Pediatricians are diagnosing an increasing number of lipid disorders in their patients. Because many
Triglyceride
and
High-Density
Lipoprotein
Cholesterol:
Predicting
Disorders
in Parents
From
Their
Children
Sheldon M. Polonsky, MD*; Loretta A. Simbartl, MS; and Dennis L. Sprecher, MD*
ABSTRACT. Objective. To determine whether lipid
disorders can be predicted in parents after such disorders are identified initially in their children. Although this relation has been well determined for children with high cholesterol or low-density lipoprotein cholesterol (LDL-C), it has not been as well described for disorders involving triglycerides (TG) or high-density lipoprotein cholesterol (HDL-C), or their interaction with LDL-C.
Methods. Serum lipid values were obtained from 232
families in the comparison population of a large genetics study. Subjects were classified into four groups based on their lipid status: 1) isolated LDL-C disorder, defined by a high LDL-C level and normal TG and HDL-C levels; 2) isolated TGIHDL-C disorder, defined by either high TG, low HDL-C, or both, and normal LDL-C; 3) combined disorder, defined by high LDL-C in addition to either high TG, low HDL-C, or both; and 4) normal, defined by the absence of any of the above disorders. The frequen-cies of these disorders were noted in both parents and children, and logistic regression analyses were conducted to determine whether the presence of these disorders in at least one child in the family could predict similar disorders in the parents.
Results. Children with isolated LDL-C or TGIHDL-C disorder were more likely to have parents with the same disorder as themselves (P = .002 and P = .04,
respective-ly). Children with the combined disorder were more likely to have parents with any lipid disorder (P = .009),
but especially isolated LDL-C (P = .002) and isolated
TG/HDL-C (P = .05).
Conclusion. A classification scheme defining disor-ders of TG and HDL-C, LDL-C, or a combination can be
useful for predicting lipid disorders in parents after such
disorders are identified initially in their children.
Pediatrics 199494:824-831; children, cholesterol,
low-den-sity lipoprotein cholesterol, triglycerides, high-density
li-poprotein cholesterol, lipid disorders.
pediatricians are screening all their patients for
cho-lesterol, and because children often receive more consistent preventive medical care than adults, many children identified with lipid disorders may have parents whose lipid status is questionable or
un-known. Evidence indicates that when the children’s
lipid disorder involves high total cholesterol or low-density lipoprotein cholesterol (LDL-C) levels, the parents are also likely to have high cholesterol as well as an increased incidence of coronary heart dis-ease.12 Thus, knowledge of their children’s high cho-lesterol levels should be a strong incentive for
par-ents to have their own cholesterol screened.
However, when the children’s lipid disorder
in-volves high triglyceride (TG) or low high-density lipoprotein cholesterol (HDL-C) levels, this situation becomes more complicated. Although high TG levels in parents have been reported to be more likely when high TG is found in their children,3 a similar
associ-ation has not been well described for the wider
spec-trum of lipid disorders incorporating both TG and
HDL-C, as well as their interaction with LDL-C. To
help describe this association more comprehensively, we used a combination classification scheme, con-ceptualized before,4’ to define the disorders of TG and HDL-C, LDL-C, or a combination. To determine whether such a classification scheme could be useful for predicting lipid disorders in parents after such disorders are identified initially in their children, we
analyzed lipid values from 232 families in the
randomly recruited comparison population of a large genetics study.6
METHODS ABBREVIA11ONS. LDL-C, low-density lipoprotein cholesterol;
TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; TG/HDL-C, triglycerides and/or high-density lipoprotein
choles-terol; LRC, National Institutes of Health Lipid Research Clinics.
From the ‘Department of Pediatrics, Children’s Hospital Medical Center,
University of Cincinnati College of Medicine, and the Department of Medicine, Lipid Research Clinic, University Hospital, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Received for publication Dec 22, 1993; accepted Mar 25, 1994.
