Neonatal screening for hyperlipidemia

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VOLUME 53 #{149}APRIL 1974 #{149}NUMBER 4

PEDIATRICS Vol. 53 No. 4 April 1974 455

Pediatrics

COMMENTARY

Neonatal

screening

for hyperlipidemia

Premature atherosclerosis, and its association

with cardiovascular disease, is a major public health

problem in this, and other industrialized countries. Considerable deliberation has recently been given to the concepts that atherosclerosis begins in child-hood and that preventive efforts should begin early in life. Atherosclerosis as a pediatric problem has been the subject of several previous commentaries and reivews.13 Among the risk factors implicated

in the development of cardiovascular disease, one

of the most important is hyperlipidemia, i.e., an

increased plasma concentration of either cholesterol

or triglycerides or both. The article by Tsang, Fal-lat and Glueck in this issue of Pediatrics addresses

some basic questions concerning the validity of

neonatal screening for hyperlipidemia and empha-sizes the importance of diet in assessing hyper-lipidemia in the first year of life.4 Their article and

most others on hyperlipidemia in infancy focus

up-on the concentrations of plasma cholesterol ,

(

C)

and of low density (beta) lipoproteins (LDL). The emphasis here will therefore be on increases

in C and LDL rather than on the concentrations of plasma triglycerides or the other major

lipopro-tein classes. The presence of hypercholesterolemia

or hyperbetalipoproteinemia in infants, as in their

older sibs and parents, may be interpreted in view of certain epidemiologic, genetic and dietary con-siderations.

In populations of infants, C and LDL are both distributed over a range of values. The mean and

standard deviation

(

SD) of each distribution are

considerably lower than those found in older

chil-dren and adults. A cutpoint is arbitrarily selected from a distribution curve, and infants with a C or LDL above the cutpoint are considered to have

hypercholesterolemia or hyperbetalipoproteinemia.

In cord blood studies a commonly selected cutpoint

for C is a value above which 2.5% (mean plus 2

SD) of the population are found. In the original

series of Glueck and co-workers, the mean C

(

± 1 SD) in cord blood was 63.8 ± 18.7 mg/100

ml and the cutpoint was a C of 100 mg/ 100 ml. As in older populations, the distribution of C was

skewed toward higher values; 65 neonates were

above the cutpoint (45 or 1,800 X 0.025 predicted).

A group of neonates who are identified in this way represent a heterogeneous group. Since C and LDL are nonspecific biochemical markers, increases in their concentrations can result from a variety of underlying etiologies. It is therefore necessary

to determine the meaning of the elevated C in

each infant. One of the main objectives of recently published cord blood studies has been to establish the effectiveness of C and LDL in the detection at birth of an inherited form of hyperlipidemia known as familial hypercholesterolemia

(

FH).

Familial hypercholesterolemia, also known as es-sential hypercholesterolemia or hypercholesterol-emic xanthomatosis, is most likely an inherited

disorder of lipoprotein metabolism.6 Increases in

LDL and C are often ‘extreme and the disorder appears to result from a single abnormal autosomal gene. It is also associated with tendon and

sub-cutaneous xanthomas and a significant risk of

pre-mature ischemic heart disease. In the classification system of Fredrickson and colleagues, FH is one of

an unknown number of genetic defects which

un-derlie familial hyperbetalipoproteinemia (type II

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456 HYPERLIPIDEMIA

hyperlipoproteinemia) and is the most commonly

identified form of familial hyperlipidemia in

child-hood.6 Forty-five percent of children

(

aged 1 to

19), born to matings of FH X N, have hyperbeta-lipoproteinemia.7 The children with FH are

rela-lively free of overt clinical symptomatology, which

begins as early as the third decade in some of

their affected parents.7 It has also been shown that

the measurement of LDL in cord blood permits

the ascertainment of children with FH when one

parent is known to have the disorder.8

To establish the effectiveness of cord-blood

screening for FH when parental phenotypes are

unknown, two questions must be answered : (1)

which infants with neonatal hypercholesterolemia

also have FH, and

(

2) how many infants with

normal cord blood C manifest FH later in life?

Answers to these questions require both family studies and reevaluation of the infants at 1 year of

age or later. Reevaluation at 12 months of age

can be particularly difficult because of the marked effects of diet on plasma lipids in the first year

of life.9’10

Tsang and co-workers report in this issue that eight of the 65 infants with neonatal

hypercholes-terolemia had FH.4 This was based on family

studies using the criteria of three-generation

trans-mission

(

grandparent to parent to neonate

)

or the

presence of both xanthomas and

hypercholesterol-emia in the affected parent. The authors estimated

that the prevalence of FH at birth is 0.44%

(

8/ 1,800) . These infants, however, were considered

to be affected on the basis of their cord blood C. At 1 year of age, five of these eight children had a normal C. One infant had been on a diet

“moderate-ly high” in cholesterol content and probably

repre-sents a false-positive result. Four others had been

on a diet low in cholesterol. It is not presently

known whether these apparent discrepancies are

false-positive results or suppressed expression of a

defect present at birth. The authors believe the

latter to be the case, but these infants have not

been returned to a regular diet to test this

hypoth-esis.

