68 PEDIATRICS Vol. 57 No. 1 January 1976
Pediatric
Familial
Type
II Hyperlipoproteinemia:
Therapy
With
Diet and Colestipol
Resin
C. J. Glueck, M.D., R.W. Fallat, M.D., M. Mellies, M.D., and R. C. Tsang, M.D.
From the Department of Medicine and Pediatrics, Lipoprotein Research Laboratory and General Clinical
Research Center, Cincinnati General Hospital, Fels Division of Pediatric Research, and Newborn Division.
Children ‘s Hospital Research Foundation, University of Cincinnati, College of Medicine, Cincinnati, Ohio
ABSTRACT. Effects of a low-cholesterol, polyunsaturate-rich diet and a synthetic organic bile sequestrant polymer (U26,597A, colestipol) were studied in 21 children,
heterozy-gous for familial hypercholesterolemia. Total cholesterol,
fi-lipoprotein cholesterol, and triglyceride were measured twice on habitual diet, monthly for six months on a low-cholesterol diet, and monthly for six months on
low-cholesterol diet plus 10 gm of colestipol per day. Total
cholesterol (mean ± 1 SD) was 295 ± 37 on habitual diet,
278 ± 29 on low-cholesterol diet, and fell significantly to
242 ± 29 mgI 100 ml on diet plus colestipol. Low-density
lipoprotein (LDL) cholesterol was 234 ± 37 on habitual
diet, 220 ± 28 on low-cholesterol diet, and fell significantly
to 179 ± 26 mg/ 100 ml on diet plus drug. Plasma
triglycer-ide levels on habitual diet were 79 ± 31, remained
unchanged on low-cholesterol diet, 86 ± 22, and were
unaffected by low-cholesterol diet plus drug, 85 ± 17
mg/100 ml. On diet alone, plasma LDL was not normalized (< 170 mg/100 ml) in any of the 21 children, and cholesterol fell to within normal limits (< 230 mg/100 ml) in only one child. The combination of diet plus colestipol resin normal-ized total and LDL cholesterol in 52% of the children. Cholesterol was lowered to a “moderately elevated” range of 230 to 250 mg/ 100 ml in an additional 14% of the children and LDL was lowered to a range of 170 to 190 mg/ 100 ml in
an additional 29%. In 33% of the children, cholesterol
remained > 250 mg/100 ml despite diet plus colestipol, while LDL was > 190 mg/100 ml in 19%. Colestipol is an
effective and well-tolerated cholesterol lowering compound which, in conjunction with diet, may prove to be very useful
in the treatment of children heterozygous for familial hypercholesterolemia. Pediatrics, 57:68-74, 1976,
BETA-LIPO-PROTEIN, CHOLESTEROL, FAMILIAL HYPERCHOLESTEROLEMIA.
diet alone8 (usually < 300 mg of cholesterol per day, P/S ratio of 1.5 to 2: 1) often produces a 10% to 20% reduction in cholesterol levels.
In children unresponsive to diet, or with elevated levels of low-density lipoprotein (LDL) despite best diet response, several combined diet and drug regimens have been suggested.58’#{176} An overall 33% reduction in cholesterol was reported for the combination of diet plus clofibrate.’#{176} West and Lloyd9 gave 8 to 24 gm of cholestyramine to hypercholesterolemic children and reported a mean decrement in plasma cholesterol of 36% (range, 27% to 47%). Drug effect was observed with and without a cholesterol-restricted diet. Glueck et a!.5 reported reduction of LDL to normal levels in 33% of 36 children heterozygous for familial hypercholesterolemia, using diet alone. Combined diet and cholestyramine resin (12 gm/day) reduced LDL to normal in six of ten children whose LDL had remained elevated on diet alone.5
Recently, a new synthetic organic bile seques-trant polymer, colestipol (U26-597A), has become available following an initial report” of marked hypocholesterolemic effects in animal models. Tliis investigational compound is a high molecu-lar weight insoluble copolymer of tetraethylene
Familial hypercholesterolemia, which is trans-mitted as an autosomal dominant,’2 highly
pene-trant in children,’3 and characterized by
increased concentrations of cholesterol and ,8-lipoprotein cholesterol23 sharply augments the risk of premature atherosclerosis. ‘ In children
heterozygous for familial hypercholesterolemia,
(Received December 9, 1974; revision accepted for publica-tion January 17, 1975.)