Reprint requests to(D.LS) Lipid Research Division, Department ofInternal
Medicine, University of Cincinnati, 231 Bethesda Avenue, Cincinnati, OH
45267-0540.
PEDIATRICS (ISSN 0031 4005). Copyright © 1994 by the American Acad-emy of Pediatrics.
Subjects
Lipid levels from families in the comparison arm of the Cin-cinnati Myocardial Infarction and Hormone Study were analyzed
for this study. White male subjects were recruited by
advertise-ment and supermarket sign-ups in 1988 and 1989 from the Cm-cinnati, Ohio metropolitan area. The availabifity of aspouse and at least one natural child living in the household was required for
inclusion in the study. Additional natural children were included
without limit, as long as at least one child was still living in the
home. For the current study, children were excluded only if their complete lipid profiles were not recorded; entire families were excluded if complete lipid profiles were not recorded for both parents and at least one child. As aresult, one entire family and 20 children from various other families were excluded from the analysis. In all, we studied 232 remaining families with 497 chil-dren, a mean of 2.1 children per family (range, I to 6). The mean
ages of these subjects are shown in Table 1. Among the children,
NORMAL
TABLE 1. Age and Serum Lipid Levels of Subjects*
Subjects Age, y Total Cholesterol, mg/dL LDL-C, mg/dL HDL-C,
mg/dL
TG, mg/dL
Fathers 44±7
(29-66)
213 ±40 [2041
(109-355)
140±36 [135]
(43-269)
48± 12 [43]
(20-94)
129 ± 82 [1231
(24-753)
Mothers 42 ±
6
(28-58)
201 ±37 [1931
(118-308)
121 ± 32 [122] (54-212)
59 ± 15 [561 (15-106)
102 ± 77 [881 (25-638)
Sons 14±4
(4-27)
164±30 [160]
(95-293)
98±26 [94J
(43-233)
51± 11[551
(29-81)
78 ±41 [581
(22-272) Daughters 14 ± 5
(6-26)
171 ± 25 [159] (112-287)
100 ±24 [941
(43-224)
57 ± I 1 [521
(29-88)
73 ± 48 [68]
(27-615)
* Data are presented as mean ± standard deviation (range) for 232 fathers and mothers each, 279 sons, and 218 daughters. Data in brackets
are the Lipid Research Clinic’s (LRC) 50th-percentile levels for subjects of the same gender and mean age. For mothers and fathers, LRC
levels for 40- to 44-year-olds are shown; for sons and daughters, LRC levels for 10- to 14-year-olds are used. Abbreviations: LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides.
parents were excluded from the analysis because they were be-lieved to be representative of the general population.
Lipid, Weight, and Height Measurements
Serum lipid profiles were obtained from subjects after a
re-ported 12-hour fast, following the guidelines of the National
In-stitutes of Health Lipid Research Clinics (LRC).7 Total cholesterol,
HDL-C, and TG levels from all subjects were measured
enzymat-ically in the same laboratory standardized by the Centers for Disease Control. We calculated LDL-C using the Fnedewald equa-tion [total cholesterol - (HDL-C) - (TG/5)].8 Because this equation
is considered accurate only when TG levels are less than 400 mg/dL, LDL-.C was not recorded in subjects whose TG levels were above this cutoff. The mean levels of total cholesterol, LDL-C,
HDL-C, and TG for all subjects were comparable to the
50th-percentile population levels reported in the Lipid Research Clinics
Population Studies Data Book7 for subjects of the same gender and mean age.
Height and weight were measured twice in all subjects to the nearest tenth of a centimeter and tenth of a kilogram, respectively.
A third measurement was taken if the first two differed by more
than 0.5 cm or 0.3 kg. An average of the two or three
measure-ments was used in data analysis. For each subject, the Quetelet index was calculated to estimate the degree to which the subjects
were overweight: [weight (kg)/height2 (cm2)] x 1000.
