Selasa, 23 Juni 2015
Some hematological problems in Indonesia
Indonesia consist of many island inhabited by many ethnic groups with
different social economic condition. As in other parts of the world,
anemia is still one of the major health problem in Indonesia. The
reported anemia prevalence differs in each area and age groups, ranging
from 5.4% in well nourished preschool children to 56.3% in primary
school children; and 19% to 62.5% in pregnant women. The causes of
anemia mostly reported were nutritional like iron deficiency, abnormal
hemoglobin besides other conditions. In Cipto Mangunkusumo Hospital as
the national referral hospital in Indonesia, in the adults groups, the
cause of anemia reported were 14% with iron deficiency, 54% aplastic,
16% hemolytic and 16% other causes. Whereas in the child health
department the cause were 29% nutritional deficiency, 31% thalassemia,
10% aplastic, 4% hemolytic and 26% other causes. Thalassemia is quite
often reported in Indonesia. In 1955 Lie-Injo first reported the HbE as
the most frequently found abnormality among many ethnic groups in
Indonesia, ranging from 2.5% to 13.2%. In later studies the prevalence
reported varies very much. It was reported as 9.5% in newborns, 22% in
pregnant women, and 15.95% to 60% in athletes. The carrier frequency in
some areas was between 6–10%, while the pattern of mutation varied
widely within each region. Hemophilia cases in Indonesia is still not
diagnosed adequetely, only 530 cases were reported. The problems were
lack of diagnostic laboratories and awareness. As many as 56.9% of the
hemophilia patients who received cryoprecipitate were reported positive
with HCV antibody. Hematological malignancy is now also became an
increasing problem in Indonesia, in child health department the
prevalence of leukemia was 57%, and lymphoma 13% among other
malignancies. In National Cancer hospital, the prevalence leukemia as
diagnosed using morphology and flowcytometry, were 51.4% AML, 19.7%
B-ALL, 14.6% T-ALL, 4.5% preB-ALL, with 9.8% cases with co expression,
and 30% other malignancies. Due to geographical situation, economic
condition and lack of diagnostic laboratory facility many abnormalities
were unable to be diagnosed properly.
Association between Multiple Cardiovascular Risk Factors and Atherosclerosis in Children and Young Adults
- Atherosclerosis leading to coronary heart disease is complex in origin. Involved in the pathogenesis of atherosclerosis are hemodynamic, thrombotic, and carbohydrate–lipid metabolic variables, along with intrinsic characteristics of the arterial wall.1 These physiologic and biochemical factors underlie the clinical events that may eventually occur. Environmental factors such as smoking or a sedentary lifestyle also contribute to this process. The progression of atherosclerotic disease and the increasing severity of atherosclerosis relate not only to the presence and extent of cardiovascular risk factors but also to the persistence of risk factors over time.2,3 Sudden death may occur in a young person with only a single lesion complicated by a coronary thrombus, without extensive vessel disease. Consequently, the extent of vascular lesions may not be directly related to the occurrence of clinical events, such as myocardial infarction. Morbidity due to coronary artery disease, however, is generally related to the extent of vascular lesions.4 In this regard, clinical risk factors are considered to be useful in predicting the severity of atherosclerosis.5
Epidemiologic studies have established that multiple risk factors increase the probability of cardiovascular events, since cardiovascular risk factors tend to reinforce each other in their influence on morbidity and mortality.6 Although a specific risk factor influences the risk that a person will have cardiovascular disease, risk factors tend to aggregate and usually appear in combination. Furthermore, since clustering of risk factors is evident in childhood and persists into young adulthood,7-10 the presence of multiple risk factors could indicate the acceleration of atherosclerosis in young people.
Coronary arteriography has contributed considerably to elucidating the relation of the severity of coronary artery disease to cardiovascular risk factors. Unfortunately, assessing the extent of atherosclerotic coronary lesions by this invasive method in asymptomatic young people is not practical, and its value is limited as compared with that of actual anatomical observations.11 Autopsy data from epidemiologic studies have shown a relation between coronary artery disease and cardiovascular risk factors; for example, high serum total cholesterol concentrations and cigarette smoking are important contributors to the development of coronary atherosclerosis.6 Autopsy studies from the Bogalusa Heart Study have demonstrated a strong association of specific antemortem risk factors with vascular lesions in children and young adults.12,13 These observations have been extended by the findings in a larger, multicenter postmortem study, Pathobiological Determinants of Atherosclerosis in Youth.14-17 Multiple risk-factor data collected ante mortem in the Bogalusa Heart Study can be applied further to autopsy data. In this study we examined the influence of multiple risk factors on the extent of atherosclerosis in the aorta and coronary arteries in young people.Methods
Study Population
The Bogalusa Heart Study is a long-term epidemiologic study of cardiovascular risk factors from birth through the age of 38 years in a biracial population (65 percent white and 35 percent black).18,19 Seven cross-sectional surveys, each including more than 3500 children, have been carried out since 1973. Since 1978, five follow-up surveys have been conducted among young adults who participated in previous cross-sectional surveys as children. Participation rates ranged from approximately 80 percent for school-age children to approximately 60 percent for the adult cohort. To date, data have been collected on approximately 14,000 people.
For the autopsy studies, a local information system was established in 1978 to obtain the family's or coroner's consent to conduct an autopsy after the death of a young person. For practical and logistic reasons, an autopsy was conducted on any resident of Washington Parish in Bogalusa, Louisiana, or adjacent parishes who died between the ages of 2 and 39 years. Not all the young people who died in this area had been eligible for the Bogalusa Heart Study's survey of cardiovascular risk factors, which was restricted to ward 4 of Washington Parish. Most deaths were due to accidents or homicide; only about 10 percent were due to renal, neoplastic, or infectious diseases or suicide. Autopsies were conducted in local funeral homes or in hospitals in adjacent communities, and selected tissues (including the heart and coronary arteries, aorta, and kidneys) were brought to the Department of Pathology at Louisiana State University Medical Center in New Orleans for study.
