WORLD HEALTH ORGANIZATION

MEMORANDUM
Classification of Hyperlipidemias
and Hyperlipoproteinemias
M ANY STUDIES OF atherosclerosis have (1) hyperlipoproteinemia very seldom occurs
indicated hyperlipidemia as a predis- without hyperlipidemia and, consequently,
posing factor to vascular disease. The relation- hyperllpidemia may be used to detect hyper-
ship holds even for mild degrees of hyperlipi- lipoproteinemia; (2) a classification based on
demia, a fact that underlines the importance lipoproteins offers more information than one
of this category of disorders. Both primary based on lipids alone; (3) a classification
and secondary hyperlipidemias represent such should distinguish between disorders in the
a variety of abnormalities that an internation- metabolism of lipoproteins as well as lipids.
ally acceptable provisional classification is The proposed classification described here
highly desirable in order to facilitate commun- includes, step by step, the use of lipid
ication between scientists with different back- analyses, lipoprotein analyses, and other clini-
grounds. cal and biologic data. It provides an approach
The present memorandum presents such a to the etiologic and to the pathogenic
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classification; it briefly describes the criteria classification by which the former will ulti-
for diagnosis of the main types of hyperlipide- mately be replaced. The classification for
mia as well as the methods of their determina- genetic purposes is based on the assumption
tion. Because lipoproteins offer more informa- that the patient has been on a standard diet
tion than analysis of plasma lipids (most of prior to the analyses.
the plasma lipids being bound to various
proteins), the classification is based on lipo- Hyperlipidemia
protein analyses by electrophoresis and ultra- Cholesterol (Chol) and triglyceride (TG)
centrifugation. Simpler methods, however, analyses are the simplest means for detecting
such as the observation of plasma and hyperlipoproteinemia. They also provide some
measurements of cholesterol and triglycerides, information about the type of hyperlipopro-
are used to the fullest possible extent in teinemia because the proportion of these
determining the lipoprotein patterns. lipids varies from one lipoprotein family to
The plasma lipids circulate in lipoproteins; another.
each of the four main lipoprotein families, Knowledge of the concentrations of choles-
chylomicrons, pre-/3 (VLDL), ,8 (LDL), and terol and triglycerides permits the distinction
a (HDL) contains cholesterol, triglycerides, of three general types of hyperlipidemia that
and phospholipids; and the metabolism of the roughly correspond to certain types of hyper-
four lipoprotein families is different. These lipoproteinemias:
facts provide keys to the classification of (1) High cholesterol concentrations and
hyperlipidemias, because they indicate that normal triglyceride concentrations-this group,
sometimes called "pure hypercholesterolemia,"
Reprinted from the Bulletin of the World Health usually corresponds to hyper-,8-1ipoprotein-
Organization 43: 891, 1970, by permission. emia.
Circulation, Volume XLV, February 1972 501
 5-02 WHO MEMORANDUM

(2) High triglyceride and normal choles- patterns described. The methods of diagnosis
terol concentrations-this group usually cor- described are arranged in the order of
responds to either "pure hyperchylomicrone- practicality. Some tests are diagnostic (defini-
mia" or hyperpre-/3-lipoproteinemia. tive) of a given type; others are not.
(3) High cholesterol and high triglyceride Type 1-Hyperchylomicronemia
concentrations-all of the major types of
hyperlipoproteinemia, except "pure" hyper-,3- Criteria
lipoproteinemia, may occur in this group. (1) Chylomicrons present.
The heterogeneity of the third group (2) VLDL (pre-/3-lipoproteins) normal or
particularly emphasizes the need for a classifi- only slightly increased.
cation based on lipoproteins. Methods of Diagnosis
It is possible to refine a little the classifica- (1) Standing plasma contains a "cream"
tions of hyperlipidemias by adding a total layer over a clear infranatant layer (diagnostic
phospholipid (PL) measurement and also by test) .
calculating the following ratios: Chol/TG and (2) Plasma cholesterol usually increased;
Chol/PL. plasma triglyceride increased; Chol/TG less
The ratio Chol/TG indicates vhether the than 0.2; a ratio of less than 0.1 occurs only in
predominant elevation is in cholesterol or in type I.
triglyceride. The ratio Chol/PL often indi- (3) Electrophoresis-a heavy chylomicron
cates elevation of HDL (a-lipoproteins) band is present and is distinct from any
when it falls under 0.5. These refinements are lipoproteins trailing from the pre-/3 region;
not necessary to detect hyperlipidemia but do sometimes a- (HDL) and /3- (LDL) lipo-
offer some assistance in classification if lipo- protein bands are not visible; a pre-/3
proteins are not determined. (VLDL) baud may be absent or it may
Hyperlipoproteinemia appear with diminished, normal, or slightly
increased intensity and with trailing into the
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Hyperlipidemia can usually be resolved into