Classification of Lipid Disorders
Subjects were classified into four categories based on their lipid levels: isolated LDL-C, isolated TG/HDL-C, combined, or normal (Fig 1). Subjects with isolated LDL-C had high LDL-C as their only abnormality. Those with isolated TG/HDL-C had either high TG
or low HDL-C, or both, but normal LDL-C. Combined patients
had high LDL-C in addition to high TG, low HDL-C, or both.
Normal patients had none of these abnormalities. Subjects with
TG greater than 400 mg/dL were classified automatically as
hay-ing isolated TG/HDL-C because of the inaccuracy of their LDL-C
values. High TG and low HDL-C were linked in this classification scheme because of the close association between the two in both normal and hyperlipidemic patients.9”#{176}This scheme is a
modifi-cation of one that we proposed previously to classify lipid disor-ders in children;4 a similar approach to classification has been proposed in adults.5
High LDL-C and TG were defined as greater than the 90th
percentile for age and gender, and low HDL-C as less than the
10th percentile, using percentiles reported in the LRC data book.7
This source also was used to determine percentiles for Quetelet
indices. Although percentiles were not reported for subjects younger than 5 years of age in this source, we applied the data from the 5- to 9-year-old group to the 4-year-olds in our study.
Data Analysis
The frequency of each of the lipid disorders in fathers, mothers,
sons, and daughters was calculated, and a test was performed
to identify any differences among the three groups. For the
iso-lated TG/HDL-C and combined disorders, a breakdown of the
specific lipids involved was also examined and compared between
these groups; because of smaller sample sizes, Fisher’s exact test was calculated rather than . Next, as a crude estimate of the
association between parents and children, we determined the percentage of children with each of the lipid disorders who also
had a parent with the same or a different disorder. Because this
estimation could be biased toward larger families having many affected children, we developed another analysis in which the family was considered as a unit and the presence of a disorder in one or more children was treated equally. Four independent
lo-gistic regressions were performed in this latter analysis. In three of
these regressions, the dependent variable was the presence of one
specific disorder in either or both parents (isolated LDL-C,
iso-lated TG/HDL-C, or combined); in the last, the presence of any
disorder in either or both parents was the dependent variable. In
all the regressions, the three independent variables of interest were the presence of each of the three specific disorders in one or
Fig 1. Venn diagram showing classifi-cation of lipid disorders based on low-density lipoprotein cholesterol (LDL-C),
Fig 2. Frequency of lipid disorders in
fathers, mothers, sons, and daughters.
Abbreviations: LDL-C, low-density
li-poprotein cholesterol; TG/HDL-C,
triglycerides and/or high-density lipoprotein cholesterol.
Percent
Aft. cted
35
30
25.
20.
15.
10.
5.
0.
Any Disorder Isolated LDL-C Isolated TGIHDL-C Combined
more children of the family. Covariates included in the model
were the mean age of the parents, the mean age of the children,
and the number of children in the family. The regressions were
run using both forward and backward stepwise selection strate-gies, keeping and eliminating variables at the P < .05 level. The
final regression model obtained was evaluated further by adding
and subtracting one variable each and exchanging each variable
for an unused variable to see whether any other equally valid
models could be found.
Finally, to evaluate which family members were overweight, we used three cutoffs of overweight status based on the subjects’ age- and gender-standardized Quetelet indices from LRC data: the
90th, 75th, and 50th percentiles. The numbers of subjects at or
above these cutoffs were compared among all categories of the
lipid classification and between parents and children, using x analysis. These three cutoffs were used instead of simply the 90th
percentile to demonstrate any progression of lipid-disorder
ire-quency in mildly, moderately, and extremely obese patients. All analyses were performed using the SAS statistical system
(version 6.06) on an Amdahl mainframe computer. Chi-square
tests were performed using the PROC FREQ procedure and the
logistic regression using PROC LOGISTIC.