As of January 1996, specimens had been collected at autopsy from 86 white males, 52 black males, 36 white females, and 30 black females, representing more than 60 percent of all known eligible deaths. The mean (±SD) age at death ranged from 20.4±6.6 years among white females to 21.8±6.8 years among black males. Of the 204 persons examined at autopsy, 93 had previously been surveyed as part of the Bogalusa Heart Study and therefore had provided data on antemortem risk factors. Among these 93 persons, the mean age at death was 19.6±5.7 years for the 41 white males, 20.4±6.2 years for the 19 white females, 21.7±5.2 years for the 23 black males, and 22.4±6.0 years for the 10 black females.Characterization of Cardiovascular Risk Factors
Essentially the same protocols were used in all surveys. The methods used to measure each risk factor have been described in detail previously.19 Height was measured to the nearest 0.1 cm and weight to the nearest 0.1 kg. Body-mass index (the weight in kilograms divided by the square of the height in meters) was used as a measure of obesity.
Blood pressure was measured in the right arm, with the subject in a relaxed, sitting position. The average of six measurements (three taken by each of two examiners) with a mercury sphygmomanometer was used in all analyses. The fourth Korotkoff phase was considered the diastolic blood pressure. Cigarette-smoking status, which was assessed by a questionnaire beginning at the age of eight and continuing through adulthood, was measured in terms of the number of cigarettes smoked per week.20 Serum total cholesterol, triglycerides, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were measured by standardized procedures,21 which met the performance requirements of the lipid-standardization program of the Centers for Disease Control and Prevention.Evaluation of Atherosclerotic Lesions
At autopsy, the aorta and coronary arteries were opened longitudinally and stained with Sudan IV to localize lipid deposition. The extent of the intimal surface that was covered with fatty streaks and raised fibrous plaques in the vessels was graded visually according to procedures developed in the International Atherosclerosis Project22; these procedures are currently used by the Department of Pathology at Louisiana State University Medical Center. The pathologists grading the lesions were unaware of the subjects' risk-factor data. Briefly, the grader first estimated the percentage of the total intimal surface area involved with any atherosclerotic lesion and then estimated the percentage distribution of fatty streaks, fibrous plaques, complicated lesions (those with evidence of hemorrhage, ulceration, necrosis, or thrombosis, with or without calcification), and calcified lesions within this lesion-covered area. The recorded percentages of individual types of lesions within the lesion-covered area were converted to percentages of the total intimal surface area by multiplying each estimate by the fraction of intimal surface area covered with atherosclerotic lesions.
Three pathologists evaluated the vessels independently; the extent of atherosclerosis was expressed as the mean of the three values assigned by these pathologists for the percentage of the intimal surface covered by lesions. The prevalence of atherosclerotic lesions was defined as the percentage of persons studied who had at least minimal sudanophilic intimal deposits.Statistical Analysis
We used z scores (standardized values) specific for the study period, race, sex, and age to eliminate the effects of age, race, sex, and potential variations in laboratory measurements on the antemortem risk-factor variables. For the 65 persons whose risk-factor status was assessed more than once, we used the average of the adjusted levels. Risk factors were defined as values above the 75th percentile (specific for study period, race, age, and sex) for the group as a whole. Antemortem values for very-low-density lipoprotein cholesterol and triglyceride values in nonfasting subjects were not included in the analyses.
Spearman correlation analysis was used to examine the association between the extent of fatty-streak or fibrous-plaque lesions in the aorta and coronary arteries and age at death and the z scores of individual risk-factor variables. A multivariate technique, referred to as canonical correlation analysis, was then used to examine the association between the two sets of variables — that is, the antemortem risk-factor variables and the extent of fatty-streak and fibrous-plaque lesions in the aorta and coronary arteries. The prevalence of atherosclerosis in various age groups was evaluated with a chi-square test. The influence of cigarette smoking on the extent of atherosclerosis and the effect of multiple risk factors on the extent of atherosclerosis were evaluated with analysis of covariance after the extent of lesions was adjusted for race, sex, and age at death; subjects with no risk factors were compared with those with one, two, and three or four risk factors. All statistical tests were two-sided. SAS software was used for all analyses.23Results
Prevalence, Extent, and Interrelations of Lesions
Essentially all persons in the age groups we studied had fatty streaks in the aorta. In contrast, the prevalence of fatty streaks in the coronary arteries increased with age from approximately 50 percent at 2 to 15 years of age to 85 percent at 21 to 39 years (P=0.01). The prevalence of raised fibrous-plaque lesions in the aorta and coronary arteries is shown in Figure 1Figure 1The Prevalence of Fibrous-Plaque Lesions in the Aorta and Coronary Arteries in 204 Children and Young Adults, According to Age.. In the aorta, there was a trend toward increasing prevalence with age (P=0.001), especially after the age of 15 years; prevalence increased to 60 percent by the age of 26 to 39 years. In the coronary vessels, this age-related trend was even more consistent (P=0.001), with the prevalence increasing from 8 percent at 2 to 15 years to 69 percent at 26 to 39 years.
