The Identification of Risk Factors in Normal Children in the Development of Arteriosclerosis

12 Pages·2015·0.87 MB·English

Annals of Clinical Laboratory Science^ Vol. 2, No. 5
Copyright © 1972, Institute for Clinical Science
The Identification of Risk Factors in Normal
Children in the Development of
Arteriosclerosis *
ALLAN DRASH, M.D. AND FAY HENGSTENBERG, B.S.
Department of Pediatrics,
University of Pittsburgh School of Medicine and
Childrens Hospital of Pittsburgh,
Pittsburgh, PA 15213
ABSTRACT major differences in the incidence of coro­
nary artery disease in different cultures.11’
Analysis of the lipid concentrations in nor­
mal school children and a selected number of 33,42 a most common observation is that
their parents and siblings documents an inci­ coronary disease increases in incidence as
dence of 1 to 2 percent with familial type II cultures go from more primitive to more
hyperbetalipoproteinemia. Similar incidence is
complex. Changes in dietary habits as well
found in the study of families of children with
as changes in life style accompany this
diabetes mellitus.
Statistical evaluation of the families of chil­ evolution. Major dietary changes, usually
dren with moderate elevations in serum cho­ associated with more complex societies, in­
lesterol concentration (>200 mg per dl), clude an increase in overall caloric intake,
documents a significant increase in the con­ increased ingestion of saturated fats, cho­
centration of cholesterol and total lipids in
lesterol, and refined sugars with a decrease
the parents of these children when compared
in starch intake. There is also the possi­
with a contrast group of comparable age. It
is probable that these individuals are an in­ bility of deficiency of a variety of micro-
creased risk for coronary disease. The screen­ nutrients associated with modern-day
ing of school children may prove to be a processing of food stuffs.8’35’46 The mechan­
valuable approach to the detection of coro-
ization of society leads to decreased re­
nary-prone individuals and may prove an op­
quirements for physical activity, excessive
portunity for effective preventive therapy.
weight gain and obesity. Also, the complex­
Arteriosclerotic coronary artery disease is ity of modem day society probably pro­
a major cause of death and disability in duces increased stress and emotional
our society. The major clinical features of
anxiety.
coronary artery disease, angina pectoris,
In a number of ongoing studies on the
myocardial infarction, and sudden death
epidemiology of heart disease, the follow-
may be the result of a number of disease
processes or etiological factors. Several
Index to Abbreviations
epidemiological studies have documented
FFA — Free Fatty Acids,
PLP —Precipitable Lipoprotein,
4 Supported in part by USPHS Grant #RR-84 LPE — Lipoprotein Electrophoresis, and
and the Renziehausen Fund. Chron — Chronological.
IDENTIFICATION OF BISK FACTORS IN ARTERIOSCLEROSIS 349
ing factors are considered of major impor­ population and to define in greater depth
tance: the concentration of cholesterol and the incidence of hypercholesterolemia.
other lipid components in blood, blood
pressure, body weight, cigarette smoking, Materials and Methods
exercise, emotional stress and genetic fac­
Phase I—School Survey
tors. The relationship between increasing
concentration of blood cholesterol and An investigative medical evaluation of a
coronary disease is well established. The public middle school in an affluent sub­
Framingham study, a prospective analysis urb of Pittsburgh, Pennsylvania was car­
of the various factors which may contribute ried out by the Division of Endocrinology
to heart disease, identifies the serum cho­ and Metabolism of the Children s Hospital
lesterol concentration as the most accurate of Pittsburgh. The school encompassed the
predictor of risk.19’20’21’22’44 Several other traditional sixth, seventh, and eighth grades
studies concur.2’6’9’23’24’32’39 These studies with an age range of 10 to 14 years. The
document an increase in vascular disease parents of the children were predominantly
associated with increasing concentrations in the upper middle or upper income
of cholesterol. While it is not clear that brackets. A large number of the fathers
there is any specifically “safe” blood cho­ were executives.