Supported in part by Public Health Service General Clinical Research Center grant No. RR00068-13. A portion of this work was done during Dr. Glueck’s tenure as an Established Investigator of the Alnerican Heart Association, 1971 to 1976.
ADDRESS FOR REPRINTS: (G.J.G.) Department of
Mcdi-cine and Pediatrics, University of Cincinnati Medical Center, 234 Goodman Street C2-3, Cincinnati, Ohio 45267.
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pentamine and epichlorohydrin with one of the
five amine nitrogens as the chloride salt. Its in
vitro cholate binding capacity is comparable to
that of cholestyramine resin or DEAE
Sepha-dex.”
In a cross-over study in adults, colestipol at a
dosage of 20 gm /day and cholestyramine resin (20
grn of active resin per day) had essentially
equiva-lent effects.’ Colestipol in adults has produced
5% to 25% decrements in cholesterol.l114
Coles-tipol therapy increased fecal excretion of bile
acids and increased cholesterol turnover.14
The current study was designed to assess the
efficacy, safety, utility, and practicability of a
combination of low-cholesterol diet plus
coles-tipol resin (10 gm/day) in 21 children
heterozy-gous for faniilial hypercholesterolemia. On diet
and colestipol resin (10 gm/day) for six months,
total and LDL cholesterol levels were reduced to
normal in 52% of the children. In conjunction
with diet, colestipol resin provides an effective
alternative approach to therapy of familial
hyper-cholesterolemia in children.
MATERIALS AND METHODS
Patients
Twenty-one children (median age, 14; range, 7
to 20) from four kindreds with well-documented
familial hypercholesterolemia were studied
(Ta-ble I). They were ascertained by family lipid
sampling in kindreds where the proband parent
had familial hypercholesterolemia. Primary
hy-percholesterolemia was present in one parent and
at least one additional first-degree relative in each
of the four kindreds. All spouses of the affected
parents had normal levels of cholesterol and
triglyceride. Hyperbetalipoproteinemia was also
present in either a sibling or a first cousin of all 21
children. The primary nature of the
hyperbetali-poproteinemia in the 21 children was further
confirmed by exclusion of disorders which
produce secondary
Diagnosis of Hypercholesterolemia and
Hyperbetalipoproteinemia in Children
Fasting “index” blood samples were obtained
from all children with weight stable and
accustomed to eating at will. Two or more
samples were taken with a two- to three-week
interval between the first and second index
samplings (Table I). The diagnosis of
hyperbetali-poproteinemia was made following an
estab-lished, previously described system.25
Age-adjusted upper normal limits for cholesterol,
/3-lipoprotein cholesterol, and triglyceride of
Fredrickson and Levy’5 and Kwiterovich et a!.2
were used for identification of affected and normal individuals.
Study Protocol
Children were entered in this study after identification of hyperbetalipoproteinemia,’’-57’
documentation of the familial nature of the disor-der, and exclusion of secondary
hypercholesterol-emia.5-75 They were enrolled in the sequential
order of presentation of their kindreds in the Family Lipid Research Center. Children under age 6 years at the time of the first index sample
were not included in the study group.
Following index sampling, metabolic dietitians instructed children and their parents in a
low-cholesterol (< 300 mg/day), polyunsaturate-rich (P/S 1.5:1) diet.11 At each monthly visit, adherence to diet was reviewed with the children and their
mothers using a 24-hour dietary recall, and
continuing efforts were made (with new recipes,
diet plans, etc.) to maintain adherence.
After six months on diet alone, colestipol resin, two packs (10 gm/day), was started. One pack was given with breakfast and one with the evening meal. Since substantial drug adherence failure had occurred with the “at school,” second
of three daily cholestyramine packets,5 the
two-pack, 10 gm/day dose schedule was picked in attempts to maximize adherence and conven-ience.
At the monthly clinic visit, a written review of adherence to medication was taken. Verbal rein-forcement was used to try to ensure that the two packs of colestipol were taken daily.
All of the children were followed once a month for six months on diet alone and monthly for six
months on diet plus drug (Tables II to V). At each
monthly outpatient visit, fasting blood was drawn for quantitation of total, high-density,
low-density, and very low density cholesterol and
triglyceride. Height, weight, blood pressure, and
any symptoms referable to the medication were
recorded. A brief physical examination was done. At every other visit, “laboratory safety tests” were obtained including full hemogram, liver
function tests, blood urea nitrogen, calcium,
phos-phorous, total protein (albumin/globulin),
elec-trolytes, plasma vitamin E,’6 and carbon dioxide.