Classification
RESULTS
Differences were noted in the frequency of lipid
disorders among family members, particularly
be-tween Sons and daughters (Fig 2). Sons were more
likely to have any lipid abnormality than daughters
(33% versus 19%, P = .001), especially isolated
TG/HDL-C and the combined disorder (isolated
TG/HDL-C: 19% versus 8%, P < .001; combined: 5%
versus 1%, P = .013). The frequency of isolated LDL-C
disorder did not differ between sons and daughters at
the P < .05 level. No significant differences in the
fre-quency of lipid disorders were found between mothers
and fathers. Although children as a group had a
some-what higher percentage of lipid disorders than their parents (27% versus 22%), and isolated TG/HDL-C in
particular (14% versus 10%), these differences were not
significant at the P < .05 level.
Although children were similar to their parents in the overall frequency of the isolated TG/HDL-C dis-order, they differed by the specific lipids affected (TG, HDL-C, or both). Among 119 subjects with the
isolated TG/HDL-C disorder, children were more
likely to have low HDL-C levels than their parents
(24% versus 10%) and were less than half as likely to
have both low HDL-C and high IC levels
(17% versus 47%). These differences were significant
at P < .001 . In contrast, among the 29 subjects with
the combined disorder, no significant differences at
the P < .05 level were seen between children and
their parents in the percentages who had high TG
alone, low HDL-C alone, or both in combination with high LDL-C. In both of these analyses, no differences were found between sons and daughters or between mothers and fathers.
Parent/Child Relations
Children classified as normal were least likely to have a parent with a disorder (33%; Fig 3A), followed
by those classified as having isolated TG/HDL-C
(42%), isolated LDL-C (53%), and combined (71%)
disorders. Children classified as normal also were very unlikely to have both parents with a disorder
(4%); those classified as having combined disorder
were the most likely (35%). Overall, 49% of children who had a lipid disorder also had at least one parent with a lipid disorder.
Sons and daughters who were identified to have
lipid disorders were equally likely to have parents with disorders. Of the children with lipid disorders,
44 of 92 sons (48%) and 20 of 42 daughters (48%) had one or both parents with disorders. Among children with lipid disorders who had only one involved parent, 17 of 27 sons (63%) and 11 of 15 daughters (73%) had affected fathers.
Families with two or more children with lipid disorders were over twice as likely to have parents with lipid disorders than were families with only one
involved child. Of families with two or more
in-volved children, 69% (18 of 26 families) had one or both parents with a disorder, compared to 33% (25 of 75) of families with only one involved child.
Children classified as having isolated TG/HDL-C or isolated LDL-C were most likely to have at least one parent who had the same disorder as themselves (32% and 36%, respectively; Figure 3B. Note that because either one of two parents, or both, could have a lipid disorder, percentages in this figure may be overlapping). Children classified as having com-bined disorder were most likely to have a parent
with isolated TG/HDL-C (41%) or isolated LDL-C
(47%), and relatively less likely to have parents with the same (combined) disorder (6%).
A
Normal Isolated TGIHDL-C Isolated LDL-C Combined
(n=363) (n=72) (n=45) (n=17)
P e
C
e n t
50
40
30
20
10
0
Classification of Children
Normal Isolated TG/HDL-C Isolated LDL-C Combined
(n=363) (n=72) (n=45) (n=17)
80
Fig 3. A, Percentages of children, by
lipid classification, whose parents have any lipid disorder. B, Percentages of
children, by lipid classification, whose
parents have specific lipid disorders. Abbreviations. TG/HDL-C,
triglycer-ides and/or high-density lipopro-tein cholesterol; LDL-C, low-density lipoprotein cholesterol.
P
C
C
C
n
t
70
60
50
40.
30
20
10 .