lesterol level, most investigators have used At the time of the study, there were 612
values below 200 mg per dl to yield the children enrolled in the school and 487
minimal level of vascular disease for our children (255 girls and 232 boys) partici­
culture. In population studies, as the mean pated in some or all phases of the health
cholesterol value increases, there is a linear survey. There were two Jewish, one Orien­
increase in morbidity and mortality from tal, and no black children included in the
coronary artery disease, so that those indi­ study. The following observations were
viduals with blood cholesterol values ex­ made:
ceeding 280 mg per dl have approximately
a four fold greater risk for the develop­ 1. Physical examination which included
ment of coronary disease than do those height, weight, span, blood pressure,
skinfold thickness, and grading of sex­
with cholesterol concentrations below 200
ual maturation according to the cri­
mg per dl, other factors being equal.
teria of Tanner41
The possible genetic aspects of coronary
2. Routine urinalysis
disease and hypercholesterolemia have re­
3. Radiograph of the hand and wrist for
ceived increasing attention with increased
determination of bone age according
research in the field of lipoprotein metabo­
to the criteria of Gruelich and Pyle15
lism.13’34 Familial hypercholesterolemia 4. Fasting venous blood for determina­
(type II or hyperbeta-lipoproteinemia) is tion of glucose, urea, hematocrit,
an autosomal dominant condition with high hemoglobin, growth hormone, FSH,
penetrance, leading to early death from LH, precipitable lipoprotein (PLP),
myocardial infarction.16’25 The relationship FFA and cholesterol.
between this condition in either the hetero­
zygous or homozygous form and the high Lipid Methods
incidence of coronary artery disease in our The methods of lipid analysis were as
society is not clear. follows: the free fatty acids (FFA) were
The present study was undertaken to de­ determined by a minor modification of the
velop norms for the blood lipids in a school cobalt soap method of Novak.80 After ex­
350 DRASH AND HENGSTENBERG
TABLE I
Boyce School Study
Tanner Classification
Females 1 2 3 4 5 Total
Number 21 89 73 54 18 255
Percentage 8 35 28 22 7 100
Mean Chron.
Age (yrs) 11.24 11.84 12.40 12.98 13.07 12.29
Range (yrs) 10.8-12.1 10.7-13.6 10.8-13.9 11.5-13.8 11.0-14.0 10.7-14.0
Height (in) 55.7 57.3 61.1 62.6 62.5 59.8
Weight (lbs) 77 84 100 112 123 97
Skin Fold
(mm) 12.8 12.9 13.0 13.9 18.3 13.5
traction of lipids from one cc of serum or classification of sexual maturation. Tan­
plasma as described by Fillerup and ner I is the rating applied to those children
Mead,12 total lipids were performed by the who were found to be completely preado­
method of Bragdon,1 cholesterol by the lescent on the basis of physical examina­
method of Sperry and Webb38 and lipid tion, while Tanner V refers to those chil­
phosphorus by the method of Dryer.10 dren who have achieved full sexual
Triglycerides were estimated by difference. maturity as assessed by physical character­
The precipitable lipoprotein (PLP) method istics. The distribution of height and
for screening was used as developed in weight in these children fits well within
our laboratory.37 Lipoprotein electrophore­ the accepted range of normality for Ameri­
sis (LPE) was performed according to the can school children.40 The earlier sexual
method of Lees and Hatch27 using a Sudan maturation characteristic of girls, in gen­
Black B dye. eral, is observed in this population. The
boys lag approximately one half year be­
Results hind the girls in rate of sexual maturation.
In tables I and II are presented anthro­ Skinfold thickness is greater in girls and
pometric data (height, weight, and skin­ increases with sexual maturity, while in
fold thickness) of the boys and girls in the boys it remains relatively constant de­
the study, analyzed on the basis of Tanner spite a major increase in body weight
TABLE II
Boyce School Study
Tanner Classification
Males 1 2 3 4 5 Total
Number 37 108 55 24 8 232
Percentage 16 46 24 10 4 100
Mean Chron.