In a longitudinal study of C in 302 English

children, Darmady et al. reported that only five of the

30 children with a cord blood C above 100 mg/ 100

ml had a C above 240 mg/ 100 ml at age 1.’ The

parents of these children had a normal C. This

study is not directly comparable with others since

the value for the mean C plus 2 SD was 124 mgI

100 ml, and a C of 240 mg/ 100 ml at age 1 was

a value between 1 and 2 SD above the mean.

Goldstein et al., using the criteria of

three-genera-lion transmission, found that five of the 125

in-fants with neonatal hyperlipidemia had FH.12 Their

estimate of the prevalence of FH at birth was

5/2,000 but follow-up studies of these infants have

not been published.

How might one interpret neonatal

hypercholes-terolemia in the majority of infants who do not

have FH? Fifty-six of the original 65 infants with

neonatal hypercholesterolemia in the Cincinnati

study were reevaluated at 1 year of age.4’5 Of the

48 infants who were judged not to have FH, 39 had

parents with normal lipid values and all but one

had a normal C at 1 year of age. Each of the

re-maining nine children had a parent with

hyper-cholesterolemia and an elevated C at 1 year of age. Diet does not appear to completely explain why

the majority of the infants with neonatal

hyper-cholesterolemia had a normal C at age 1. Thirty

of the above 39 children were on a diet “moderately

high” in cholesterol content. Several other possible

explanations can be suggested. Little information

is available on the effects of such factors as

neo-natal distress, duration of labor, and maternal drugs

and anesthesia on the levels of lipids in cord blood.

Mafernal lipids do not ordinarily cross the

pla-cental barrier, but prolonged clamping of the cord

increases the chance of maternal contribution to

the cord blood sample.1#{176}If the distributions for C

and LDL at birth and throughout the first year

of life differ for male and female children, separate

cutpoints for each sex would be required. Genetic

factors may be operating in the remaining infants

who maintained their hypercholesterolemia. Some infants may have “polygenic” forms of

hypercholes-terolemia.13 A few might be probands for familial

combined hyperlipidemia, a recently described form of “monogenic” hyperlipidemia, which, in a

pre-liminary report, was detected in four families from

2,000 infant propositi.12’13

What proportion of infants with normal cord

blood C later develop hypercholesterolemia

(false-negative results)? In the Tsang study, none of

the 42 subjects with normal cord blood C developed hypercholesterolemia at 1 year of age.4 Greten

and co-workers found that 1 of 65 German infants

with normal cord blood C developed

hypercholes-terolemia when reevaluated at 1 year of age.

Darmady et al. restudied 243 of the 268 children

who had a cord blood C below 100 mg/ 100 ml.

One of these children had FH.11 Additional data from larger numbers of children are certainly need-ed before the frequency of false-negative results can be assessed definitively.

Agreement has not yet been reached as to which

biochemical tests are the most effective for

neo-natal screening. We have previously reported that

cord blood C did not exceed 100 mg/ 100 ml in

six of the 16 infants classified as abnormal by LDL

determinations.8 Greten et al. found that 92 of

1,323 infants had a cord blood C or LDL in the

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COMMENTARY 457 upper 2.5% of the group.’4 It is noteworthy that

37 of the 92 had increased LDL but normal C

and six had increased C but’normal LDL.14 These

results suggest that LDL has greater diagnostic

power than C. This is at least partially due to the

prominent contributions made to cord blood C by the high density lipoproteins (HDL) 8 Moreover, in the individual infant with FH, the absolute

amount of HDL appears to be decreased, as it is

in older patients.8 The apparent discrepancy

be-tween elevated LDL and C at birth observed in

the above studies was not observed by Tsang and

co-workers.4 Clearly more comparative information

is needed on the diagnostic and predictive value

of LDL and C in the cord blood.

The numerous studies on the marked effects of

various formulas and diets on the plasma lipid

levels in infancy have been recently summarized.’#{176}

The above discussion considered the influence of

diet on the diagnostic validity of hyperlipidemia

at the age of 1. Several other important

considera-tions remain concerning the influence of dietary

modification in the first year of life. Formulas low

in cholesterol and saturated fats, with increased

amounts of polyunsaturated fats, have been used

to significantly lower C in infants with FH.#{176}Longer periods of follow-up are needed to determine if

this dietary modification will affect the response

to diet later in life. For example, a treated infant

may have significantly different C later in

child-hood than the untreated infant who began the diet

at 1 year of age. There are no apparent side effects

of dietary treatment on growth and development,

but potential side effects must be kept in mind.

