, water, and human blood, hair, and urine from Keshan disease-affected areas (11 provinces, 42 counties, 77 spots) and nonaffected areas (20 provinces, 86 counties, 110 spots) were collected. The data indicated that the samples containing less than 20 nanograms/gram (ng/g) of Se in blood or 120 ng/g in hair or 10 ng/g in cereals were almost exclusively from Keshan disease-affected areas, whereas samples with Se content of more than 50 ng/g in blood or 200 ng/g in hair or 20 ng/g in cereals were all from nonaffected areas (Yang et al. 1982). These data could be considered the threshold of Se content in assessing the risk of Keshan disease, especially for those who live on a rather simple diet composed mainly of locally grown cereals (Table IV.D.3.5).
Similar results from more than 10,000 samples were reported by the Institute of Geography, Chinese Academy of Sciences (Group of Environmental and Endemic Disease 1982; Xu et al. 1982). Based on a large amount of data, a map of selenium distribution in China was published in The Atlas of Endemic Diseases and Their Environments in the People’s Republic of China (1989). It shows that low-selenium areas are distributed in a belt extending from northeast to southwest China, which is consistent with the geographical distribution of Keshan disease.
Table IV.D.3.4. Blood gluthathione peroxidase (GPX) activities of children from Keshan disease-affected and nonaffected areas in 1975
| Subjects | Blood GPX (units) |
| KD-affected areas | |
| KD child patients | 57.1 ± 6.1 (22)a |
| Healthy children | 60.5 ± 5.6 (63)a |
| Se-supplemented children | 76.1 ± 8.4 (58)b |
| Nonaffected areas (near KD areas) | |
| Children in farmer’s family | 73.6 ± 13.8 (20)b |
| Nonaffected areas (far from KD areas) | |
| Children in farmer’s family | 77.5 ± 9.8 (22)b |
Note: Values are means ± SD; number of samples is in parentheses; values not sharing a common superscript are significantly different (P < 0.01) by the t-test.
Table IV.D.3.5. Selenium contents of blood, hair, and grains in Keshan disease-affected and nonaffected areas
| Samples | KD areas (ng/g) |
Overlapping areas (ng/g) |
Non-KD areas (ng/g) |
| Human blood | < 20 | 20-50 | > 50 |
| Human hair | <120 | 120-200 | >200 |
| Staple grain | < 10 | 10-20 | > 20 |
The results obtained by medical, veterinary, and geographical scientists all indicated that Keshan disease occurs only in selenium-deficient areas, which explains the epidemiological characteristic of its regional distribution.The fact that the blood and hair Se levels and GPX activity of farming residents are lower than those of nonfarming residents in the same Keshan disease-affected areas at least partially explains the characteristic of population susceptibility. In view of the results just described, it was concluded that selenium deficiency is the basic cause of Keshan disease occurrence.
Biochemical Changes
There were no significant differences in Se status and GPX activity between Keshan disease patients and other residents of the same areas (Zhu, Xia, and Yang 1982).There were also no changes in hair Se content to accompany the seasonal or yearly fluctuation of Keshan disease prevalence (Sun et al. 1980). These facts suggest that the etiology of Keshan disease cannot be explained by selenium deficiency alone and that there is a need to understand the ways in which selenium prevents Keshan disease.
A Study on Keshan Disease Patients
A comprehensive scientific survey of Keshan disease in Chuxiong prefecture, Yunnan Province, southwestern China, was conducted from 1984 to 1986 by 293 workers from 16 laboratories in seven provinces.The objective was to examine 3,648 children from 56 villages in Keshan disease-affected and nonaffected areas and compare the two groups. One hundred and sixty-seven children who were Keshan disease patients were treated, and 27 autopsies were carried out on patients who had died of subacute Keshan disease. Autopsy controls consisted of those who died from other diseases in both affected and non-affected areas. The results of this survey were published in the Collected Work of Comprehensive Scientific Survey on Keshan Disease in Chuxiong Prefecture (1984-1986) (Yu 1988).