Age (yrs) 11.98 12.07 12.78 13.07 13.49 12.38
Range (yrs) 10.8-14.1 10.7-13.8 11.1-14.2 11.8-14.9 13.2-13.8 10.7-14.9
Height (in) 57.6 59.0 61.25 64.5 67.04 60.2
Weight (lbs) 86 92 103 119 134 98
Skin Fold
(mm) 10.2 12.2 12.0 10.0 10.6 11.6
IDENTIFICATION OF RISK FACTORS IN ARTERIOSCLEROSIS 351
TABLE III
M enarche— Incidence and Age
Tanner Classification
1 2 3 4 5
Total Number 21 89 73 54 18
No Menses 21 86 61 8 1
Menses 0 3 12 46 17
Percent Menses 0 3.4 16.5 85 94
Avg. Age at
_
Menarche (yrs) 12.0 12.4 12.3 11.7
Chron. Age
Pre-Menarche (yrs) 11.3 11.8 12.3 13.1 11.0
associated with achievement of full sexual determination was carried out on all speci­
maturity. mens. This technique was developed in our
In table III is presented the relationship laboratory for the screening of lipoprotein
between the Tanner classification and tim­ abnormalities. Experience with hospitalized
ing of menses in the girls studied. Thirty children established that the “normal
percent of the total group of girls had ex­ range” of PLP for children was from 20
perienced menarche, most of those being to 40 units. Serum specimens with PLP
classified as Tanner IV or V at the time values exceeding 40 units were usually
of examination. Not unexpectedly, none of associated with one or more of the follow­
the children considered preadolescent ing findings: serum cholesterol concentra­
(Tanner I) had started menses. However, tion exceeding 200 mg per dl, serum trigly­
several girls who were very early into ceride estimated to exceed 100 mg per dl,
adolescence as indicated by physical find­ the presence of a heavy beta or heavy pre­
ings had already experienced menarche. beta pattern on electrophoresis (table V).
In table IV is presented, in a diagramatic Of the 441 specimens analyzed, 97 were
form, the handling of the fasting blood found to have PLP values exceeding 40
specimens obtained in the school survey. units. All of these specimens were studied
Blood specimens were available from 414 further for lipoprotein patterns by paper
of the total 487 children examined. PLP lipoprotein electrophoresis (LPE) and
TABLE IV
School Lipid Survey
441
(PLP)
344 97
(PLP <40) (PLP >40)
238
(not further studied)
106 97
Cholesterol LPE Cholesterol LPE
/ I I / / \
104 2 106 64 33 64 30
( <200 mg/dl) ( >200 mg/dl) (OK) (<200 mg/dl) (>200 mg/dl) (OK) (+)
352 DRASH AND HENGSTENBERG
quantitative serum cholesterol determina­
tion. Thirty-three specimens had serum
C0O0 d<M 05* C^0 cholesterol concentration exceeding 200 mg
-H -H -H -H -H per dl and 25 of these had the character­
NNiOO
O00 N(N N C1H5 istic heavy beta band on electrophoresis.
Of the 64 specimens with cholesterol con­
centration below 200 mg per dl but with
increased PLP numbers, 8 were found to
| -H -H | -H | -H
10 have a heavy prebeta pattern on electro­
O LO
tTh- <0M0 phoresis.
Of those 344 specimens with PLP values
less than 40 units, 106 were chosen ran­
CO domly for further analysis by LPE and
■H cholesterol determination, while 238 speci­
TH mens were not studied further. Electropho­
resis was normal in all specimens and only
two specimens were found to have choles­
O(CV1I OilOO NO htH^^ 0 h0m °1h o terol values exceeding 200 mg per dl. If
o> -H -H -H -H -H -H -H a similar cholesterol concentration distri­
Is -s 1"HC0iOU}O5'*i4<Niß
bution occurred in the remaining un­
t ?No NN o0 02 ffl r! N
es analysed specimens, approximately 9 per­
i
ud cent of the total school population would
t
S have had serum cholesterol concentration
~ ifj 00 1-t ui
Lipid SQ45 g-HOU3- lHOO- HK^O- HißO- HWW- H0O0- MH(M exIcne etdaibnlge 2V0I0 ims gp rpeesre ndtle.d a comparison of
ic Mw* I(N> C<NO O 01-0i cholesterol and PLP findings between hos­
r
t
a pitalized controls and the school popula­
i
d
e tion. The mean cholesterol concentration
P
O <N ^
«HMNOO of 170 mg per dl in the school children is
” -H -H -H -H -H -H undoubtedly “too high” because it is
HiOONO-^NOOOh OC?O weighted heavily with the high cholesterol
lO ’—1
Q
cc subjects, while the mean of 157 mg per dl
O
is “too low” because of the removal of
'ö *2 73 these subjects. If all 441 subjects had been
•TS © O h ONNOO ti
o-H-H-H-H-H-H-H cd studied for cholesterol concentration, it is
tel <3 0<5n cCoD bb-- oTofH aCO iß oco<l estimated that the mean value would have
been approximately 165 mg per dl with
8 5 two standard deviations taking the upper
Q. O
• a & S. limit of normal to 210 to 215 mg per dl.