No supplemental fat-soluble vitamins (A, D, K, E)
were given.
Statistical Analysis
TABLE I
70 FAMI LIAL HYPERLIPOPROTEINEMIA THERAPY
INDEX CHOLESTEROL, B-LIPOPROTEIN CHOLESTEROL, AND TRIGLYCERIDE LEVELS IN 21 CHILDREN WITH FAMILIAL HYPERCHOLESTEROLEMIA
No. Patient Kindred
Age
(yr) Sex
Plasma Levels0
Cholesterol
(mg/100 ml)
LDL
(mg/100 ml)
Triglyceride (7ng/100 ml)
1. L.L. G.L. 12 F 240 240 190 183 54 80
2. J.M. C.W. 15 F 333 260 250 174 60 95
3. S.S. L.S. 20 F 360 362 275 269 78 81
4. R.S. L.S. 19 M 365 371 281 283 124 132
5. BR. C.W. 8 F 280 262 240 202 53 191
6. R.R. C.W. 13 M 283 244 241 186 70 126
7. A.W. C.W. 7 M 316 260 255 213 47 40
8. MW. C.W. 12 F 245 254 179 193 116 98
9. MW. C.W. 11 F 310 343 233 250 84 87
10. MW. C.W. 19 F 320 343 238 256 57 84
11. C.F. C.W. 13 F 305 288 260 240 67 54
12. M.F. C.W. 15 F 294 300 243 251 81 70
13. K.F. C.W. 7 F 309 294 245 243 8041
14. JR. C.W. 16 F 315 300 237 254 155 88
15. L.R. C.W. 19 M 324 315 280 258 68 84
16. L.R. C.W. 7 F 374 350 296 259 45 48
17. P.R. C.W. 10 F 348 307 296 259 82 94
18. R.R. C.W. 20 F 320 323 255 260 60 49
19. LH. C.W. 11 M 288 234 233 178 89 92
20. K.K. K.K. 20 F 278 290 204 206 86 70
21. R.M. C.\%’. 15 M 242 283 175 199 66 10)
#{176}Twoindex samples taken, with a two- to three-week interval between first and second sampling.
plus drug period, using Student’s f-test (Tables II to IV).’7
RESULTS
Cholesterol, LDL Cholesterol and
Triglyc-ende in the 21 Children on Free Diets
The two index levels for cholesterol, LDL cholesterol, and triglycerides for the 21 children with familial hypercholesterolemia are
summa-rized in Table I. All children had index levels for
cholesterol and LDL cholesterol above suggested
upper normal limits of 230 and 170 mg/ 100 mi.2”5
None of the children had major elevations of plasma triglyceride on the index samples (Table I). One child (J.R., No. 14) had a mild elevation of triglyceride to 155 mg/ 100 ml (suggested upper
normal limits for triglyceride, 140 mg/ 100 ‘
In J.R., the type Il-b lipoprotein phenotype was characterized by increased LDL and very low density lipoprotein cholesterol and
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index: Free
Cholesterol#{176}
Diet
LDL#{176}
Diet Only, Months 1 to 6
Cholesterol#{176} LDL#{176} No. Patient (mg/100 ml) (mg/100 ml) (mg/100 ml)
1 L.L. 240 190 250 ± 15
Diet Plus Colestipol, Months 7 to 12
(mg/lOOml)
Cholesterol#{176} LDL#{176}
(mg/lOOm!) (mg/lOOm!)