one of the abnormal lipoprotein patterns massive chylomicron band (usually diagnos-
summarized in table 1. For the sake of tic).
simplicity, these patterns or types can be (4) Ultracentrifugation-chylomicrons, mark-
numbered according to the system of Fred- edly increased; VLDL, usually increased
rickson and his colleagues. These patterns are (separation from chylomicrons incomplete);
not to be equated with single diseases and LDL markedly decreased; HDL markedly
each may have multiple causes. Most, but not decreased.
all, hyperlipidemia is represented by the six Comment. It must be noted that, in type I,
chylomicrons may sometimes be accompanied
Table 1 by an apparent modest increase in VLDL
Major Abnormal Lipo protein Patterns* and Their (pre-,3). This is partly due to the difficulty of
Type Numrzbers separating these two lipoprotein families. The
LDL VLDL Floating
amount of excess VLDL, however, is always
Type Chylomicrons (W-lp) (pre-,8-1p) d-lipoproteinst far less than the overwhelming amount of
I + chylomicrons.
Ila +
IIb + + Recommended Tests for Diagnosis
III + (1) Examination of standing plasma.
Iv + (2) Electrophoresis.
V + +
Type II-Hyper-p-lipoproteinemia
*+ indicates which lipoprotein "family" (families) Criterion
occurs in concentration above "normal" in the dif-
ferent abnormal patterns. Abnormal increase in LDL (,8) concentra-
tAlso known as "broad $-lipoproteins." tion.
Circulation, Volume XLV, February 1972
 HYPERLIPIDEMIAS, HYPERLIPOPROTEINEMIAS 503

Note. For some purposes it may be (2) Plasma cholesterol usually increased;
convenient to distinguish between two sub- plasma triglyceride always increased; Chol/
types of this pattern. These are referred to TG is variable (not diagnostic).
here as lla and lIb. In both, the criterion for (3) Electrophoresis-,3-lipoprotein band is
type II, an increase in LDL (,/3), is present, intensely stained; pre-,B band is increased in
but in one (IIb) an increase in VLDL intensity. Chylomicrons are not visible; a-
(pre-,8) is also present. Recognition of lipoproteins are usually normal (diagnostic
Ilb is important because it may require only if accompanied by estimations of LDL
treatment additional to that required for and VLDL concentrations) .
"pure" hypercholesterolemia. Both patterns (4) Ultracentrifugation-LDL (Sf 0-20) is
may occur in the same kindreds affected with increased; VLDL (Sf 20-400) is increased;
familial hyper-/3-lipoproteinemia; it is mainly chylomicrons are not increased; HDL is
for this reason that they must at present be usually normal (diagnostic).
considered under the main rubric of type II. Comment. Definite determination of type II
depends upon the establishment of an abnor-
Type Ila mal increase in LDL (,8) concentrations. This
Criteria is most precisely obtained by analytical or
(1) IncreaseinsLDL (/). preparative ultracentrifugation. It may also be
(2) Normal VLDL (pre-/3) concentra- estimated from the cholesterol, triglyceride,
tions. and HDL-cholesterol concentrations, as de-
Methods of Diagnosis
scribed above.
LDL can also be measured by immuno-
(1) Standing plasma clear (very helpful;
not always diagnostic). chemical analysis of the 1.006 infranatant
fractions using anti-LDL sera. (Such antisera
(2) Plasma cholesterol usually increased;
plasma triglycerides normal; Chol/TG al- also react with VLDL and therefore do not
permit accurate LDL determinations on
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ways > 1.5.