For each type of lesion, there was a trend toward involvement of an increasing percentage of the intimal surface with increasing age. In the aorta, the mean (±SD) percentage of the surface involved with fatty streaks increased from 13.8±15.5 percent at 2 to 15 years of age to 28.8±15.3 percent at 26 to 39 years (P<0.001), and the percentage involved with fibrous plaques increased from 0.2±0.5 percent to 4.0±7.4 percent, respectively (P<0.001). In the coronary arteries, the percentage of the surface involved with fatty streaks increased from 0.5±0.7 percent to 7.1±8.2 percent (P<0.001), and the percentage involved with fibrous plaques increased from 0.2±0.9 percent to 6.9±11.4 percent (P<0.001).
With respect to the interrelation of types of lesions in the aorta and coronary arteries, the correlation of the extent of fatty streaks and fibrous plaques in the aorta with the extent of lesions of the same type in the coronary arteries was only moderate (r=0.36 to 0.37, P=0.001). Furthermore, the correlation between the extent of fatty streaks and that of fibrous plaques was much greater in the coronary arteries (r=0.60, P<0.001) than in the aorta (r= 0.23, P=0.03).Relation of Lesions to Specific Risk Factors
Correlations between the extent of lesions and specific antemortem risk factors are shown in Table 1Table 1Correlation between the Extent of Lesions in the Aorta and Coronary Arteries and Antemortem Risk-Factor Variables.. The extent of atherosclerotic lesions correlated positively and significantly with body-mass index, systolic blood pressure (except in the case of fibrous plaques in the aorta), diastolic blood pressure (this was true only for fibrous plaques in the coronary arteries), serum total cholesterol concentrations (except for fibrous plaques in the aorta and coronary artery), serum LDL cholesterol concentrations (except for fibrous plaques in the aorta), and serum triglyceride concentrations (except for fatty streaks in the aorta). Furthermore, canonical correlation analysis showed that the extent of fatty-streak and fibrous-plaque lesions in the aorta and coronary vessels as a group were associated moderately strongly with body-mass index (r=0.48), systolic blood pressure (r=0.55), serum triglyceride concentrations (r= 0.50), and LDL cholesterol concentrations (r=0.43) and associated weakly with diastolic blood pressure (r=0.22) and HDL cholesterol concentrations (r= –0.16). On the other hand, antemortem risk-factor variables as a group were most strongly associated with the extent of fatty streaks in the coronary arteries (r=0.55), followed by the extent of fibrous plaques in the coronary arteries (r=0.52), fibrous plaques in the aorta (r=0.40), and fatty streaks in the aorta (r=0.38). Overall, the highest canonical correlation between antemortem risk-factor variables and the extent of lesions in the aorta and coronary arteries was 0.70 (P<0.001).
The influence of cigarette smoking on the prevalence and extent of aortic and coronary-artery lesions is shown in Figure 2Figure 2The Influence of Cigarette Smoking on the Prevalence (Top Panels) and Extent (Bottom Panels) of Atherosclerosis in the Aorta and Coronary Arteries in Children and Young Adults.. The prevalence of lesions in these vessels was similar in the 15 smokers and the 34 nonsmokers (for the remaining subjects, smoking status was unknown). The mean (±SE) percentage of the intimal surface involved with fibrous-plaque lesions in the aorta was higher in smokers than in nonsmokers (1.22±0.62 percent vs. 0.12±0.07 percent, P=0.02), as was the percentage involved in fatty-streak lesions in the coronary vessels (8.27±3.43 percent vs. 2.89±0.83 percent, P=0.04).
Relation of Lesions to Multiple Risk Factors
The mean percentage of the intimal surface covered by lesions in patients with different numbers of risk factors (0, 1, 2, and 3 or 4) is shown in Figure 3Figure 3The Effect of Multiple Risk Factors on the Extent of Atherosclerosis in the Aorta and Coronary Arteries in Children and Young Adults.. The risk factors we evaluated included body-mass index, systolic blood pressure, serum triglyceride concentration, and serum LDL cholesterol concentration. In subjects with 0, 1, 2, and 3 or 4 risk factors, 19.1 percent, 30.3 percent, 37.9 percent, and 35.0 percent, respectively, of the intimal surface area was involved with fatty streaks in the aorta (P for trend=0.01). In the coronary arteries, 1.3 percent, 2.5 percent, 7.9 percent, and 11.0 percent, respectively, of the intimal surface was involved with fatty streaks (P for trend=0.01), and 0.6 percent, 0.7 percent, 2.4 percent, and 7.2 percent was involved with collagenous fibrous plaques (P for trend=0.003). The extent of fatty-streak lesions in the coronary arteries was 8.5 times as great in persons with three or four risk factors as in those with none (P=0.03), and the extent of fibrous-plaque lesions in the coronary arteries was 12 times as great (P=0.006).
Discussion
Observations from autopsy studies by the Bogalusa Heart Study and the multicenter Pathobiological Determinants of Atherosclerosis in Youth study clearly documented a strong relation between coronary atherosclerosis and cardiovascular risk factors in young people.12-17 Our observation that specific antemortem risk factors such as elevations in body-mass index, systolic blood pressure, serum LDL cholesterol concentration, and serum triglyceride concentration and cigarette smoking are significantly related to the extent of atherosclerotic lesions in young people is in agreement with the findings in those studies. Furthermore, the prevalence and extent of lesions in the coronary arteries, especially fibrous-plaque lesions that encroach on the lumen, increased with age in the young people we studied. Previous studies of the natural history of atherosclerosis indicated that in populations with high rates of premature coronary artery disease, advanced lesions begin to appear with greater frequency during childhood and young adulthood.24 Although there has been some question about the clinical significance of fatty streaks in the aorta, which some suggest are evanescent, their presence in association with fibrous plaques in coronary vessels is considered to indicate that atherosclerosis is progressive and severe.25 In the current study, the correlation between the extent of fatty streaks and that of fibrous plaques was much greater in the coronary arteries than in the aorta. Also, the proportion of collagenous fibrous plaques in relation to fatty streaks was greater in the coronary vessels than in the aorta.
