Download Plasma Ferritin, Iron Intake, and the Risk of Colorectal Polyps

American Journal of Epidemiology
Copyright O 1996 by The Johns Hopkins University School of Hygiene and Public Hearth
All rights reserved
Vol. 144, No. 1
Printed In USA.
Plasma Ferritin, Iron Intake, and the Risk of Colorectal Polyps
Cristy L Bird, 1 John S. Witte, 1 Marian E. Swendseid,2 James M. Shikany,3 Isabella F. Hunt,2
Harold D. Frankl,4 Eric R. Lee,6 Matthew P. Longnecker,6 and Robert W. Haile1
High iron exposure has been associated with colorectal neoplasia in several studies. The authors investigated plasma ferritin, an indicator of iron stores, and iron intake as risk factors for adenomatous polyps,
intermediate markers for colorectal cancer. During 1991-1993, they collected fasting blood samples from and
administered questionnaires to men and women 50-75 years old who visited free sigmoidoscopy clinics at a
health maintenance organization. Data from 965 subjects (467 cases, 498 controls) were analyzed. Compared
with those who had low-normal plasma ferritin concentrations (73-141 /tg/liter), those with elevated concentrations (>289 /xg/liter) had a multivariate-adjusted odds ratio of 1.5 (95% confidence interval (Cl) 1.0-2.3) after
excluding subjects with possible non-iron-related elevations in ferritin. Compared with subjects consuming an
adequate amount of iron (11.6-13.6 mg/day), multivariate-adjusted odds ratios were 1.6 (95% Cl 1.1-2.4) for
<11.6 mg/day and 1.4 (95% Cl 0.9-2.0) for >27.3 mg/day. These results provide further support for a weak
positive association between iron exposure and colorectaJ polyps. Am J Epidemiol 1996; 144:34-41.
colonic polyps; colorectal neoplasms; ferritin; iron
Using data from the First National Health and Nutrition Examination Survey (NHANES I), Stevens and
coworkers (1) found that high body iron stores may be
a risk factor for cancers common in Western populations, including colorectal cancer. If iron causes cancer, the two most likely mechanisms are that readily
available body iron 1) spurs the growth of transformed
cells and/or 2) acts as a prooxidant, increasing carcinogenic DNA changes or increasing general oxidative
stress. Support for the high iron stores hypothesis
comes from animal experiments (2-6) and a few epidemiologic studies (1, 7-10). Studies of people with
the excessive iron accumulation of hereditary hemochromatosis (11-15) have consistently found a high
risk of liver cancer but equivocal results for other
cancers.
Iron deficiency may also increase the risk of some
cancers. Although little work has been done in this
area, this effect has been suggested by animal experiments (16, 17) and by descriptive observations in
humans. In the first half of this century, iron-deficient
Scandinavian women with Plummer-Vinson syndrome
(18-20) frequently presented with upper alimentary
cancers; and it has been proposed that iron deficiency
contributes to the development of gastric cancer in
South America (21). Iron deficiency and iron overload
both appear to impair immune function (22, 23).
Few studies have examined blood measures of iron
exposure in relation to colorectal polyps (8-10),
which are widely held to be intermediate markers of
colorectal cancer (24). No study has examined total
iron intake (including supplemental iron) as a risk
factor for colorectal polyps. We hypothesized that
total iron intake and plasma ferritin, a blood measure
that reflects body iron stores over a wide range (2527), might exhibit a U-shaped relation to the prevalence of colorectal polyps.
Received for publication June 16, 1995, and accepted for publication November 10, 1995.
Abbreviation: NHANES, National Health and Nutrition Examination Survey.
1
Department of Preventive Medicine, School of Medicine, University of Southern California, Los Angeles, CA.
2
Department of Community Health Sciences, School of Public
Health, University of California, Los Angeles, CA.
3
Division of Preventive Medicine, Department of Medicine, University of Alabama, Birmingham, Al_
4
Division of Gastroenterology, Kaiser Permanente Medical Center, Los Angeles, CA.
5
Division of Gastroenterology, Kaiser Permanente Medical Center, Bellftower, CA.
6
Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA.