Table IV.D.3.6 Selenium contents and glutatbione peroxidase (GPX) activities in tissues from patients with subacute Keshan disease (Sub-KD) and controls in affected (Control-A) or nonaffected areas (Control-NA)
| sub-KD | Control-A | Control-NA | ||
| Selenium (ng/g fresh) | Heart | 25 ± 10 (6)a | 55 ± 32 (4)a | 134 ± 32 (3)b |
| Liver | 52 ± 30 (6)a | 89 ± 50 (4)a | 256 (1) | |
| GPX(U/mg protein) | Heart (H2O2) | 10 ± 5 (11)a | 26 ± 21 (7)b | 73 ± 12 (20)c |
| (t-BOOH) | 10 ± 5 (11)a | 29 ± 25 (7)b | 80 ± 12 (2)c | |
| Liver (H2O2) | 7 ± 4 (4)a | 38 ± 11 (3)b | ||
| (t-BOOH) | 23 ± 5 (4)a | 47 ± 25 (3)b | ||
| Kidney (H2O2) | 20 ± 7 (4)a | 78 ± 39 (3)b | ||
| (t-BOOH) | 32 ± 2 (4)a | 85 ± 36 (3)b |
Note: Values are means ± SD: number of samples is in parentheses; values not sharing a common superscript in a horizontal row are significantly different (P < 0.01) by the t-test.
The comparison of Se content and GPX activity in the tissues of patients with subacute Keshan disease (Sub-KD) and those of the controls in affected (Control-A) and nonaffected areas (Control-NA) is shown in Table IV.D.3.6.There was a tendency for Keshan disease patients to have lower heart and liver Se levels than the controls, and their GPX activity was significantly lower than that of the controls. Other results supported the hypothesis that the heart is the organ most susceptible to selenium deficiency.
Other oxidant defense indices in the myocardium of child patients with Sub-KD were measured. The results showed that the activity of superoxide dismutase (SOD) in the myocardia of Sub-KD patients was significantly lower than that of Control-NA subjects, but malondialdehyde (MDA) and free radicals were higher than those of Control-NA. These results indicated that there was an accumulation of lipid peroxides and free radicals in Keshan disease patients. However, there were no differences between Sub-KD patients and controls in glutathione reductase (GR) and glutathione-S-transferase (GST) activity.
Ultrastructural observations showed that mitochondria in the myocardia of Sub-KD patients appeared to be most commonly and conspicuously affected and were involved early. In general, the changes in biochemical functions occurred before the structural damage. The results indicated that the activity of succi-nate dehydrogenase (SDH), cytochrome C oxidase (CCO), and H+-ATPase, and content of Co Q in the myocardial mitochondria of Sub-KD patients were lower than those of Control-NA. These findings implied that the lesions of the mitochondria affect mostly the respiratory chain of the inner membrane. Changes in membrane potential and decreased fluidity of membrane lipid were observed in the myocardial mitochondria of Sub-KD patients. The content of Se in the mitochondria was one-eighth that of Control-NA (Yu 1988). It is likely that the structural and functional abnormalities of the myocardial mitochondria of patients with Keshan disease may result from selenium deficiency. In addition, the mitochondria constitute one of the calcium pools and play an important role in regulating the calcium concentration in cells. The increased calcium content in the myocardial mitochondria of Sub-KD patients may have an intrinsic relationship with the functional abnormalities.
From this comprehensive survey, it was concluded that relatively weak oxidant defenses, mainly low GPX activity, and insufficient vitamin E (less than 8 μg/ml plasma in people living in Keshan disease-affected areas) created a selenium-deficient population susceptible to oxidant stresses that resulted in damage to myocardial structures and functions and finally in the occurrence of Keshan disease.