s J^s &
W When comparing the lipid findings be­
s s = CO oj ^ oj
5se. s0i -2 bS0p ¿£°3 ■fgclH3} -$OSPP g..hg .3&£|7 tswureveeny ,t hite wmaasl efso uanndd fthemata ltehse imn ethane svcahluoeosl
S3TO3 %CL £ a-i a§ of cholesterol and PLP were slightly, but
*C _§ 'd
®P &aH 53 not statistically, higher in girls. There were
^^ -copS -cP3o ^©EEuh h.PW h+PHh+ ^l^O hiaUi no significant changes in cholesterol con­
* •«—++ centration with age or level of sexual ma­
turity. Of those 35 children with choles-
IDENTIFICATION OF BISK FACTORS IN ARTERIOSCLEROSIS 353
TABLE VI
Comparison op N ormal Adolescents with Pediatric Hospital Controls
Cholesterol Predpitable
N (mg per dl) N Lipoprotein
Hospital Controls 30 177 ± 6.0 40 28.5 ± 0.8
School Survey 203 170 ± 3.5 441 34.0 ± 0.5
Choi. < 200 mg/dl 168 157 ± 2.0 168 24.9 ± 0.7
Choi. > 200 mg/dl 35 228 ± 6.5 35 46.3 ± 1.2
Values are mean ±SEM.
terol concentrations exceeding 200 mg per studied. All sera were analyzed for the
dl, 25 were female and 10 were male. concentration of cholesterol, total lipid,
Twenty-three of those (16 female and 7 PLP and LPE. The results are presented in
male) had cholesterol values between 200 table VII.
to 220 mg per dl. If rigid criteria had been The mean concentration of cholestreol in
applied to the diagnosis of familial type II the fathers of those children was 248 mg
hyperlipoproteinemia, using cholesterol per dl while the mean concentration in the
concentrations of 235 to 249 mg per dl as mothers was significantly lower at 220 mg
probable and those in excess of 250 mg per dl. It was of interest to note that those
per dl as definite, 9 children qualified in five mothers exceeding 45 years of age had
the former category and 7 in the latter, elevations in total lipid, cholesterol and
giving an incidence of 1.5 to 2 percent of PLP significantly higher than the total
this normal school population who met the group of mothers analyzed together. The
cholesterol and LPE criteria for type II concentration of total lipid and cholesterol
hyperlipoproteinemia. was slightly, but not statistically, higher in
the female siblings than in the male sib­
Phase II—Family Studies in Children lings.
with Hypercholesterolemia In the families of the 13 index children
The families of the 35 children who had with serum cholesterol concentration ex­
a serum cholesterol concentration exceed­ ceeding 220 mg per dl, 10 parents (8
ing 200 mg per dl were contacted and fathers and 2 mothers) had cholesterol
were requested to report to the hospital values exceeding 250 mg per dl. In only
for fasting blood lipid studies. Of the 35 one family did both the mother and father
families, 27 agreed to participate. In all, have such elevations. LPE in all of the 10
23 fathers, 23 mothers and 78 siblings were parents had a heavy beta band which was
TABLE VII
Lipid Studies— High Cholesterol Families
Total Total
Mean Lipid Cholesterol PLP
N Age (mg/dl) (mg/dl) Units
Fathers 23 43.9 783 ± 48 248 ± 7 66 ±3
Mothers 23 41.8 650 ± 25 220 ± 10 50 ±3
Mothers > 45 Yrs 5 53 715 ± 85 261 ± 41 61
Male Siblings 36 12.9 556 ± 14 178 ±4 41 ± 1
Female Siblings 42 13.3 580 ± 17 188 ±4 41 ± 1
Values are mean ±SEM.