193±21 249±21 188±18
2 J.M. 333 250 289 ± 26 225 ± 4 235 ± 21t 161 ± 16t
3 5.5. 360 275 323 ± 11 279 ± 6 304 ± 32 252 ± 32
4 R.S. 365 281 327 ± 27 273 ± 25 283 ± 18t 231 ± 22t
5 BR. 280 240 266 ± 25 207 ± 27 226 ± 39 165 ± 52
6 R.R. 283 241 237 ± 20 188 ± 23 222 ± 31 167 ± 34
7 A.W. 316 255 274 ± 23 222 ± 23 244 ± 15t 184 ± 20t
8 M.W. 245 179 223 ± 12 170 ± 15 210 ± 24 148 ± 27
9 MW. 310 233 322 ± 16 230 ± 19 265 ± 30t 166 ± 30t
10 M.W. 320 238 291 ± 18 219 ± 22 274 ± 17 190 ± 18t
11 CF. 305 260 272 ± 23 222 ± 28 229 ± 23t 170 ± 27t
12 M.F. 294 243 266 ± 21 210 ± 21 223 ± 21t 173 ± 22t
13 K.F. 309 245 266 ± 19 211 ± 38 228 ± 14 161 ± 31t
14 JR. 315 237 283 ± 14 228 ± 14 215 ± 25t 156 ± 25t
15 L.R. 324 280 283 ± 20 230 ± 17 225 ± 26t 172 ± 26t
16 L.R. 374 319 320 ± 18 268 ± 9 261 ± 32t 203 ± 36t
17 P.R. 348 296 299 ± 28 234 ± 25 262 ± 24t 189 ± 33t
18 R.R. 320 255 286 ± 20 228 ± 13 224 ± 17t 159 ± 16t
19 L.H. 288 233 242 ± 15 190 ± 9 200 ± 23t 156 ± 19t
20 K.K. 278 204 286 ± 18 206 ± 19 288 ± 44 201 ± 45
21 R.M. 242 175 251 ± 21 189 ± 24 216 ± 22t 159 ± 26
TABLE II
EFFECTS OF DIET AND DIET PLUS COLESTIPOL ON CHOLESTEROL AND LDL CHOLESTEROL
#{176}Mean ± 1 SD of six separate determinations.
tP < .05, comparison of levels on diet plus colestipol to those on diet alone.
The other 20 children had the type Il-a
lipopro-tein phenotype, with normal very low density
lipoprotein cholesterol and triglyceride.’
Effects of Diet and Colestipol on Cholester-ol, LDL CholesterCholester-ol, and Triglyceride
On diet alone the mean total cholesterol for all
Entcrs OF DIET AND DIET PLUS COLESTIPOL ON TRIGLYCERIDES
GROUP MEAN LEVELS FOR CHOLESTEROL, /3-LIPOPR0TEIN CHOLESTEROL, AND TRIGLYCERIDES
rol
/l-lipoprotein 234 ± 37
cholesterol
Triglyceride 79 ± 31
220 ± 28 179 ± 26#{176}
86±22 85±17
OP < .001, comparison of levels on diet plus colestipol to those on diet alone.
TABLE III TABLE IV
72 FAMILIAL HYPERLIPOPROTEINEMIA THERAPY No. Pa-tient Triglyceride Levels (mg/lOO ml) index: Free Diet Diet Plus ENet Only, Colestipol, Months 1 to 6#{176} Months 7 to 12#{176}
1 L.L. 54 77 ± 32 79 ± 23
2 J.M. 60 106±31 90±19
3 S.S. 78 75 ± 15 96 ± 25
4 R.S. 124 124 ± 32 96 ± 25
5 B.R. 53 106 ± 47 98 ± 32
6 R.R. 70 106 ± 39 82 ± 18
7 A.W. 47 70 ± 17 78 ± 25
8 MW. 116 117 ± 16 130 ± 20
9 MW. 84 77 ± 12 87 ± 17
10 M.W. 57 57 ± 8 66 ± 43
11 C.F. 67 58 ± 10 81 ± 25
12 M.F. 81 72 ± 12 76 ± 10
13 K.F. 80 60 ± 30 55 ± 13
14 JR. 155 96 ± 15 109 ± 28
15 L.R. 68 66 ± 24 66 ± 20
16 L.R. 45 84 ± 26 75 ± 21
.
17 P.R. 82 94 ± 30 99 ± 25
18 R.R. 60 52 ± 10 58 ± 11
19 L.H. 89 100 ± 26 84 ± 12
20 K.K. 86 122±20 94±27
21 R.M. 66 78±30 79±23
#{176}Mean± 1 SD of six separate determinations.
significant fall in the individual total and LDL
cholesterol and triglyceride levels (Tables II and III).