Reprint requests to Dr. Robert W. Haile, Department of Preventive Medicine, School of Medicine, University of Southern California,
Parkview Medical Building Room B106B, 1420 San Pablo Street,
Los Angeles, CA 90033.
MATERIALS AND METHODS
Study population
Subjects were eligible for the study if they underwent screening by flexible sigmoidoscopy at either of
two Southern California Kaiser Permanente medical
34
Iron and the Risk of Colorectal Polyps
centers from January 1, 1991, through August 25,
1993. Eligible men and women were 50-75 years old;
were free of invasive cancer, inflammatory bowel disease, and familial polyposis; were fluent in English;
had had no previous bowel surgery; were residents of
Los Angeles County; and had no physical or mental
disability precluding an interview. In addition, subjects who had symptoms suggestive of any organic
intestinal disease were excluded. Cases were subjects
diagnosed for the first time with one or more histologically confirmed adenomatous polyps. Controls had
no polyps of any type discovered at sigmoidoscopy,
had no history of polyps, and were individually
matched to cases by sex, age (±5 years), date of
sigmoidoscopy (±3 months), and Kaiser center. The
study was approved by the Human Subjects Protection
Committee of the University of California, Los Angeles, and by the Kaiser Permanente Institutional Review
Board. This was a case-control study of polyps with
regard to the rectosigmoid region only inasmuch as
controls did not undergo colonoscopy. However, most
carcinomas arising from polyps may arise from polyps
in the rectosigmoid region (28).
Additional details of subject recruitment and data
collection have been provided elsewhere (29). Briefly,
polyps data were obtained from Kaiser pathology reports. Data on a variety of nondietary risk factors were
obtained during a script-standardized, in-person interview, administered on average 5 months after sigmoidoscopy.
Assays of plasma ferrftin and other biochemical
indicators
A fasting blood sample was drawn in the morning,
on average 6 months after sigmoidoscopy, into a tube
coated with ethylenediaminetetraacetic acid. The
plasma was placed in a cryogenic tube and stored at
—70°C until the day of assay. Plasma ferritin samples
were assayed in batches over time by one medical
technologist, who was blinded as to case-control status. All assays were performed using Allegro ferritin
radioimmunoassay kits (Nichols Institute, San Juan
Capistrano, California) and Beckman Gamma 5500 or
Gamma 4000 gamma counters (Beckman Instruments,
Fullerton, California).
A plasma pool and two commercial control samples
(Bio-Rad Lyphochek, Levels 1 and 3; Bio-Rad Laboratories, Hercules, California) were used to monitor
accuracy and between-run variation in plasma ferritin
results. At mean plasma ferritin levels of 59.8, 99.1,
and 487.8 /i-g/liter, the between-run coefficients of
variation during the study were 3.5, 4.2, and 5.4 percent, respectively. The within-run coefficient of variAm J Epidemiol
Vol. 144, No. 1, 1996
35
ation, using multiple aliquots of a plasma pool (mean
level = 72.7 jig/liter), was 4.3 percent.
Other nutritional indicators measured were several
plasma carotenoids, whole blood ascorbate, plasma
folate, and red cell folate. Samples for all assays were
treated with stabilizing agents, if needed, and stored at
-70°C. Plasma carotenoid samples were assayed later
by high performance liquid chromatography. Whole
blood ascorbate samples were assayed using a spectrophotometric, bis-2,4-diphenylhydrazine method.
Both whole blood and plasma folate samples were
assayed using Quantaphase and Quantaphase II radioassay kits (Bio-Rad Laboratories). Hematocrits were
measured using freshly drawn whole blood samples on
a Coulter counter.
Iron intake
Diets were assessed by means of a modified version
of a 126-food semiquantitative food frequency questionnaire (30) that was mailed and that contained questions about diet in the year before sigmoidoscopy. The
questionnaires were reviewed for completeness during
the in-person interview and analyzed using the Nutrition Data System (31) for nutrients from foods and a
supplement database developed for the questionnaire.
Eighty percent of multivitamin users who provided
complete information about their supplement used one
that contained iron. Therefore, for the 15 percent of all
subjects unable to describe the specific multivitamin
supplement used, it was assumed that they used one
containing the US Recommended Dietary Allowance
for iron.