We found that the extent of atherosclerotic lesions in the coronary vessels increased markedly in young people with multiple risk factors. This finding supports the concept that multiple risk factors have a synergistic effect on morbidity and mortality from coronary heart disease in middle age and later, as has been demonstrated by epidemiologic studies such as the Framingham Study.26 We could not examine the effect of multiple risk factors on the extent of atherosclerosis separately according to race and sex because of the small numbers of persons in each group within our sample.
The multiple risk factors we evaluated included high values for body-mass index, systolic blood pressure, and LDL cholesterol and triglycerides in serum. Cardiovascular risk factors such as dyslipidemia, hypertension, hyperinsulinemia or insulin resistance, and obesity often coexist in both children and young adults.9,10 Since the clustering of these conditions — termed syndrome X,27 the deadly quartet,28 or insulin-resistance syndrome29 — is seen so frequently, a common pathophysiologic mechanism involving insulin resistance has been suggested. Although we did not measure plasma insulin and glucose concentrations as indicators of carbohydrate–lipid metabolism, it is reasonable to suggest that these variables may be part of the cluster of risk factors in the study population, as we have shown previously.9,10,30 In this regard, the effects of elevated glycosylated hemoglobin concentrations and of obesity on atherosclerosis are evident throughout the group of 15-to-34-year-old subjects in the Pathobiological Determinants of Atherosclerosis in Youth study.16
Our observation that the extent of fatty-streak lesions in the coronary vessels of children and young adults was higher in cigarette smokers than in nonsmokers is in agreement with the findings of the Pathobiological Determinants of Atherosclerosis in Youth study.14,17 Therefore, it is to be expected that cigarette smoking by young people who have multiple other risk factors will adversely influence the extent of coronary atherosclerosis.
The effects of multiple risk factors on coronary atherosclerosis give further justification for the evaluation of cardiovascular risk in young people and provide a rationale for both prevention and intervention. It may be important to focus on multiple cardiovascular risk factors early in life, rather than on a specific risk factor, such as hypercholesterolemia. Interventions related to modifiable risk factors, such as the prevention of smoking, weight control, and encouragement of physical exercise and a prudent diet, if undertaken early in life, may retard the development of atherosclerosis.Supported by grants from the National Heart, Lung, and Blood Institute (HL-38844) and the National Institute of Child Health and Human Development (HD-32194).
We are indebted to the many people who collaborated with the Bogalusa Heart Study for their cooperation, to Bettye Seal for her work as community coordinator, and to the children and young adults of Bogalusa, Louisiana, without whom this study would not have been possible.Source Information
From the Tulane Center for Cardiovascular Health, Tulane School of Public Health and Tropical Medicine (G.S.B., S.R.S., W.B., W.A.W.); and the Department of Pathology, Louisiana State University Medical Center (W.P.N., R.E.T.) — both in New Orleans.
Address reprint requests to Dr. Berenson at the Tulane Center for Cardiovascular Health, Tulane School of Public Health and Tropical Medicine, 1501 Canal St., 14th Fl., New Orleans, LA 70112-2824.
Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia
Immunosuppressive
therapy can produce hematologic improvement in a large proportion of
patients with severe aplastic anemia. Antithymocyte globulin (ATG) is
the current treatment of choice for patients who do not have
histocompatible sibling donors or who are otherwise inegligible for
allogeneic bone marrow transplantation. About 50% of patients respond to
an initial course of ATG, and many nonresponders can be salvaged by
subsequent treatment with cyclosporine (CsA). To determine whether
simultaneous administration of these agents could further improve
response rates, we enrolled 55 patients in a therapeutic trial of 4 days
of ATG and 6 months of CsA. Among the 51 patients who had not received
previous courses of ATG or CsA, 67% had responded by 3 months, and 78%
had responded by 1 year (response was defined as an increase in
peripheral blood counts sufficient that a patient no longer met the
criteria for severe disease). There was a high incidence of relapse (36%
actuarial risk at 2 years), but most relapsed patients responded to
additional courses of immunosuppression, and relapse was not associated
with a significant survival disadvantage. Evolution to myelodysplastic
syndromes and acute leukemia was rare (1 of 51 patients), but the later
appearance of paroxysmal nocturnal hemoglobinuria was more common (5 of
51 patients). Actuarial survival was 86% at 1 year and 72% at 2 years.
These data support the use of a combination immunosuppressive regimen
containing both ATG and CsA as first-line therapy for severe aplastic
anemia.
- Copyright © 1995 by The American Society of Hematology
Short-term modified alternate-day fasting: a novel dietary strategy for weight loss and cardioprotection in obese adults1,2,3
Background:
The ability of modified alternate-day fasting (ADF; ie, consuming 25%
of energy needs on the fast day and ad libitum food
intake on the following day) to facilitate weight
loss and lower vascular disease risk in obese individuals remains
unknown.
Objective: This study examined the effects of ADF that is administered under controlled compared with self-implemented conditions on
body weight and coronary artery disease (CAD) risk indicators in obese adults.
Design: Sixteen obese subjects (12 women, 4 men) completed a 10-wk trial, which consisted of 3 phases: 1) a 2-wk control phase, 2) a 4-wk weight loss/ADF controlled food intake phase, and 3) a 4-wk weight loss/ADF self-selected food intake phase.