On the low-cholesterol diet plus colestipol,
group mean total cholesterol fell 13% from 278 to
242 mg/100 ml (Table IV). Triglyceride remained
Low-Low- Cholesterol
Habitual Cholesterol Diet Plus
Diet Diet Colestipol
Measure (mg/100 ml) (mg/ 100 ml) (mg/ 100 ml)
Total choleste- 295 ± 37 278 ± 29 242 ± 29#{176}
unchanged at 86 mg/ 100 ml and group mean
/3-lipoprotein cholesterol fell 19% from 220 to 179
mg/100 (Table IV). On diet plus colestipol
signif-icant individual decrements in total and LDL cholesterol, as compared to mean levels on diet alone, were noted respectively in 13 of 21 and 14 of 21 chldren (Table II). Individual triglyceride levels were not changed during diet plus
coles-tipol therapy (Table III).
On diet alone, mean plasma cholesterol was reduced to normal (< 230 mg/100 ml) in only one child (Table II). On diet alone, f3-lipoprotein cholesterol was normalized (< 190 mg/ 100 ml)
in none of the 21 children. On diet plus colestipol,
mean cholesterol fell to < 230 mg/ 100 ml in 11 of the 21 children, and /3-lipoprotein cholesterol fell to < 170 mg/ 100 ml in 9 children (Table II).
TABLE V
PERCENTAGE OF CHILDREN WITH NORMAL, MODERATELY
ELEVATED, AND HIGH LEVELS
Level (mg/100 ml)
Diet Alone (%) Diet Plus Colestipol (%) Cholesterol Normal(<230)
Moderately elevated (230 to 250) High(>250) 5 14 81 52 14 33 LDL
Normal (< 170)
Moderately elevated (170 to 190)
High (> 190)
-19 81 52 29 19 Triglyceride
Normal (< 140)
Moderately elevated (140 to 160) High(>160) 100 -100
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Whereas LDL was not normalized and total
cholesterol was normalized in one child by diet
alone, both were normalized in 52% of the
children I)y diet plus added colestipol (Table V).
Diet alone maintained cholesterol and LDL in the
“moderately elevated” range in 14% and 19% of
the children, respectively, while 14% and 29%
were sustained in this range on diet plus colestipol
(Table V). On combined diet and drug, only 19%
of the children had LDL > 190, while 33%
maintained total cholesterol levels above 250 mg/
1(X)
nil.Effects of Colestipol Therapy on Vitamin E
Levels
Plasma levels of vitamin E were unchanged by
addition of colestipol to diet. Mean ± 1 SD
vitamin E was 1.2 ± 0.4 mg/100 ml on diet
alone, and was 1.1 ± 0.3 on diet plus colestipol.
Effects of Drug Therapy on Weight Gain,
Growth, and Laboratory Safety Tests
Weight gain and growth progressed during the
12- and 18-month study period along normal
growth percentiles without percentile shifts.
There were no abnormalities or any consistent
changes in any of the laboratory safety tests.
Drug Adherence
Seventeen of the 21 children routinely took two
packages of colestipol (10 gm/day). Three of 21
children took an average of 1.5 packages of
colestipol per day (7.5 gm/day). One child took
only one package of colestipol per day, (the
morning pack), because of a persistent problem
with “loss of appetite” with the evening pack.
Three of 21 children had transient constipation for the first two months of drug therapy. No
children had persistent changes in bowel habits.
DISCUSSION
Atherosclerosis may begin in childhood and
progress silently until the third, fourth, and fifth
decades when it may be first outwardly
mani-fested I)y the coniplications of cardiovascular
disease. Cardiac morbidity and mortality is
extraordinarily increased in the third, fourth, and
fifth decades of life in subjects with familial
hypercholesterolemia. Familial
hypercholester-olemia can be easily documented and diagnosed
in children,’25 providing an opportunity for
early therapeutic intervention.
Diet and drug regimens show variable
effec-tiveness in reducing total and LDL cholesterol in children with familial
hypercholesterolemia.5-Extensive interest has grown in exploring effec-tive, safe, and practical methods for normalizing plasma cholesterol in these children. In children heterozygous for familial hypercholesterolemia, diets alone generally reduce total plasma choles-terol from about 10% to 25%, usually not into the normal range.5-7-8-’ In the current study, diet alone was insufficient to induce notable changes in cholesterol or LDL, with an average decre-ment of 6% for both (as compared to habitual diet levels). Addition of colestipol (10 gm/day)
produced an additional 13% drop in total
choles-terol and an additional 19% decrement in LDL, giving an overall 19% decrement in total and 25% decrement in LDL cholesterol. Nearly all of the children were able to take the two packs (10 gin / day) of colestipol, and there were limited and transient gastrointestinal side effects. At the two pack/day level the real difficulties of an at-school drug dose are avoided.5 Cholesterol and LDL cholesterol were lowered into the normal or
near-normal ranges by diet plus colestipol respectively
in 66% and 81% of the children. Increasing the colestipol dose to three or four packs (15 to 20 gm/day) is currently being evaluated in the
children whose values did not normalize on 10 gm/day. The relative ease of drug adherence coupled with the lack of change in laboratory
safety tests and reasonable decrements in total
and LDL cholesterol were encouraging for long-range prospects.