354 DBASH AND HENGSTENBERG
consistent with type II hyperbeta-lipo- diabetes mellitus and was under treatment
proteinemia. with insulin.
In the families of the 14 index children
III—
with cholesterol concentration between 200 Phase Lipid Studies in Families of
to 219 mg per dl, 6 parents ( 4 fathers and D iabetic Children
2 mothers) had serum cholesterol values The families of 28 children with insulin-
exceeding 250 mg per dl. All had a heavy requiring diabetes mellitus followed at
beta pattern on electrophoresis. In no fam­ Children’s Hospital of Pittsburgh were eval­
ily did both the father and the mother have uated for blood lipid concentrations. Fast­
elevated values. ing venous specimens were obtained and
The cholesterol distribution in the total analyzed for total lipid, cholesterol, PLP,
group of 105 children studied (27 index and LPE. In all, 28 fathers, 28 mothers and
cases and 78 siblings) revealed that 62 a total of 53 siblings were studied. The
had serum cholesterol values under 200 children with diabetes were excluded from
mg per dl, 27 from 200 to 234 mg per dl, the analysis. The results are presented in
9 from 235 to 250 mg per dl, and 7 ex­ table VIII. The mean cholesterol concen­
ceeded 250 mg per dl. LPE was abnormal tration in the fathers was 210 mg per dl
with a heavy beta pattern in 20 of the and 183 mg per dl in the mothers. In the
children, all of whom had associated ele­ seven women exceeding 45 years of age,
vations in cholesterol concentration. the mean cholesterol was 193 mg per dl.
Detailed medical histories and physical The overall distribution of serum choles­
examinations were not available on the terol values in the 53 siblings of children
parents in the 27 families. However, one with insulin-requiring diabetes mellitus
father was known to have died from myo­ was 46 below 200 mg per dl, 5 between
cardial infarction while another had a myo­ 200 to 220 mg per dl and 2 above 250 mg
cardial infarction prior to 40 years of age. per dl. Eight children had a heavy beta
Four parents (2 fathers and 2 mothers) pattern on electrophoresis. This included
were previously known to have had hyper­ the seven children with cholesterol exceed­
cholesterolemia and were on therapy for ing 200 mg per dl and the child with a
this condition through their family physi­ serum value of 190 mg per dl.
cian. Two of them had xanthoma. In one There were eight parents (6 males and
family, several members were known to 2 females) with cholesterol values between
have hypertension while in two other fam­ 230 to 305 mg per dl, all of whom had
ilies, either the mother or father was heavy beta patterns. In only three inci­
known to have hypertension. The mother dences were the “high cholesterol” parents
of one of the children was known to have (father or mother) and “high cholesterol”
TABLE VIII
Lipid Studies— Diabetic Families
Mean Age Total Lipid Total Chalest. PLP
N (yrs) (mg/dl) (mg/dl) Units
Fathers 28 41.7 670 ± 30 210 ± 8.5 60.9 ± 2.8
Mothers 28 39.5 535 ± 28 183 i 6.1 44.0 ± 2.0
Mothers > 45 Yrs 7 49.7 537 ± 42 193 ± 14 42.0 ± 2.8
Siblings 53 13.2 494 ± 20 160 ± 7 39.2 db 1.3
Diabetic 23 10.8 513 ± 60 180 ± 11 43 ± 2.5
Values are Mean ±SEM.
IDENTIFICATION OF BISK FACTORS IN ARTERIOSCLEROSIS 355
HIGH CHOLESTEROL FAM.