Results: Dietary
adherence remained high throughout the controlled food intake phase
(days adherent: 86%) and the self-selected food
intake phase (days adherent: 89%). The rate of
weight loss remained constant during controlled food intake (0.67 ± 0.1
kg/wk)
and self-selected food intake phases (0.68 ± 0.1
kg/wk). Body weight decreased (P < 0.001) by 5.6 ± 1.0 kg (5.8 ± 1.1%) after 8 wk of diet. Percentage body fat decreased (P < 0.01) from 45 ± 2% to 42 ± 2%. Total cholesterol, LDL cholesterol, and triacylglycerol concentrations decreased (P
< 0.01) by 21 ± 4%, 25 ± 10%, and 32 ± 6%, respectively, after 8 wk
of ADF, whereas HDL cholesterol remained unchanged. Systolic
blood pressure decreased (P < 0.05) from 124 ± 5 to 116 ± 3 mm Hg.
Conclusion: These findings suggest that ADF is a viable diet option to help obese individuals lose weight and decrease CAD risk. This
trial was registered at clinicaltrials.gov as UIC-004-2009.
INTRODUCTION
Obese individuals are at greater risk of developing coronary artery disease (CAD) (1). A decrease in energy intake by means of dietary restriction has been shown to lower the risk of CAD in obese populations
(2). The most common form of dietary restriction implemented is daily calorie restriction (CR), which requires individuals to
decrease their energy intake by 15–40% of baseline needs each day (3). Another form of dietary restriction used, although far less commonly, is alternate-day fasting (ADF) (4).
ADF regimens were created to increase adherence to dietary restriction
protocols because these regimens only require energy
restriction every other day rather than every day,
as with CR. ADF regimens consist of a “feed day” (ad libitum food intake
for 24 h) alternated with a “fast day” (complete
fast for 24 h). Modified ADF regimens that allow for the consumption of
20–25%
of energy needs on the fast day have also been
implemented.
To date, 3 ADF studies in humans have been performed (5–7). Results from the 2 trials performed in normal-weight men and women indicate that 2–3 wk of ADF (complete fast on the fast
day) significantly lowered body weight by 2.5% from baseline (5, 6). Decreases in triacylglycerol concentrations and increases in HDL-cholesterol concentrations were also observed (5, 6). Findings from the third trial conducted in overweight adults showed that 8 wk of modified ADF (20% restriction on the fast
day) significantly lowered body weight by ≈8% from baseline (7). This trial also showed LDL-cholesterol and triacylglycerol reductions of 10% and 40%, respectively, when posttreatment
values were compared with baseline (7). Whether or not these weight loss and cardioprotective effects can be reproduced in obese individuals by using ADF remains
unknown.
Nutrition intervention studies often provide participants with food to ensure that the trial is carefully controlled for energy
intake and macronutrient distribution (8).
At the conclusion of the study, when food is no longer provided, the
individual generally returns to their baseline food
intake/meal pattern. In some trials, dietary
counseling is provided to the participant at the end of the study to aid
the
subject in maintaining his or her newly acquired
healthy eating regimen (9). The ability of an obese individual to maintain an ADF regimen by providing the subject with dietary counseling, after a
period of controlled food intake, is of great interest but has yet to be tested.
Accordingly, this study examined the
ability of ADF to facilitate weight loss and beneficially modulate key
indicators of
CAD risk in obese men and women. Additionally, this
study compared the degree of weight loss that could be achieved by ADF
during a period of controlled food intake compared
with a period of self-selected food intake combined with dietary
counseling.
SUBJECTS AND METHODS
Subjects
Subjects were recruited from the
greater Chicago area by means of advertisements placed in community
centers and libraries.
A total of 52 individuals expressed interest in
the study, but only 20 were deemed eligible to participate after the
preliminary
questionnaire and body mass index (BMI; in kg/m2) assessment (Figure 1).
Key inclusion criteria were as follows: age 35–65 y, BMI between 30 and
39.9, weight stable for 3 mo before the beginning
of the study (ie, <5 kg weight loss or weight
gain), nondiabetic, no history of cardiovascular disease, lightly
active [ie,
<3 h/wk of light-intensity exercise at
2.5–4.0 metabolic equivalent tasks for 3 mo before the study (10)],
nonsmoker, and not taking weight loss or lipid- or glucose-lowering
medications. Perimenopausal women were excluded from
the study, and postmenopausal women (absence of
menses for >2 y) were required to maintain their current hormone
replacement
therapy regimen for the duration of the study.
The experimental protocol was approved by the Office for the Protection
of
Research Subjects at the University of Illinois,
Chicago, and all volunteers gave their written informed consent to
participate
in the trial.
FIGURE 1
Study flowchart. ADF, alternate-day fasting.
Study design
A 10-wk trial, which consisted of 3
consecutive intervention phases, was implemented to test the study
objectives. The 3 consecutive
phases were as follows: 1) 2-wk preloss control phase, 2) 4-wk weight loss/ADF controlled food intake phase, and 3) 4-wk weight loss/ADF self-selected food intake phase.
Phase 1: preloss control protocol
During the first phase, subjects were required to keep their body weight stable by maintaining their usual eating and exercise
habits. As such, each subject served as his or her own control.
Phase 2: weight loss/ADF controlled food intake protocol
The second phase consisted of a 4-wk controlled food intake ADF period. The baseline energy requirement for each subject was
determined by the Mifflin equation (11).
All subjects consumed 25% of their baseline energy needs on the “fast”
day (24 h) and then consumed food ad libitum on
each alternate “feed” day (24 h). During this
controlled food intake phase, subjects were provided with a
calorie-restricted
meal on each fast day, and consumed food ad
libitum at home on the alternate day. All meals were prepared in the
metabolic
kitchen of the Human Nutrition Research
Center at the University of Illinois, Chicago, and were provided as a
3-d rotating
menu. The nutrient composition of the
provided fast day meal is shown in Table 1.