Statistical analysis
Plasma ferritin values were obtained for 980 subjects, of whom 15 were dropped from the dataset
because they lacked food frequency questionnaires.
The final data set contained 402 matched pairs as well
as unmatched controls (n = 96) and cases (n = 65).
The latter generally occurred when one subject in a
pair did not provide a blood sample or the sample was
not assayed, but a few occurred for other reasons (e.g.,
nonfluent in English).
Plasma ferritin values were divided into quartiles
and total iron intakes (food plus supplements) into
quintiles, using their distributions across all subjects.
The second to lowest quartile of ferritin values and the
second to lowest quintile of iron intake were designated the reference categories. The reference levels
were chosen a priori to be biologically meaningful.
For example, the reference quartile for plasma ferritin
was the quantile most unlikely to contain subjects with
either iron overload or iron deficiency, while the ref-
36
Bird et al.
erence quintile for iron intake contained the lowest
estimated iron intakes not expected to produce iron
deficiency over time. (Using quartiles of iron intake
mingled subjects with adequate and inadequate intakes
in the lowest quartile.) Prevalence odds ratios were
computed in a Mantel-Haenszel analysis. We used
these results to determine whether logistic regression
models should be fit to categorical or continuous
forms of the iron variables (32).
A conditional logistic regression model (n = 402
pairs) was fit to a plasma ferritin or iron intake variable, with and without potential confounding variables. The matching was then broken, and unconditional logistic regression models were fit, stratifying
on the matching variables, the same potential confounders, and using the same 804 subjects. The conditional and unconditional analyses yielded similar
results, which was expected inasmuch as they both
controlled for the matching variables (33). Next, unconditional models with all 965 subjects (including the
unmatched) were examined. These models also gave
similar results. Results reported in this paper are from
unconditional models that included all subjects for
whom we had information.
RESULTS
This was an ethnically diverse population of men
and women around retirement age and living in relatively urban neighborhoods in Los Angeles County.
There were 167 female cases, 167 female controls, 300
male cases, and 331 male controls, of whom 54 percent were white, 17 percent black, 19 percent Latino,
9 percent Asian/Pacific Islander, and 1 percent
"other." Ethnicity, education, and income did not vary
appreciably between cases and controls (not shown).
In table 1, medians and ranges of plasma ferritin and
other relevant variables are shown. The median
plasma ferritin concentration was higher in cases than
in controls, although this was not statistically significant in either sex (Wilcoxon signed rank test). Plasma
ferritin concentrations covered a wide range in both
sexes, including values suggestive of nonexistent body
iron stores (<12 /xg/liter) as well as the high values
typically seen either in iron overload diseases (>400
jxg/liter) or in common pathologic conditions (>200
/xg/liter) (34). Few control women (3.9 percent) had
plasma ferritin levels >500 /xg/liter, whereas 13.1
percent of male controls had levels >500 /xg/liter.
Although it is usual for men to average higher ferritin
values than women (34), the ferritin distribution for
men displayed a shift toward unusually high values.
The initial analysis of plasma ferritin revealed no
evidence of a relation with polyps risk (table 2). Ferritin levels may be increased by pathologic conditions
not accompanied by excess body iron (35, 36). Therefore, we repeated the analysis after excluding subjects
likely to have such conditions: those with very high
ferritin levels (>500 /Ag/liter) or with low or missing
hematocrits (females, <35 percent; males, <41 percent). We chose low hematocrit as a criterion because
anemias in older people are usually associated with
non-iron-related elevations in ferritin levels (35, 36).
After the exclusions, the odds ratio for the highest
category increased slightly (table 3). A weak U-shaped
relation emerged; this was consistent across sex (not
shown) and unaltered by adjustment for various potential confounding variables (table 3). Adjusting for
whole blood ascorbate and red cell folate did not
materially alter ferritin odds ratios (not shown).