0.
one parent with a disorder
U Both parents with a disorder
B
D Isolated TGIHDL-C in at least one parentU Isolated LDL-C in at least one parent
Conthined in at least one parent
presence of isolated TG/HDL-C in at least one child
of the family predicted isolated TG/HDL-C in at
least one parent (P = .04). Similarly, the presence of
isolated LDL-C in at least one child was predictive of isolated LDL-C in at least one parent (P = .002). In
contrast, the presence of the combined disorder in at least one child predicted isolated LDL-C or isolated
TG/HDL-C in at least one parent (P = .002 and P =
.05, respectively), or any disorder in general (P =
.009), but did not predict the combined disorder
itself. The results of the forward and backward step-wise regression strategies were identical for all
anal-yses. In one analysis (with isolated TG/HDL-C in
parents as the dependent variable), the presence of
Classification of Children
the combined disorder in children was added to the final model because it became significant (at P =
.0489) when added but was not included in either
stepwise strategy. The only covariate that was sig-nificant was mean parental age, which was related to
isolated LDL-C (P = .04) and isolated TG/HDL-C
(P = .01) in the parents. This covariate was kept in
these models to adjust the other variables for its effect. Note that the mean age of the children in the family and the number of children were not signifi-cant in any analyses.
TABLE 2. Lipid Disorders in Children That Were Predictive of Parental Disorders*
Children’s Disorder #{149}Parents’ Disorder
P
Isolated TG/HDL-C Isolated LDL-C Combined
Isolated TG/HDL-C Isolated LDL-C Any abnormality Isolated LDL-C Isolated TG/HDL-C
.04
.002 .009 .002 .05t
* Results of logistic regression linking lipid disorders in at least one child of the family with the presence of a lipid disorder in one or both parents. Only those independent variables remaining in
the final model are shown. Abbreviations: TG/HDL-C, triglycer-ides and/or high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
t Added to the final model (not induded in stepwise strategies but
significant at
P
= .0489 when added).Specifically, three tests were considered: 1) isolated
LDL-C in at least one parent was considered a
pos-itive outcome, and either isolated LDL-C or
com-bined disorder in at least one child was a positive test; 2) isolated TG/HDL-C in at least one parent was a positive outcome, and either isolated TG/HDL-C
or combined disorder in at least one child was a
positive test; and 3) any disorder in at least one parent was a positive test, and combined disorder in at least one child was a positive test. The combined disorder was included in all three tests because it predicted isolated LDL-C and isolated TG/HDL-C in the parents, as well as any disorder in general. Over-all, the tests had a higher specificity than sensitivity, but a higher negative than positive predictive value. Influence of Weight
The largest proportion of subjects who were over-weight at or above any cutoff (50th, 75th, or 90th percentile) was found in the combined classification
group, followed by isolated TG/HDL-C, isolated
LDL-C, and normal (Fig 4). The differences among groups were statistically significant at each cutoff (P < .01,
x2
analysis).Overall, children and parents were similar in the
proportion who were overweight, with no
differ-ences at any cutoff at the P < .05 level of significance. Children and parents also showed some similarities
when weight was considered among the various
lipid classification groups (Table 4). Within the iso-lated TG/HDL-C group, both children and parents were significantly more likely to be overweight, re-gardless of cutoff, than their counterparts in the
nor-ma! group. Within the isolated LDL-C group, both
parents and children were only slightly more likely to be overweight than normal subjects, if at all, and
this finding was only significant at the P < .05 level for parents who were above the 50th percentile cut-off. However, some differences were seen between children and parents in this analysis. Unlike parents,
children in the combined group were significantly
more likely to be overweight than their normal
coun-terparts at any cutoff. Furthermore, among children,
the highest proportion of overweight subjects at any cutoff was found in the combined classification; among parents, the highest proportion was found in the TG/HDL-C classification.
DISCUSSION
Our study suggests that a classification scheme
defining disorders of TG and HDL-C, LDL-C, or a
combination can predict lipid disorders in parents
after such disorders are identified initially in their
children. In particular, children with isolated LDL-C
or TG/HDL-C disorders are more likely to have
parents with the same disorder as themselves,
whereas children with the combined disorder are
more likely to have parents with any lipid disorder,
but especially isolated LDL-C and isolated TG/
HDL-C. Our study also suggests that similarities in overweight status between parents and children may be associated with similarities in lipid disorders; spe-cifically, both children and parents with the isolated
TG/HDL-C disorder were more likely to be
overweight than normal subjects.