When compared to diet-cholestyramine resin programs,5 as has been noted for adults,’2 coles-tipol and cholestyramine resins appear to have
nearly equivalent effects, providing that
equiva-lent doses of the active resins are given and that
adherence to the drug regimens is similar.
Eighty-one percent (17 of 21) children reportedly
adhered to the two pack/day regimen for
colesti-p01. This response was considerably better than the 50% of children who routinely took three
packs/day of cholestyramine resin.5 In children
heterozygous for familial hypercholesterolemia who are unresponsive to diet, addition of coles-tipol or cholestyramine resin to diet may lead to normalization of total and LDL cholesterol in a
majority of subjects. Whether this normalization
74 FAMILIAL HYPERLIPOPROTEINEMIA THERAPY
regimens in children which will need to be monitored. A watchful stance must be maintained
in terms of long-term subtle and otherwise
unan-ticipated side effects of low-cholesterol diet and cholesterol-binding agents. With these warnings in mind, colestipol resin appears to offer an effective and acceptable alternative approach to cholesterol lowering in children heterozygous for familial hypercholesterolemia.
REFERENCES
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2. Kwiterovich P0 Jr, Fredrickson DS, Levy RI: Familial hypercholesterolemia (one form of familial type II
hyperlipoproteinemia): A study of its biochemical,
genetic, and clinical presentation in childhood.
J Clin Invest 53:1257, 1974.
3. Stone NJ, Levy RI, Fredrickson DS, Verter J: Coronary
artery disease in 116 kindred with familial type II hyperlipoproteinemia. Circulation 49:476, 1974. 4. Larsen R, Glueck CJ, Tsang RC: Special diet for familial
type II hyperlipoproteinemia. Am J Dis Child 128:67, 1974.
5. Glueck CJ, Fallat RW, Tsang RC: Pediatric familial type II hyperlipoproteinemia: Therapy with diet and cholestyramine resin. Pediatrics 52:669, 1973. 6. Fredrickson DS, Levy RI: Dietary Management of
Hyperlipoproteinemia: Type II. Washington DC: Government Printing Office, 1969, publication 1667, p 395.
7. Glueck CJ, Fallat RW, Tsang RC: Hypercholesterol-emia and hypertriglyceridemia in children: A pedi-atric approach to primary atherosclerosis preven-tion. Am J Dis Child 128:569, 1974.
8. Fallat RW, Tsang RC, Glueck CJ:
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12. Glueck CJ, Ford 5, Scheel D, Steiner P: Colestipol and cholestyramine resin: Effects in familial type II hyperlipoproteinemia. JAMA 222:676, 1972. 13. Miller NE, Clifton-Bligh P, Nestel PJ, et a!: Controlled
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15. Fredrickson DS, Levy RI: Familial hperlipoprotein-emias. In, Stanbury JB, Wvngaarden JB, Fredrick-son DS (eds): The Metabolic Basis of Inherited Disease, ed 3. New York, McGraw-Hill, 1972, p 545.
16. Glueck CJ, Tsang RC, Fallat RW, Scheel D: Plasma
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17. Snedecor GW, Cochran WG: Statistical Methods, ed 6. Ames, Iowa, Iowa State College Press, 1967,
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18. Beaumont JL, Carlson LA, Cooper CR, et a!:
Classifica-tion of hyperlipidemias and hvperlipoproteinemias. Bull WHO 43:891, 1970.
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1976;57;68
Pediatrics
C. J. Glueck, R. W. Fallat, M. Mellies and R. C. Tsang
Resin
Pediatric Familial Type II Hyperlipoproteinemia: Therapy With Diet and Colestipol
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1976;57;68
Pediatrics
C. J. Glueck, R. W. Fallat, M. Mellies and R. C. Tsang
Resin
Pediatric Familial Type II Hyperlipoproteinemia: Therapy With Diet and Colestipol
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