Categorized by the site and size of the largest adenoma, 30 percent of cases had rectal polyps (vs. left
colon polyps), and 19 percent of all cases had polyps
more than 1 cm in diameter. The U-shaped relation
between plasma ferritin and polyps was of greatest
TABLE 1. Medians and ranges of relevant variables describing the sigmoldoscopy study population, Los Angeles, California,
1991-1994*
Females
Cases
(n = 167)
Median
Plasma ferritin (ng/liter)
Hematocrit (%)t
Calories (kcal)
Total iron intake (mg)
Supplemental iron use (%)
Iron users with low hemocrits (%)t
Range
3-582
105
40.6 28.9-48.1
1,676
550-5,302
19.7 3.4-143.9
45.5
5.3
Males
Conlrots
C .= 167)
Cases
C = 300)
Controls
(n = 331)
Median
Range
Median
Range
Median
100
40.6
1,650
19.4
35.3
1.7
7-1,182
34.7-48.8
454-5,128
3.1-133.5
179
45.0
2,004
18.4
33.0
13.0
7-1,734
32.2-54.8
308-5,570
1.9-165.2
168
45.0
1,852
17.1
31.4
8.7
Range
1-1,479
32.7-53.7
435-5,975
3.2-151.8
* All data = median (range), except where indicated.
t Mean (range).
$ (Number of subjects using iron supplements who had low hematocrits) x 100/(number of subjects who used iron supplements). Low
hematocrits were defined as <35% for women and <41% for men.
Am J Epidemiol
Vol. 144, No. 1, 1996
Iron and the Risk of Colorectal Polyps
37
TABLE 2. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association of quartiles of
plasma ferritin with colorectal polyps, Los Angeles, California, 1991-1994*
Plasma terrain (jig/flter)
73-141
<73
Adjusted ORs (n - 965)
Women (n = 334)
Men (no 631)
142-288
2289
OR
95% Cl
OR
OR
95% Cl
OR
95% Cl
1.1
1.1
1.2
0.8-1.6
0.6-1.8
0.7-1.9
1.0
1.0
1.0
1.2
1.2
1.2
0.8-1.7
0.7-2.2
0.8-1.9
1.2
1.1
1.3
0.8-1.8
0.5-2.3
0.8-2.0
* Unconditional logistic regression models fitted to quartiles of plasma ferritin. All models controlled for
matching variables: age (±5 years), sigmoidoscopy date (±3 months), sex, and clinic.
TABLE 3. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association of quartiles of
plasma ferritin with colorectal polyps, excluding subjects with levels over 500 jig/liter or low hematocrlts
(<35% for females and <41% for males), Los Angeles, California, 1991-1994*
Ptasma lerrtln (jag/ltac)
73-141
<73
142-288
289-500
OR
95% Cl
OR
OR
95% Cl
OR
95% Cl
All polyps
Adjusted (n- 815)
Further adjustedf
(n = 815)
1.1
0.8-1.6
1.0
1.2
0.8-1.8
1.5
0.9-2.3
1.2
0.8-1.7
1.0
1.2
0.8-1.8
1.5
1.0-2.3
By polyp site
Rectum* (n - 535)
Left colon (n - 698)
1.4
1.2
0.8-2.5
0.8-1.7
1.0
1.0
1.6
1.2
0.9-2.8
0.8-1.8
1.7
1.4
0.9-3.4
0.9-2.3
* Excluded to reduce potential nullward bias caused by non-iron-related elevation of ferritin levels by pathologic
conditions. Unconditional logistic regression models fitted to quartiles of plasma ferritin. All models controlled for
matching variables (see table 2). Cases: n = 395. Controls: n - 420.
t Further adjusted for smoking (nonsmoker vs. subjects smoking £5 years before sigmoidoscopy) and intakes
of calories, red meat (g/day), total fruits/vegetables (servings/day), saturated fat (g/day), and ethanol (grouped as
0, >0 and <7, and 27 g/day). However, results were identical when all potential confounders except the matching
variables and smoking were dropped from the model. Smoking was associated with levels of several biochemical
indicators in subjects who had quit up to 5 years before. Smoking dose did not appear to be associated with
plasma ferritin. We selected potential confounders for inclusion in multivariate models based on the colorectal
cancer/polyps literature and on observed associations in the data. Covariates examined in other models included
plasma beta-carotene, whole blood ascorbate, red cell rotate, plasma folate, and total fat intake.