The combination of TG and HDL-C, with or without
LDL-C, is a unique aspect of our study. Data from the
LRC family study1 demonstrated an increasing per-centage of hypertriglyceridemic offspring in assoda-tion with increasing severity of hypertriglyceridemia in probands. Although higher TG levels have been
re-ported in parents of children with high TG,3 this
asso-dation was not extended to indude HDL-C levels. In another study, parents of 37 children who were
re-ferred to a spedalty clinic for hyperlipidemia had a
high prevalence of unrecognized or untreated
hyper-lipidemia2; although LDL-C, TG, and HDL-C levels
were all considered in this study, these lipids were not combined into specific dinical entities. Nevertheless, there is evidence for an assodation between high TG and low HDL-C as a distinct familial disorder.13 In our study subjects, isolated TG/HDL-C was the most com-mon lipid disorder, and occurred more frequently in parents whose children had the same disorder. Of note, children with this disorder manifested low HDL-C
1ev-els alone more frequently than their parents. These
children would have been missed had only TG levels been considered in the analysis, yet their parents were still at risk for significant TG and HDL-C disorders.
The clinical importance of these TG/HDL-C disor-ders, however, is controversial. For example, the study noted above, which linked high TG in children to high parental TG,3 failed to show excess coronary artery mortality in family members of children with high TG. In general, the epidemiologic evidence pointing to high TG as an independent risk factor for coronary artery disease is inconclusive.14 Neverthe-less, low HDL-C has been well established as a risk factor for coronary artery disease,’5 and high TG may act synergistically with low HDL-C to increase this risk.’6 In one recent study, the combination of high TG and low HDL-C in families was identified as one of the most common familial lipid abnormalities in patients with premature coronary artery disease.5 For these reasons, identification of patients with the potential for the isolated TG/HDL-C disorder
seems to be a worthwhile goal for counseling and
treatment.
The combination of TG or HDL-C and LDL-C in
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0% 1
I
a
ott percentile or aboveU 75th-89th percentile
D SOth-74th percentile
0 <50th percentile
I
Isolated TGIHDL-C
(n=119)
TABLE 3. Test Characteristics for Predicting Adult Disorders From Disorders in Children*
Positive Outcome
-Positive Test Sensitivity Specificity Positive
Predictive
Value
Negative
Predictive
Value
Isolated LDL-C in at least one parent Isolated LDL-C or combined in one or
more children
45% 84% 35% 89%
Isolated TG/HDL-C in at least one parent Isolated TG/HDL-C or combined in one
or more children
42% 74% 28% 84%
Any disorder in at least one parent Combined in one or more children 13% 97% 69% 67%
* Abbreviations: LDL-C, low-density lipoprotein cholesterol; TG/HDL-C, triglycerides and/or high-density lipoprotemn cholesterol.
Fig 4. Proportions of overweight
sub-jects (parents and children combined), by Quetelet index, compared among lipid-disorder classifications. All per-centiles were age- and gender-stan-dardized based on Lipid Research
Clinics data. Abbreviations: LDL-C, low-density lipoprotein cholesterol; TG/HDL-C, triglycerides and/or high-density lipoprotein cholesterol.