Effects of Se Deficiency
It was not clear whether differences in dietary patterns (aside from selenium intake) between people in Keshan disease-affected and nonaffected areas were involved in the etiology of Keshan disease. Three studies were carried out in 1987, 1989, and 1991 in Mianning and Dechang Counties, Sichuan Province, where there was a very high incidence of Keshan disease there was during the 1970s. These two counties are only 150 kilometers (km) apart and have the same dietary patterns. According to the results from a nutrition survey in 1985, conducted by the Anti-Epidemic Station of Liangshan Autonomous Prefecture, the dietary selenium intake was 11 μg per day for both counties. The only difference was a supplementation of selenized salt (15 μg selenium per g salt, as sodium selenite) in Mianning County from 1983 onward, so the people of Mianning had 69 μg of extra selenium per day, giving them a total selenium intake of 80 μg per day. Table IV.D.3.7 shows the results of a study conducted in 1987 (Xia, Hill, and Burk 1989; Hill et al. 1996) following selenized salt supplementation for 4 years. Not only were the blood Se levels of children in Mianning County higher than those in Dechang County, but the GPX activity of their plasma was three times as high, and plasma selenoprotein P concentrations were also much higher. Linear regression analysis of plasma showed that selenium concentration, GPX activity, and selenoprotein P concentration correlated well with each other. There were no differences in other indices for oxidant defense capability between the residents of the two counties.
Table IV.D.3.7. Indexes for axidant defense capability in the blood of children from Dechang and Mianning Counties in 1987
| Dechang (-Se) | Mianning (Se-salt) | ||
| Selenium | Blood (ng/g) | 18 ± 10 (22)a | 47 ±9 (18)b |
| Plasma (ng/g) | 13 ± 55 (22)a | 40 ± 11 (18)b | |
| RBC (ng/g) | 26 ±9 (22)a | 47 ±9 (19)b | |
| GPX | Plasma (U/L) | 29 ± 15 (21)a | 87 ± 15 (15)b |
| RBC (U/gHb) | 2.8 ± 1.7 (21)a | 8.4 ± 3.3 (19)b | |
| Selenoprotein P | Plasma (U/L) | 0.10 ± 0.04 (22)a | 0.39 ± 0.17 (17)b |
| SOD | RBC (U/mgHb) | 17 ± 7 (22) | 17 ±3 (19) |
| Catalase | RBC (U/gHb) | 238 ± 48 (22) | 231 ± 29 (19) |
| Glutathione reductase | RBC (U/gHb) | 3.3 ± 1.0 (22) | 4.2 ± 1.3 (19) |
| GSH | Plasma (μM) | 4.7 ± 0.6 (21) | 4.4 ± 1.0 (16) |
| RBC (mM) | 2.5 ± 0.4 (19) | 2.1 ± 0.7 (19) | |
| Vitamin E | Plasma (μg/ml) | 4.0 ± 1.2 (22) | 3.8 ± 1.2 (19) |
| MDA | Plasma (nmol/ml) | 6.7 ± 2.2 (22) | 6.0 ± 2.6 (19) |
Note: Values are means ± SD: number of samples is in parentheses; values not sharing a common superscript in a horizontal row are significantly different (P < 0.001) by the t-test.
Effects of age and sex. In the 1989 study, blood samples were taken from 401 healthy subjects (half male and half female) in Dechang County. The lowest levels of selenium and GPX activity were found in the youngest (2 to 5 years old) and oldest (more than 60 years old), and no significant sex difference was found. These data were consistent with the occurrence of Keshan disease in children, the susceptible population group (Xia et al. 1994).
Changes in selenium intake. It was found that the selenium status and GPX activity of residents of Dechang County increased gradually year after year to reach the levels of persons in nonaffected areas in 1991. Coincidentally, there was no occurrence of Keshan disease in this year. Therefore, it was necessary to check the selenium intake of the local residents. In the 1991 study, the selenium contents of rice, table salt, and the mixed diet were measured. The data showed that selenium in rice was 16.6 ± 4.3 μg/kg (n = 10), which was in the same range as that of KD-affected areas (<20 ng/g in grain, see Table IV.D.3.5), but selenium intake from the diet was estimated to be 38 ± 28 μg/day (n = 30), which reached the minimum requirement of 20 μg/day (Yang et al. 1985; Yang and Xia 1995). This change probably resulted from the inadvertent distribution of selenized salt in Dechang County and, with the improvement of the local economy, the increased consumption of food from selenium-adequate areas. It was confirmed that the decrease of Keshan disease incidence in Dechang County correlated with an improved selenium status because of an increase in dietary selenium intake.