$ Adjusted for matching variables and smoking. Rectal cases: n = 115. Left colon cases: n = 278.
magnitude for cases with rectal polyps (table 3); results did not clearly differ by polyp size (not shown).
Sixteen percent of cases and 13 percent of controls
were referred for specific minor symptoms (29), including the 10.9 percent of all cases and 6.4 percent of
controls referred because of possible bleeding (e.g.,
visible or occult blood in stool). Excluding subjects
with possible bleeding or with any minor symptoms
did not alter ferritin odds ratios.
The association between iron intake and polyps also
displayed a weak U-shaped pattern. The lowest quintile of energy-adjusted total iron intake and the two
highest quintiles were associated with increased risk
(table 4). This weak U-shaped relation persisted after
adjustment for smoking, calories, red meat, total fruit
and vegetables, saturated fat, and ethanol (table 4), as
well as when adjusted for whole blood ascorbate and
plasma beta-carotene concentrations (not shown). A
clear difference in the iron intake-polyp association for
Am J Epidemiol
Vol. 144, No. 1, 1996
rectal versus left colon polyps was not found (table 4),
nor did there appear to be a difference across polyp
size (not shown). The iron intake results were not
substantially altered when we excluded subjects with
low hematocrits (who might have been taking iron
supplements), those with blood in stool, or those referred for symptoms.
The two highest quintiles of iron intake contained
many subjects who consumed iron supplements.
Therefore, the analysis was repeated, excluding subjects when total (supplemented) iron intake placed
them in a higher quintile than did food iron intake
alone. The association between iron intake and polyps
was eliminated when the quintile of iron intake assigned was dependent on food iron alone (table 5).
At high levels, either iron intake or body iron stores
could lead to an increase in colorectal cancer risk (37).
Orally ingested iron could be absorbed and contribute
to body iron stores; or it could act from within the
38
Bird et al.
TABLE 4. Odds ratios (ORs) and 95% confidence Intervals (Cts) for the association of quintiles of total iron intake with
colorectal polyps, Los Angeles, California, 1991-1994*
Iron Inlake (mg/day)
=11.6
11.6-13.6
13.7-17.2
17.3-27.3
>27.3t
OR
95% Cl
OR
OR
95% Cl
OR
95% Cl
OR
95% Cl
All subjects
Adjusted (n - 985)
Further adjusted}: (n = 965)
1.7
1.6
1.1-2.4
1.0
1.0
1.1
1.1
0.7-1.6
0.7-1.7
1.4
1.5
1.0-2.2
1.0-2.3
1.3
1.4
0.9-1.9
0.9-2.0
Further adjusted
Women (n - 334)
Men ( n - 631)
0.9
2.1
0.4-1.9
1.3-3.5
1.0
1.0
0.6
1.4
0.3-1.4
0.9-2.4
0.9
1.9
0.4-1.8
1.2-3.2
1.0
1.6
0.5-2.0
0.9-2.8
By site
Rectum§ (n - 636)
Left colon (n - 824)
1.4
1.8
0.7-2.6
1.1-2.7
1.0
1.0
1.2
1.0
0.6-2.2
0.7-1.6
1.6
1.4
0.9-2.9
0.9-2.2
1.6
0.8-2.9
0.8-1.9
1.2
* Unconditional logistic regression models fitted to quintiles of energy-adjusted nssiduals of iron intake, including iron from supplements.
All models stratified on matching variables (see table 2). Cases: n - 467. Controls: n » 498.
t Ranges (iron in mg/day) estimated by entering the study population median caloric intake (1,901 kcal) into the equation: total iron - a°
+ a^kcal) + a.
$ Further adjusted using the same potential confounding variables in table 3.
§ Stratified on matching variables only. Rectal cases: n - 138. Left colon cases: n •= 326. Controls: n = 498. Site data missing for n - 3.