Normal Isolated
(n=727) LDL-C
(n=86)
Combined (n=29)
TABLE 4. Percentages of Overw Children) by Lipid Classification*
eight Subjects ( Parents and
Lipid Classification Quetelet Index
5Oth
Percentile
75th
Percentile
9Oth
Percentile
Normal
Children (n = 363) 45% 22% 8%
Parents (n = 364) 50% 27% 9%
Isolated LDL-C
Children (n = 45) 56% 31 % 7%
Parents (n = 41) 68%t 37% 17% Isolated TG/HDL-C
Children (n = 72) 65% 43% 24%
Parents (n = 47) 81% 57% 38%
Combined
Children (n = 17) 94%:1: 82% 47%
Parents (n = 12) 67% 42% 25%
* All percentiles are age- and gender-standardized based on Lipid
Research Clinics data. Abbreviations: LDL-C, low-density
lipopro-tein cholesterol, TG/HDL-C, triglycerides and/or high-density lipoprotein cholesterol.
1Differs from normal group at P < .05 ( analysis).
4:
Differs from normal group at P < .01 (x analysis).smaller sample size of this combined subset, parents of children with the combined disorder were still
significantly more likely to have a lipid disorder as
well, especially isolated LDL-C and isolated TG/
HDL-C. Of note, over a third of children with the
combined disorder had both parents affected by a
lipid disorder, suggesting that the genetic interaction
between two parents may be important for transmis-sion of the combined disorder. This interaction is supported by the finding that children with corn-bined disorders were not more likely to have parents with the same disorder, although this finding may also be due in part to the relatively small number of subjects who had the combined disorder in our study (12 parents and 17 children).
The combined disorder, as we have defined it, as well as the isolated lipoprotein conditions, may overlap to some degree with the more classically defined famil-ial combined hyperlipidemia. Cortner et al,17’18 using children as probands, identified familial combined hy-perlipidemia when a child and a parent had LDL-C, TG, or both above the 90th percentile and at least one other family member with elevated TG. The combined
disorder in our study is both more indusive (subjects
could be defined by low HDL-C without high TG) and
less inclusive (subjects had to be identified with two
abnormal lipid values, not on the basis of a combina-tion of lipid abnormalities in the family). Heterogeneity in apolipoprotein B synthesis, the major protein in
TG-and cholesterol-rich lipoproteins, and/or TG-rich
par-tide processing, e.g., very low-density lipoproteins, may explain in part the variability in expression of these lipoprotein subtypes.’9
LDL-C disorder were significantly more likely to have the same disorder; over a third of children with isolated LDL-C had at least one parent with isolated LDL-C.
The test characteristics of the above relations
sug-gested that they would not be appropriate tests, by
themselves, on which to base parental screening.
Certainly they are not very sensitive, which suggests
that many parents have lipid disorders that cannot be predicted by their children’s values. Although the tests are reasonably specific, their positive predictive values are fairly low, which may be due to the
rela-tively low prevalence of lipid disorders in the
gen-eral population. Regardless, the American Heart
As-sociation recommends that serum total cholesterol be
screened in all adults over the age of 20.20 Thus, although the relations we have demonstrated should not be the sole criteria for screening parents, the
presence of lipid disorders in their children can be
presented as a legitimate risk factor and an addi-tional incentive for them to do a full lipoprotein profile, as well as the screening that would be
oth-erwise recommended. The identification of parents
with lipid disorders in these families also may be useful in reinforcing the dietary or life-style changes that would be recommended; presumably, children will be more likely to comply with these
recommen-dations if the whole family is involved and if the
parents have a personal interest in supporting a
change in family habits.
Both parents and children classified as having
iso-lated TG/HDL-C disorder in our study were more
likely to be overweight than other subjects, suggest-ing that similarities in weight may be a factor in the familial association of the isolated TG/HDL-C disor-der. Certainly, obesity has been linked to hypertrig-lycendemia both in adults2’ and children;
more-over, weight loss and dietary management are
recommended as the first approach to the treatment of hyperthg1yceridemia. Nevertheless, the cause-and-effect relation between hypertriglyceridemia and obesity has not been well described, nor can it be
established from our own data. In our study, the
association in weight that we observed between par-ents and children with the isolated TG/HDL-C dis-order may be due to genetic factors, environmental factors, or a combination of the two. This question
could be examined by careful analysis of diet or
activity levels.