900 - DIABETIC FAM
•o 800
Figure 1. Statistical
comparisons of the con­
centrations of total lipid </> 700
and cholesterol in family
members from the “high
. 600
cholesterol” and “dia­
betic families.” Values
are mean ± SEM. t- 500 -
400 -
SIBS MOTHERS FATHERS SIBS MOTHERS FATHERS
children found in the same families. There been statistically compared with the fam­
was one classic example of type II hyper­ ilies of the “high cholesterol” index chil­
lipoproteinemia in a father-son combina­ dren. This phase of the project has not
tion and a possible type II father-daughter yet been completed. A somewhat less
combination. The highest cholesterol value ideal contrast group, the families of chil­
observed in a child, 290 mg per dl, oc­ dren with insulin-requiring diabetes mel-
curred in a girl whose parents or siblings litus, have been utilized. Because of the
did not have hypercholesterolemia. known problems of lipid metabolism in
A number of parents and children had persons with diabetes mellitus and the
moderately heavy pre-beta bands. None of high rate of genetic transmission of dia­
these were associated with hypercholes­ betes mellitus, one might assume that
terolemia. In one family, the mother and cholesterol and total lipid concentrations
four children had a distinctly abnormal in such families would be higher than the
electrophoretic pattern with a “split” beta general population. This, indeed, may be
or possible double pre-beta band. Total true.
lipids and cholesterol concentration in all Statistical comparison between the two
of these were well within the normal range. family groups was made by comparison of
the means, utilizing the student T test.
Phase IV—S ta tistical C om parison Be­ Individual comparative analysis was car­
tw een “H igh C h olesterol F am ilies” and ried out for the fathers, mothers and
“D iabetic F am ilies” siblings. The total lipid and cholesterol
One of the major objectives of this study concentrations are compared in figure 1.
was to ascertain whether or not hypercho­ In each comparison, the “high cholesterol
lesterolemia in the child was regularly as­ family” individuals (siblings and parents)
sociated with hypercholesterolemia in one were found to have statistically higher mean
or both parents. Ideally, family studies values for total lipids and cholesterol. It is
for blood lipid determination should have of interest to note that there was an in­
been carried out in families derived from crease in cholesterol and total lipids with
the school survey study from index children increasing age and that males had higher
found to have cholesterol values below 200 values than females in this analysis.
mg per dl. These families then would have In figure 2 is presented, in similar form,
356 DHASH AND HENGSTENBERG
Figure 2. Statistical
comparisons of the PLP
concentration and lipo­
protein abnormalities in
family members from the
“high cholesterol” and
“diabetic families.”
the comparison for PLP and LPE analysis. opinion that the concentration of choles­
The mean PLP values were statistically terol and other blood lipid components rise
higher for the siblings and mothers in the gradually from early infancy through old
“high cholesterol” families and higher, but age. Several recent studies clarify the
not reaching statistical significance, for the situation during the childhood years.
fathers. The analysis of LPE is pre­ Glueck et al determined the concentration
sented as percentage of abnormal results in of cholesterol in cord blood in 1,800 con­
each subgroup, considering as abnormal secutive births14 and reported that the
only those electrophoreses with a heavy mean concentration was 63.8 ± 18.7 mg per
beta and/or heavy pre-beta pattern. The dl. Using 100 mg per dl as the upper limit of
total number of LPE abnormalities were normal, 3.5 percent of the total group of in­
approximately twice as common in the fants studied were found to be elevated
high cholesterol families. Eighty percent above this level. By evaluating the parents
of those abnormalities were a heavy beta of those children with elevated cholesterol
band. Of the LPE abnormalities in the values, approximately 1 percent of the total
diabetic families, half of the abnormalities group were found to have familial type II
were a heavy beta pattern and half were hyperbeta-lipoproteinemia. The clinical sig­
heavy pre-beta patterns. nificance of the cholesterol elevations in
the remaining 2.5 percent is not clear but
Discussion may represent simply the upper extreme of
The range of “normality” for the con­ the normal distribution. However, it is
centration of cholesterol in serum or, more possible that “hypercholesterolemia” in
importantly, the optimal range for minimal these infants is the result of a variety of
incidence of coronary artery disease has factors unrelated to familial hypercholes­
not been definitely established.45 It is pos­ terolemia but may represent a tendency
sible, if not probable, that the variously re­ toward early development of vascular dis­
ported “normal ranges” were derived not ease. Expansion of such studies and long­
from a uniform population with a Gaussian term followup on such infants should re­
distribution but from two or more dis­ sult in important new information.