TABLE 5. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association of categories of total iron intake with
colorectal polyps after excluding subjects whose placement in total Iron Intake quintile was dependent on Iron supplement use,
Los Angeles, California, 1991-1994*
Iron IntakB (mg/day)
=11.6
11.6-13.6
13.7-17.2
17.3-27.4
>27.4f
OR
95% Cl
OR
OR
95% Cl
OR
95% Cl
OR
95% Cl
All subjects
Adjusted (n =645)
Further adjusted} (n • 645)
1.5
1.2
0.9-2.4
0.7-1.9
1.0
1.0
0.8
0.7
0.5-1.2
0.5-1.1
0.7
0.6
0.4-1.1
0.4-1.1
1.0
0.8
0.5-2.0
0.4-1.7
Further adjusted
Women (n =• 206)
Men (n = 439)
0.7
1.5
0.3-1.8
0.9-2.8
1.0
1.0
0.8
0.7
0.4-1.7
0.4-1.2
0.2
1.0
0.0-0.6
0.6-1.9
0.5
0.9
0.1-2.3
0.4-2.2
* Unconditional logistic regression models fitted to categories of energy-adjusted residuals of total iron intake (categories defined by
quintiles using all subjects). Subjects were excluded if total (supplemented) iron intake placed them in a higher quintile than did food iron
intake alone. All models stratified on matching variables (see table 2).
t Ranges (iron in mg/day) estimated by entering the study population median caloric intake (1,901 kcal) into the equation: total iron = a°
+ a 1 (kcal) + a.
% Further adjusted using the same potential confounding variables in table 3.
intestinal lumen, increasing polyps risk even if never
absorbed. Therefore, we included iron intake and
plasma ferritin in the same model; odds ratios for both
variables were unchanged, and confidence intervals
widened only slightly (not shown). Plasma ferritin was
only weakly associated with some of the factors
known to influence iron absorption: intakes of total or
food iron, red meat, or alcohol (Pearson r = 0.100.20). It was not associated with other dietary variables examined (e.g., heme intake).
Slowly progressing polyps may predominate in subjects screened for the first time. Hypothetically, a lack
or excess of iron could increase polyp incidence or,
alternatively, could slow the progression of colorectal
polyps to cancer. Therefore, we restricted the cases in
one analysis to those with a previously negative sigmoidoscopy (within the past 10 years). For plasma
ferritin quartiles (83 cases, 420 controls), the odds
ratios (95 percent confidence intervals) from the first
(lowest) to the fourth quartiles were 0.9 (0.5-1.8), 1.0
(referent), 1.3 (0.7-2.5), and 1.2 (0.5-2.5). (See the
"further adjusted" model in table 3 for comparison.)
For iron intake quintiles (100 cases, 420 controls), the
odds ratios from the first (lowest) to the fifth quintiles
were 1.2 (0.5-2.6), 1.0, 1.2 (0.6-2.4), 2.1 (1.1-4.3),
and 1.4 (0.7-3.0). (Compare with the "further adjusted" model for all subjects in table 4.) To summarize, the weak association of low iron (plasma ferritin
or intake) with polyps was largely eliminated, and the
association of high iron and polyps was not.
Am J Epidemiol
Vol. 144, No. 1, 1996
Iron and the Risk of Colorectal Polyps
DISCUSSION
We did not find a strong relation, U-shaped or
otherwise, between iron variables and adenomatous
polyps. A weak association between high plasma ferritin concentrations, high iron intake, and increased
polyps risk was present. In all previous reports, blood
indicators of iron status have been positively associated with colorectal neoplasia (1, 8-10), although
sample sizes were small and results were not statistically significant in some studies (1,9). Serum ferritin
has been measured in only one of these studies: Nelson
and coworkers (8) observed a strong positive ferritinpolyps association, especially for polyps of the rectum
and right colon. The association in our data was also
strongest for rectal polyps (we did not have data on
right colon polyps).
In this study, the ferritin-polyps association became
statistically significant only after excluding subjects
whose ferritin levels may have reflected inflammation
or aging rather than iron stores. Examining NHANES
I data, Yip and Dallman (38) reported evidence of
inflammation (elevated erythrocyte sedimentation
rate) in 24 percent of women and 30 percent of men
60-74 years old, which were two to four times the
percentages in younger age groups. Thus, there could
be an appreciable bias toward no association in any
evaluation of a ferritin-polyps relation in studies not
excluding subjects whose elevated ferritin levels reflected factors other than high iron stores. Because
serum ferritin is considered the best blood measure of
body iron stores over a broad range (25-27), its use
here was reasonable; but additional measures of iron
status and of inflammation would have been useful.