In contrast, children with the combined disorder
were much more likely to be substantially
over-weight in our study than were similarly affected parents, even though parents with the combined
dis-order were modestly more overweight than their
normal counterparts. Although such a generational discordance again could be explained by the small
number of parents with the combined disorder, an
alternative reason may be that increased weight
al-lows the combined disorder to manifest earlier in
life, thus being more of a prerequisite for the disor-der in children than in parents.
The children in our population were somewhat
overrepresented by sons (56%), who were more
likely to have a lipid disorder in our study. Although
this may present a bias compared to the general
population, we also noted that sons and daughters with lipid disorders were equally likely to have par-ents with lipid disorders, suggesting that the relation between parents and children should remain valid in a population in which the genders are more equal.
The classification scheme we used, involving only
the measurement of TG, HDL-C, and LDL-C, values
commonly obtained in lipid panels, was chosen
be-cause of its inherent convenience for general practice. As our knowledge of the pathophysiologic basis for coronary heart disease increases, other tests may prove even more useful for identifying coronary risk:
for example, Lp(a), which has been shown to be
associated with myocardial infarction,24 and
apoli-poprotein B, which may be a major determinant of
coronary disease risk, particularly in familial com-bined hyperlipidemia subjects.26 At present, how-ever, the clinical usefulness of these measurements is not well established, especially in children.
In conclusion, as pediatric interest in evaluating and treating lipid disorders continues to grow, more and more children will be identified with these
dis-orders, and many will have TG and HDL-C
disor-ders with or without elevated cholesterol. In our experience, up to a third of children referred to our
pediatric lipid clinic, ostensibly with high total
cho-lesterol, have high TG or low HDL-C but normal or
only borderline LDL-C.4 Furthermore, many parents who bring their children to our clinic have no knowl-edge of their own lipid status. Our study provides a
framework for classifying TG, HDL-C, and LDL-C
disorders in these patients and indicates that parents of children with such disorders are more likely to have lipid disorders themselves, and should be en-couraged to have their own lipid status evaluated.
ACKNOWLEDGMENT
This study was supported by the National Institutes of
Chil-dren’s Health and Human Development grant HC-18281-05 “Genetic Epidemiology of Sex Hormones and Lipoproteins.”
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RONALD McDONALD CHILDREN’S CHARITIES
1994 AWARD OF EXCELLENCE WINNER
AUDREY EVANS, MD
Twenty years ago, Dr Evans’ idea-Ronald McDonald House-became a reality in Philadelphia.
She was, and is, a doctor at The Children’s Hospital of Philadelphia, a specialist in children’s oncology, who dreamed of a house where the families of her seriously ill young patients could stay . . . an inexpensive home-away-from-home within walking distance of the hospital, where families could care for one another in a
supportive environment. Now there are more than 160 Ronald McDonald Houses
in 11 countries around the world and 1.5 million family members have called them home.
Today, Dr Evans divides her workday between the bedsides of her patients and the research lab, where she is getting closer to a better understanding of neuro-blastoma, a deadly childhood cancer. She and her team of researchers are zeroing in on the reasons why tumors of the nervous system will sometimes spontaneously regress.
Meanwhile, survival rates continue to rise. When she began her career in the early 1950s, only one child in ten survived. “Now,” she says, “we cure more than 75% of the children with cancer.”
Throughout her career, Dr Evans has been just as concerned with nourishing the
spirits of her patients as she has been in stabilizing their illnesses. She believed so strongly in the importance of a hospital chaplain that she paid the chaplain’s salary until the hospital administrators agreed. She did the same for the hospital’s first social worker.
As a doctor, scientist, and humanitarian, Audrey Evans knows how to get the right things done. Twice a year, she organizes a Celebration of Life, an emotional service with music, laughter, and tears, that celebrates the lives of the children who have died. She also helped create an ongoing healing program for entire families. Several months after the death of a child, the families are invited back to talk to other families “to work through what it was like then and how they’re doing now.”