tinctly different populations. Owen et al reported on cholesterol
In the past, it has been the general analysis of 1942 pre-school children from
IDENTIFICATION OF RISK FACTORS IN ARTERIOSCLEROSIS 357
I to 6 years of age.31 The mean concentra­ adolescents.4’17 On epidemiological, if not
tion was 159 mg per dl for the 1 to 2 year statistical, grounds this may make good
old group and 165 ± 25 mg per dl (± stan­ sense as several earlier studies used this
dard deviation) for the 2 to 6 year old chil­ level as the concentration over which there
dren. Our own experience, reported here, was an increasing incidence of coronary
for the 10 to 14 year age group was ex­ disease with rising cholesterol concentra­
tremely similar; our unreported experience tion.
in a much smaller group of 3 to 10 year old A number of investigators have docu­
chlidren would concur that there is little mented the trend toward increasing cho­
or no mean change in the cholesterol con­ lesterol and triglyceride concentration with
centration from 2 to 14 years and no statis­ increasing age.43 In a 12 year followup of
tically significant sex differences. 400 West Point graduates, the mean cho­
Clarke et al reported similar findings in lesterol concentration rose from 183 mg
885 Vermont junior and senior high school per dl at 19.5 years to 249 mg per dl at
students varying from 12 to 18 years of 31.5 years.3 Danowski et al reported a rise
age.4 A mean cholesterol concentration of in mean cholesterol concentration from 210
approximately 166 ± 30 mg per dl (S.D.) mg per dl in women averaging 33 years
was reported with no significant differences of age to approximately 260 mg per dl in
for age or sex. women of 60 years of age.5 Frederickson
Frederickson et al, on a much smaller
et al reported the upper limit of “normar
sample, indicated that the mean cholesterol
to rise from 230 mg per dl in childhood
concentration for the age group from birth
to 330 mg per dl at 60 years of age.13 The
to 19 years was 175 ± 33 mg per dl.13
majority of individuals afflicted with coro­
The cumulative evidence would seem to nary disease are found within these ‘nor­
indicate that the cholesterol concentration mal” limits.26 If there is an etiological rela­
in the neonate is approximately 65 mg per tionship between the concentration of
dl with an upper limit of 100 mg per dl. cholesterol in peripheral blood and the
During the first year of life there is a 2 development of arteriosclerotic disease, a
to 2.5 fold increase in concentration. By redefinition of normality is in order.
approximately 2 years of age, a mean con­
Ibraham et al demonstrated that adults at
centration of 165 mg per dl is achieved
risk may be identified by a study of school
and remains stable until early adult life.
children, using a multifactorial analysis in­
If two standard deviations above the
cluding serum cholesterol and uric acid
mean is to be considered the upper limit of
concentration, blood pressure, and body
the normal range, cholesterol values ex­
weight.18 Our studies, utilizing cholesterol
ceeding 225 mg per dl probably should be
concentration alone, lead to the detection
considered abnormal in children and ado­
of approximately 2 percent of the school
lescents. Such criteria are probably appro­
population with familial type II hyper­
priate if the objective is detection of those
lipoproteinemia. In addition, evaluation of
patients with familial hypercholesterolemia,
the families of those children with serum
most of whom will have cholesterol values
cholesterol values greater than 200 mg per
exceeding 235 mg per dl. Owen s report of
dl results in the detection of a group of
approximately 2 percent incidence of type
adults with cholesterol and total lipid con­
II hyperlipoproteinemia in a preschool pop­
centration significantly higher than those
ulation31 is quite similar to our own ex­
perience reported here. in a contrast group of adults of the same
However, several workers have sug­ mean age, drawn from chlidren with dia­
gested that 200 mg per dl be considered the betes mellitus.
upper limits of normal for children and Whether or not the parents and children