The association between iron intake and polyps appears to support the ferritin-polyps association. However, iron intake odds ratios were dependent on iron
supplement use; there was no association between iron
ingested from food only and polyps risk. Previous
studies also found that increased iron from food was
not associated with increased polyp risk (39, 40).
Unfortunately, these studies did not have data on supplemental iron. Something associated with supplement
use may have been responsible for the present association. However, adjusting for lifestyle-associated factors (e.g., smoking) and excluding subjects who might
have had gastrointestinal bleeding did not alter our
results. It may be that iron promotes carcinogenesis
only when ingested separately from food or in large
single doses. Phytates and other factors present in food
interact with iron, perhaps eliminating carcinogenic
activity (4, 41, 42).
The association in our data between high plasma
ferritin levels and polyps was not as strong as previously reported (8). In discussing our preliminary reAm J Epidemiol
Vol. 144, No. 1, 1996
39
sults (43), Nelson and coworkers (8) suggested that
having controls with adenomas in the right colon, not
detected by sigmoidoscopy, may have masked a strong
ferritin association. Our odds ratios may have been
attenuated by false-negative controls, but not greatly.
Only about 15 percent of individuals with no family
history of colorectal cancer have polyps exclusively in
the right colon (44, 45).
The association observed between low plasma ferritin levels and polyps was very weak and not statistically significant It is still possible that undetected
chronic bleeding was responsible for the association
(46). However, bleeding does not explain the statistically significant association of low iron intake with
polyp prevalence.
Using the lowest category of each iron variable as
the reference category would not have altered our
conclusions. One finds that high plasma ferritin values
are still associated with polyps risk, but the association
no longer achieves statistical significance. That this is
not a chance observation is nevertheless suggested by
the findings of previous studies (1, 8-10). Moreover,
the second lowest category consistently displays an
odds ratio less than 1.0. When the analysis is restricted
to subjects known to have had a previous negative
sigmoidoscopy, this apparent inverted risk disappears,
and risk appears to increase with increasing iron exposure (from ferritin or iron intake).
The present study population was large and consisted of older people who had a sigmoidoscopy free
of charge, usually as part of the routine health screening encouraged at Kaiser (29). This is in contrast to
most studies of colorectal polyps, in which both cases
and controls generally have had gastrointestinal symptoms or other diagnostic evidence of abnormality. The
high recruitment rate of the study minimizes the
chance that results were distorted by selection bias.
Unlike previous studies, iron exposures from food,
from supplements, and in body stores were estimated
concurrently. Also, comprehensive data were collected
and considered during data analysis, including several
different nutritional assays of blood.
However, a potential weakness of the study is that
blood was collected an average of 6 months after
sigmoidoscopy. Although it is possible that subjects
changed lifestyle habits and their plasma ferritin levels
after polyp diagnosis, results were unchanged when
we adjusted for the time elapsed from examination to
blood collection. Because this was a prevalence study
with largely asymptomatic subjects, polyps inclined to
progress quickly to cancer may have been underrepresented relative to slowly developing polyps. (Individuals with cancer were excluded from the study.) If
so, iron exposure levels that were lower than normal
40
Bird et al.
(referent) levels may have been associated with polyps
in this study because a lack of iron prevented adenomas from progressing quickly to cancer (47).
In conclusion, this study found a weak positive
association between plasma ferritin, iron intake, and
colorectal polyps. A possible interpretation is that excess iron increases polyp incidence. If this interpretation proves correct, there are important policy implications. Iron deficiency continues to be a serious
problem in some population groups. However, iron
fortification of foods and iron supplement use are
widespread; and serum ferritin concentrations have
displayed an unexplained increase in NHANES data
over time, especially in men (48). The ferritin values
reported here are higher than those reported in past
population studies (49-51), which seems to support
the NHANES findings. It remains to be determined
whether the serum ferritin increase reflects secular
increases in body iron stores or dietary iron, and
whether either of the latter constitutes a serious health
threat.
ACKNOWLEDGMENTS
This study was supported by research grants from the
National Institutes of Health (CA 42710, CA 49565, CA
51923) and from Carnation Nutritional Products, Glendale,
California.
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