On the ad libitum food intake day, subjects were instructed to limit
fat intake to <30% of energy needs by choosing low-fat
meat and dairy options. The feed/fast days
began at midnight each day, and all fast day meals were consumed between
1200 and
1400 to ensure that each subject was
undergoing the same duration of fasting. On each fast day, the subjects
were allowed
to consume energy-free beverages, tea,
coffee, and sugar-free gum and were encouraged to drink plenty of water.
View this table:
TABLE 1
Nutrient composition of fast day meals during the controlled food intake phase1
Phase 3: weight loss/ADF self-selected food intake protocol
The third phase consisted of a 4-wk
ADF self-selected food intake period in conjunction with weekly dietary
counseling. During
this phase, subjects still consumed 25% of
their baseline energy needs on the fast day and consumed food ad libitum
on the
feed day. However, during this period, no
food was provided to the subjects. Instead, subjects met with a
registered dietitian
at the beginning of each week to learn how to
maintain the ADF regimen on their own at home. During each counseling
session,
the dietitian worked with the subject to
develop individualized fast day meal plans. These plans included menus,
portion sizes,
and food lists that were consistent with
their food preferences and prescribed calorie levels for the fast day.
During these
sessions, subjects were also instructed how
to make healthy food choices on the ad libitum food intake days by
choosing low-fat
meat and dairy options. Subjects were asked
to consume fast day meals between 1200 and 1400.
Blood collection protocol
Twelve-hour fasting blood samples were
collected between 0700 and 0900 at baseline (day 1), at the end of
phase 1 (day 14),
at the end of phase 2 (day 41: feed day; day 42:
fast day), and at the end of phase 3 (day 69: feed day; day 70: fast
day).
The subjects were instructed to avoid exercise,
alcohol, and coffee for 24 h before each visit. Blood was centrifuged
for
15 min at 520 × g at 4°C to separate plasma from red blood cells and was stored at −80°C until analyzed.
Analyses
Adherence to ADF diets
During phase 2 (controlled food
intake phase), subjects were instructed to eat only the fast day food
provided and to report
any extra food item consumed by using an
“extra food log.” During phase 3, subjects were provided with
individualized meal
plans that were consistent with their food
preferences and prescribed calorie levels for the fast day. Subject was
asked to
report any extra food item consumed on the
fast day that did not comply with their prescribed plan by using the
extra food
log. The log was collected and reviewed by
study personnel each week. If the log indicated that the subject ate an
extra food
item on a fast day, that day was labeled as
“not adherent.” If the log revealed that the subject did not eat any
extra food
item, that day was labeled as “adherent.”
Adherence data were assessed each week as 1) absolute adherence (number of days adherent with diet) and 2) percentage adherence calculated by applying the following formula:
Weight loss and percentage body fat assessment
Body weight measurements were taken
to the nearest 0.5 kg at the beginning of every week with subjects
wearing light clothing
and without shoes by using a balance beam
scale at the research center (HealthOMeter; Sunbeam Products, Boca
Raton, FL). BMI
was assessed as kilograms divided by meters
squared. Percentage body fat was assessed in triplicate after the
weigh-in by
using a tetra-polar bioelectrical impedance
analyzer (Omron HBF-500; Omron Health Care, Bannockburn, IL) (12). The within-group CV for percentage body fat was 2.7%.
Plasma lipid profile, blood pressure, and heart rate determination
Plasma total cholesterol,
HDL-cholesterol, and triacylglycerol concentrations were measured in
duplicate by using enzymatic
kits, standardized reagents, and standards
(Biovision Inc, Mountainview, CA) and analyzed by using a microplate
reader (iMark
Microplate Reader; Bio-Rad Laboratories Inc,
Richmond, CA). The concentration of LDL cholesterol was calculated by
using the
Friedewald, Levy, and Fredrickson equation (13).
The within-group CVs for total cholesterol, HDL-cholesterol, and
triacylglycerol concentrations were 3.1%, 2.6%, and 2.5%,
respectively. Blood pressure and heart rate
were measured in triplicate with the subject in a seated position after a
10-min
rest.
Statistics
Results are presented as means ± SEMs. Tests for normality were included in the model. Sample size was calculated by assuming
a 10% change in LDL-cholesterol concentrations, with a power of 80% and an α risk of 5%. One-factor analysis of variance was performed to determine an overall P value for each variable.
Bonferroni correction was used to
assess significance. Relations between continuous variables were
assessed by using simple
regression analyses as appropriate. Data were
analyzed by using SPSS software (version 17.0 for Mac OS X; SPSS Inc,
Chicago,
IL).
RESULTS
Subject dropout and baseline characteristics
Twenty subjects commenced the study,
with 16 completing the entire 10-wk trial. Two subjects dropped out due
to time constraints,
whereas 2 others dropped out due to inability to
comply with the ADF protocol. Baseline characteristics of the subjects
who
completed the entire 10-wk trial are shown in Table 2.
View this table:
TABLE 2
Characteristics at baseline in subjects who completed the 10-wk trial (n = 16)
Adherence to ADF diets
During the ADF controlled food intake
phase, subjects were adherent with the provided fast day meals (ie, no
extra food items
consumed) for 3.8 ± 0.1 of 4 d during week 3,
2.6 ± 0.1 of 3 d during week 4, 3.6 ± 0.1 of 4 d during week 5, and 2.1 ±
0.2
of 3 d during week 6. During the ADF
self-selected food intake phase, subjects were adherent with prescribed
kcal goal for
3.5 ± 0.2 of 4 d during week 7, 2.5 ± 0.2 of 3 d
during week 8, 3.8 ± 0.1 of 4 d during week 9, and 2.8 ± 0.1 of 3 d
during
week 10. When expressed as percentage adherence (Figure 2),
there was no drop in adherence over the course of the controlled food
intake phase or the self-selected food intake phase.