Marginal vitamin E status. Vitamin E (VE), an important constituent of the oxidant defense system, protects biological membrane tissue as a free-radical scavenger and has a synergistic effect with selenium. Animal studies have indicated that cardiac injury can be developed in animals fed a diet deficient in both selenium and vitamin E but that neither deficiency by itself causes cardiac injury (Van Vleet, Ferrans, and Ruth 1977; Konz et al. 1991). Other animal studies have indicated that myocardial injury can occur in animals fed a diet of foods from Keshan disease-affected areas and that this condition can be alleviated by the supplementation of selenium or vitamin E or both (Wang et al. 1991). Plasma vitamin E of residents of Keshan disease-affected areas ranged from 2 to 8 μg/ml, which is a low marginal status (Keshan Disease Research Group, Chinese Academy of Medical Sciences 1977a; Li et al. 1988; Xia et al. 1989; Zhu et al. 1991).This low marginal vitamin-E status could act as a promoting cofactor in the occurrence of Keshan disease. If so, vitamin E supplementation might be helpful in improving the low selenium status of residents of Keshan disease areas.
The Etiology of Keshan Disease
Although the overall incidence of Keshan disease has steadily declined since the 1980s, there was a question of whether there was a corresponding change in the selenium status of local populations at risk. Geographic scientists collected 4,600 samples (rock, soil, water, cereals, animal fur, and human hair) from 217 sampling spots and monitored the incidence of Keshan disease for three years in the 1980s (Tang et al. 1991).The results (see Table IV.D.3.8) indicated that the environmental selenium status was still as low as that in the 1970s, but the selenium level in hair had increased to a normal level (see Table IV.D.3.5). It is believed that in addition to deliberate selenium supplementation, there has been inadvertent supplementation as a previously self-sufficient lifestyle gave way to a commodity economy, in which foods with higher selenium content were imported into the affected Table IV.D.3.8. Comparison of selenium contents in cereals and human hair between the 1970s and 1980s areas. In addition there has been an increase in the consumption of animal products in recent years. All of this would seem to confirm that an adequate selenium status is necessary for the prevention of Keshan disease.
Table IV.D.3.8. Comparison of selenium contents in cereals and human hair between the 1970s and 1980s
| 1970s | 1980s | |
| Corn (μg/kg) | 13 ± 6 (157)a | 10 ± 9 (90)b |
| Rice (μg/kg) | 14 ± 8 (47) | 15 ± 11 (31) |
| Wheat (μg/kg) | 14 ± 7 (115) | 13 ± 9 (96) |
| Hair (μg/kg) | 85 ± 32 (815)a | 192 ± 96 (44)b |
Note: Values are means ± SD; number of samples is in parentheses; values not sharing a common superscript in a horizontal row are significantly different (P < 0.001) by the t-test.
Although selenium deficiency can explain the epidemiological characteristic of the regional distribution of Keshan disease, it only partially explains the susceptibility of populations. Because the selenium status of residents in Keshan disease-affected areas does not change with seasonal fluctuation of the incidence of the disease, another potential cofactor (or cofactors) must be involved in its occurrence. Such cofactors would act as promoters or stimulators during selenium deficiency.
The potential cofactors in the etiology of Keshan disease can be classified into four categories:
- An insufficiency of nutrients that have relative biological function with selenium, such as VE, methio-nine, and iodine.
- An excess of elements that have antagonistic interaction with selenium, leading to poor availability of selenium.
- The prevalence of mycotoxins that contaminate foods and damage the myocardium.
- A virus infection in which the target organ is the heart (Su 1979; Bai et al. 1984).
Present information does not permit ruling out any one of these as a cofactor in selenium deficiency and in the etiology of Keshan disease.
Clearly, much work remains to be done, even though studying the etiology of Keshan disease presents some difficulties. One problem is that there are no ideal animal models for Keshan disease; another is that almost no new Keshan disease patients can be found (only 57 new patients were reported in the whole country in 1995). However, it is believed that the pathogenic factors in Keshan disease areas are still active because, according to the Annual Report from the Ministry of Public Health of China there are about 50,000 latent Keshan disease patients in the country. Therefore, work will continue.