These include the increased requirement for

vita-mm E in children on a diet high in polyunsaturated

fats. As infants with FH progress through

child-hood, it is likely that many will require the

ad-dition of a drug like cholestyramine to lower their

C and LDL into the normal range.15 Finally, the

benefit of early treatment in infants with FH on

the prevention of premature atherosclerosis remains

an attractive but unproven hypothesis.

Much of the attention in previous studies on

neonatal screening for hyperlipidemia has focused

on the detection of the infant with FH. Although

it is reasonably well established that the disorder

can be detected at birth, a variety of questions

remain concerning the efficiency of detecting FH.

Clearly, more studies are needed on the natural

history of C in those infants who are normal at birth. The issue of which biochemical tests to use

(

C or LDL) must be resolved. Influences of

peri-natal events and maternal drugs and anesthesia on lipids in the cord blood need to be better under-stood. Lastly, longitudinal studies must be per-formed so that the genetic and medical significance

of neonatal hyperlipidemia, as it relates to the general problem of premature atherosclerosis, can be determined.

Baltimore, Maryland

PETER 0. KWITEROVIGH, JR., M.D.

Director, Lipid Research Clinic

Department of Pediatrics Johns Hopkins University

School of Medicine

REFERENCES

1. Mitchell, S., Blout, S. C., Jesse, M. J., et at. : The

pediatrician and atherosclerosis. Pediatrics, 49: 165, 1972.

2. Kannel, W. B., and Dawber, T. R. : Atherosclerosis as

a pediatric problem. J. Pediat., 80:544, 1972.

3. Drash, A. : Atherosclerosis, cholesterol and the pedia-trician. J. Pediat., 80:693, 1972.

4. Tsang, R. C., Fallat, R. W., and Glueck, C. J.: Cholester-ol at birth and age 1: Comparison of normal tsnd hypercholesterolemic neonates. Pediatrics, 53:458,

1974.

5. Glueck, C. J., Heckman, F., Schoenfeld, M., et al.: Neo-natal familial type H hyperlipoproteinemia: Cord blood cholesterol in 1800 births. Metabolism, 20:

597, 1971.

6. Fredrickson, D. S., and Levy, R. I. : Familial hyper-lipoproteinemia. In Stanbury, J. B., Wyngaarden,

J. B., and Fredrickson, D. S. (eds. ): The Meta-bolic Basis of Inherited Disease, ed. 3. New York: McGraw-Hill, 1972.

7. Kwiterovich, P. 0., Jr., Fredrickson, D. S., and Levy,

R. I. : Familial hypercholesterolemia (one form of familial type H hyperlipoproteinemia) : A study

of its biochemical, genetic and clinical

presenta-tion in childhood. J. Clin. Invest., to be published.

8. Kwiterovich, P. 0., Jr., Levy, R. I., and Fredrickson,

D. S.: Neonatal diagnosis of familial type II hy-perlipoproteinemla. Lancet, 1 : 118, 1973.

9. Glueck, C. J., and Tsang, R. C. : Pediatric familial type

II hyperlipoproteinemia: Effects of diet on plasma cholesterol in the first year of life. Amer. J. Clin.

Nutr., 25:224, 1972.

10. Fredrickson, D. S., and Breslow, J. L. : Primary hyper-lipoproteinemia in infants. Ann. Rev. Med., 24: 315, 1973.

11. Darmady, J. M., Fosbrooke, A. S., and Lloyd, J. K.: Prospective study of serum cholesterol levels dur-ing first year of life. Brit. Med. J., 2:685, 1972.

12. Goldstein, J. L., Albers, J. J., Hazzard, W. R., et al:

Genetic and medical significance of neonatal hy-perlipidemia. ( abstract). J. Clin. Invest., 52:128, 1973.

13. Goldstein, J. L., Schrott, H. R., Hazzard, W. R., et al.: Hyperlipidemia in coronary heart disease: II.

Genetic analysis of lipid levels in 176 families and

delineation of a new inherited disorder, combined

hyperlipidemia. J. Clin. Invest., 52: 1544, 1973. 14. Greten, H., Wengeler, H., and Wagner, H. : Early

diagnosis of familial type II hyperlipoproteinemia. Nutr. Metabol., 15:128, 1973.

15. Glueck, C. J., Fallat, R., and Tsang, R. : Treatment of

. pediatric familial hyperlipoproteinemia. Pediatrics, 52:669, 1973.

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1974;53;455

Pediatrics

Peter O. Kwiterovigh, Jr.