Moreover, no changes in physical activity habits
were reported over the course of the trial; thus, changes in body
weight
and clinical parameters may be attributed
primarily to change in diet.
FIGURE 2
Mean (±SEM) body weight and percentage adherence during the 10-wk trial. A: Body weight of subjects (n = 16) at each week. B: Percentage adherence values of subjects (n = 16) on the fast day at each week. Percentage adherence was calculated as shown in Equation 1. There was no difference in percentage adherence between weeks during the 10-wk trial. ADF, alternate-day fasting. Overall
P value (P = 0.0001 for
body weight) was calculated with the use of one-factor ANOVA. Values
with different superscript letters are significantly
different, P < 0.05 (Bonferroni analysis).
Weight loss and change in percentage body fat by ADF
During the preloss control phase, body weight of the subjects remained stable (Figure 2).
Throughout the ADF controlled food intake phase, there was a mean body
weight loss of 0.67 ± 0.1 kg/wk. This rate of weight
loss remained consistent during the ADF
self-selected food intake phase (0.68 ± 0.1 kg/wk). Total weight loss (P < 0.001) over the course of the trial was 5.8 ± 1.1% from baseline (5.6 ± 1.0 kg). Mean BMI of the subjects at baseline was
33.7 ± 1.0. At the end of the controlled food intake phase, BMI decreased (P < 0.001) to 32.8 ± 1.0, and by the end of the self-selected food intake phase, BMI further decreased (P < 0.01) to 29.9 ± 2.1. At baseline, mean percentage body fat was 45.0 ± 1.6%. Percentage body fat was not changed after 4
wk (43.3 ± 2.1%) but was reduced (P < 0.01) after 8 wk of ADF (42.1 ± 2.0%). Fat mass decreased (P < 0.01) by 5.4 ± 0.8 kg after 8 wk of diet, whereas changes in fat-free mass were not significant (−0.1 ± 0.1 kg). Rate of
weight loss was related to percentage of days adherent to diet per week (r = 0.43, P < 0.05).
Changes in plasma lipids by ADF
Mean plasma lipid concentrations over the 10-wk trial are presented in Table 3 (values presented in the text are an average of the food intake and fast days). Total cholesterol concentrations were lowered
(P < 0.001) by 18.0 ± 4.3% after
completion of the controlled food intake phase and by 21.2 ± 4.3% after
completion of the self-selected
food intake phase. Lowered LDL cholesterol (P < 0.01) was noted after 4 and 8 wk of ADF (26.0 ± 8.2% and 24.8 ± 9.6%, respectively). HDL-cholesterol concentrations were
not affected by the ADF diet. Circulating triacylglycerol concentrations were lowered (P < 0.01) by 25.3 ± 7.0% after the controlled food intake phase and further lowered (P
< 0.01) by 32.2 ± 6.4% after the self-selected food intake phase. No
differences between food intake and fast day values
were observed for any lipid parameter. Decreases
in LDL cholesterol were associated with decreased body weight (r = 0.48, P < 0.05) posttreatment. Decreased triacylglycerol concentrations were related to reductions in body weight (r = 0.45, P < 0.05) and percentage body fat (r = 0.38, P < 0.05) at the end of the study.
View this table:
TABLE 3
Plasma lipid concentrations at baseline and at the end of each phase of the trial1
Changes in blood pressure and heart rate by ADF
The effects of 8 wk of ADF on blood pressure and heart rate were also assessed. Systolic blood pressure was lowered (P
< 0.05) by 4.4 ± 1.8% after completion of the controlled food intake
phase and by 5.1 ± 1.6% after completion of the self-selected
food intake phase (Figure 3).
No differences between food intake and fast day values were observed
for systolic blood pressure. Diastolic blood pressure
values at baseline (80.3 ± 2.7 mm Hg) did not
differ from those at week 6 (79.2 ± 2.1 mm Hg) or from those at week 10
(78.8
± 2.5 mm Hg). Heart rate was significantly
lowered (P < 0.05) from baseline after 8 wk of diet (Figure 3). Changes in body weight, BMI, and percentage body fat were not related to blood pressure or heart rate values.
FIGURE 3
Mean (±SEM) systolic blood pressure and heart rate during each phase of the 10-wk trial. A: Systolic blood pressure values
of subjects (n = 16) at each week. B: Heart rate values of subjects (n = 16) at each week. ADF, alternate-day fasting. Overall P values (P = 0.009 for blood pressure; P =
0.012 for heart rate) were calculated with the use of one-factor ANOVA.
Values with different superscript letters are significantly
different, P < 0.05 (Bonferroni analysis).
DISCUSSION
This study is the first to show that ADF
is an effective dietary intervention to help obese individuals lose
weight and lower
CAD risk. Specifically, we show here that an ADF
regimen, which allowed participants to consume 25% of their energy needs
on the fast day, resulted in a mean weight loss of
5.8% from baseline after only 8 wk of treatment. Decreases in several
key
biomarkers for CAD risk, such as total cholesterol,
LDL cholesterol, triacylglycerols, systolic blood pressure, and heart
rate, were also observed. Additionally, we show
here that a similar rate of weight loss was achieved during the ADF
controlled
food intake period when compared with the ADF
self-selected food intake period. These data suggest that subjects were
able
to maintain the ADF meal pattern when preparing
their own meals at home (ie, when removed from a clinically controlled
environment).
Although CR is more frequently implemented than ADF to facilitate weight loss (4, 14), many obese patients find it difficult to adhere to CR because food intake must be limited every day by 15–40% of baseline
needs (15–17). ADF regimens were created to increase adherence to dietary restriction protocols because these regimens require energy
restriction only every other day (4).
In the present study, we measured the ability of obese subjects to
adhere to their fast day energy goal. Our data show
that adherence to ADF was high (days per week
adherent: ≈85%) and that this level of adherence remained constant
throughout
the 8-wk trial. We also show here that adherence to
the ADF protocol was similar between the controlled food intake phase
and the self-selected food intake phase. These
findings suggest that obese individuals are capable of self-selecting
foods
to meet their individual fast day energy goals. It
should be noted, however, that the subjects met weekly with a registered
dietitian. In view of this, future studies should
examine the ability of obese subjects to adhere to ADF regimens without
the help of a dietitian. Such data would be more
indicative of the efficacy of the ADF regimen for weight loss in the
general
population. It should also be noted that of the 20
subjects initially recruited to partake in the study, 2 individuals
dropped
out due to inability to comply with the fast day
diet protocol. Thus, on the basis of these findings, it is possible that
this dietary restriction protocol may not be well
tolerated by 10% (or possibly more) of the obese population.
Nevertheless,
dropout rate data from ADF trials with larger
sample sizes (eg, n = 68 subjects, calculated with a power of 80% and an α
risk of 5%) are still required before solid conclusions can be reached.
It should also be noted that this trial was not controlled.
The need for a randomized controlled trial to test
similar hypotheses is clearly warranted.
Decreases in body weight are directly related to degree of dietary adherence (17–20).
In the present ADF study, obese subjects lost an average of 0.68 kg/wk,
which corresponded to a total weight loss of 5.6
kg over 8 wk (95% CI: −7.4, −3.8). Because rate of
weight loss was correlated to percentage weekly adherence, it can be
assumed
that the high adherence rate to ADF diets played a
significant role in the total weight loss achieved. We also show here
that
rate of weight loss remained constant after the
subjects switched from the ADF controlled food intake phase to the ADF
self-selected
food intake phase. Thus, the ADF diet may be an
effective dietary strategy to help obese individuals achieve a stable,
healthy
rate of weight loss, even during periods of
self-implementation. We predicted that subjects would lose a total of
4.5 kg fat
mass after 8 wk (on the basis of a 75% decrease in
energy intake on the fast day, with no change in energy intake on the
feed
day). The actual fat mass lost (5.4 kg) exceeded
our predictions. This indicates that these subjects were also limiting
their
energy intake on the feed day, which may have
occurred because the subjects knew they were enrolled in a weight loss
trial.
Our weight loss findings are similar to those of
Johnson et al (7) (8% weight loss after 8 wk of ADF in overweight individuals). However, the trial by Johnson et al (7) takes precedence both in time and study design because it was a randomized controlled trial study. The degree of weight
loss achieved by the present ADF regimen is also comparable to that of short-term CR trials (14, 21, 22).
In view of these similar effects on body weight, ADF may be considered a
suitable alternative to CR to help obese individuals
lose weight. A study that directly compares the
effects of ADF to that of CR on body weight and body composition is
undoubtedly
an important next step in the ADF field. It must
also be noted, however, that the degree of weight loss achieved by ADF
may
not be sustainable long term. Whether or not obese
individuals are able to adhere to ADF over the long term and experience
sustained weight loss will be an important focus of
future research.
Beneficial modulations in several key CAD
risk indicators were also noted in response to ADF. Total and
LDL-cholesterol concentrations
decreased by 21% and 25%, respectively, after 8 wk
of diet. Triacylglycerol concentrations were also lowered by 32% when
baseline
values were compared with posttreatment values.
These modulations in LDL-cholesterol and triacylglycerol concentrations
are
similar to those observed by Johnson et al (7).
We also show that improvements in plasma LDL-cholesterol and
triacylglycerol concentrations were correlated to changes
in body weight and percentage body fat
posttreatment. Thus, the degree of weight loss achieved by this ADF
regimen most likely
played a major role in the degree to which these
plasma lipids were altered (23).
No changes in HDL-cholesterol concentrations were observed throughout
the trial. This lack of effect of ADF on HDL cholesterol
is not surprising because this cardioprotective
lipid parameter is generally augmented only in response to exercise
training
(24).
An important next step in the ADF field will be to incorporate an
exercise program into this lifestyle regimen. Perhaps
with the addition of physical activity,
HDL-cholesterol concentrations will increase, thus beneficially
modulating the entire
lipid profile. Findings from the majority of CR
trials also report no change in HDL cholesterol after short durations of
treatment
(21, 22, 25).
Lipid variable measurements were assessed on consecutive food intake
and fast days at the end of each diet phase (after
a 12-h fasting blood draw). Results reveal that
consumption of food or fasting the day before the lipid assessment has
no
effect on lipid concentrations. Findings from the
present study also show that 8 wk of ADF in obese individuals may reduce
systolic blood pressure and heart rate. In view of
the powerful association of high blood pressure with risk of CAD (26, 27), this finding further supports the cardioprotective actions of ADF.
In summary, our findings indicate that
ADF may be implemented as an effective diet strategy to help obese
individuals lose
weight and to confer protection against CAD. ADF
should therefore be considered a viable option for obese patients who
wish
to lose weight through dietary restriction but who
are unable to adhere to daily CR.
Acknowledgments
The authors’ responsibilities were as
follows—KAV: designed the experiment, analyzed the data, and wrote the
manuscript; SB
and ECC: conducted the clinical trial, performed
the laboratory analyses, and assisted with the preparation of the
manuscript;
and MCK: coordinated food preparation and
distribution, provided technical assistance during the analysis phase of
the experiment,
and assisted with the preparation of the
manuscript. The authors had no conflicts of interest to report.
- Received July 12, 2009.
- Accepted September 1, 2009.