(3) Electrophoresis-an intensely stained
whole plasma.)
The type IIa pattern can usually be
,8-lipoprotein band is present; a pre-,3 band is ascertained by the cholesterol and triglyceride
either not present or, if present, is of normal
intensity. Chylomicrons are not visible; a-
analyses alone, especially when the Chol/TG
ratio is > 2. The exceptions are those patients
lipoproteins are usually normal (diagnostic
who may have abnormally increased LDL
only if accompanied by estimation of LDL
concentrations in the presence of a normal
concentration) .
plasma cholesterol concentration.
(4) Ultracentrifugation-LDL (Sf 0-20) is
increased. VLDL (Sf 20-400) is normal, HDL
The type IIb pattern is difficult to ascertain
from plasma lipids alone.
is usually normal, and chylomicrons are not
increased (diagnostic). Recommended Tests
Type IIb
(1) Chol plus TG plus electrophoresis,
when Chol/TG > 2.
Criteria
(2) Chol plus TG plus HDL (cholesterol
(1) Increase in LDL (/3). measurements after precipitation) for calcu-
(2) Increase in VLDL (pre-,8). lation of LDL (applicable only when type III
Methods of Diagnosis is excluded and TG < 400). If estimated LDL
(1) Standing plasma either clear or faintly is increased, assignment of subtypes is: lla
turbid throughout, without a chylomicron when TG is normal; JIb when TG is
( "cream") layer on the top (not diagnos- increased.
tic). (3) Ultracentrifugal analyses.
Circulation, Volume XLV, February 1972
 504 WHO MEMORANDUM
Type III-"Floating /" or "Broad /3" Pattern (4) Ultracentrifugation-in the analytical
Criterion ultracentrifuge the normally predominating
Presence of VLDL having abnormally high LDL subclass of density 1.010-1.063 (Sf 0-12)
cholesterol content and abnormal electropho- is greatly decreased and the LDL subclass of
retic mobility ("floating-/3"; ",/-VLDL"). density 1.006-1.019 (Sf 12-20) is disproportion-
Methods of Diagnosis
ately increased. The VLDL subclass (Sf
(1) Standing plasma usually turbid, fre- 100-400) is also increased. Chylomicrons may
be increased. This inversion of the usual
quently with a faint chylomicron "cream" concentrations of LDL and VLDL usually
layer (helpful but not diagnostic). provides a characteristic pattern in type III;
(2) Plasma cholesterol nearly always in- however, it is possible to have similar changes
creased; plasma triglycerides nearly always in total Sf 0-20 and Sf 20-400 subclasses in
increased; Chol/TG frequently about 1, but other types (very helpful but not always
may vary from 0.3 to > 2.0.
(3) Electrophoresis-on paper, agarose, or diagnostic).
cellulose acetate, there is usually a "broad /3"
The combination of preparative ultracentri-
fugation and electrophoresis described above
band extending from the position into the may be augmented by a measurement of
pre-,e position. This occurs in about two thirds
of plasma containing "floating /3." A distinct cholesterol and triglycerides in the VLDL
(density < 1.006) ultracentrifuge fraction
pre-/3 band is sometimes present and may be
increased in intensity: a-lipoproteins usually
(the latter may possibly be substituted for the
appear normal. A faint chylomicron band is
former). Normally, the Chol/TG ratio in
VLDL is 0.2 or less. Significantly higher ratios
often present even during periods of very low ( >0.4) are indicative of type III (probably
fat intake (helpful but not diagnostic). On diagnostic).
polyacrylamide gel electrophoresis (PGE) a Comment. The type III anomaly indicates
broadened pre-/3 (VLDL) band is present, the presence of abnormal VLDL or, more
and no lipoproteins are seen in the usual
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precisely, of abnormal LDL in the VLDL

position occupied by /-lipoproteins (LDL) fraction of plasma lipoproteins. It may be
on this medium. The concomitant presence of
suspected from a Chol/TG ratio of 1,
,3-migrating lipoproteins on paper, agarose, or especially when repeated analyses show
cellulose acetate and their absence on poly- marked lability of both Chol and TG concen-
acrylamide gel is a presumptive test for the trations, and a "broad 83', band appears on
type III anomaly and is about 95% accurate.
(The combination electrophoretic test is con- conventional electrophoresis. This combina-
sidered diagnostic.) tion may permit a presumptive diagnosis;
On starch-block electrophoresis of isolated however, the diagnosis should never be made
VLDL, two bands are obtained, one in the alone from conventional electrophoresis on a
usual a2 position (sometimes called "a(-
single medium.
VLDL") and one in an abnormal position The definitive test is the demonstration of
(",3-VLDL") (diagnostic). "floating /,," but an analysis of equivalent
Paper, agarose, cellulose acetate, or starch value may prove to be the measurement of
electrophoresis of the supernatant fraction of cholesterol and triglyceride in VLDL; com-
plasma after ultracentrifugation at its unadjust- bining electrophoresis on PGE and one other
ed salt density of 1.006 reveals /8-migrating medium permits a presumptive diagnosis. A
lipoproteins. Normally only pre-/3 migrating simpler, accurate diagnostic test is still de-
lipoproteins are present in the lipoprotein sired.
fraction of density <1.006. (The demonstra- Recommended Tests
tion of "floating is at present the definitive When the plasma Chol/TG ratio is close to
standard against which other diagnostic tests 1 and a "broad /3" band is suspected on
must be compared.) electrophoresis:
Circulation, Volume XLV, February 1972
 HYPERLIPIDEMIAS, HYPERLIPOPROTEINEMIAS 50S
(1) Plasma lipoprotein patterns obtained always used to assess pre-/3 concentrations
on polyacrylamide gel and on either paper, with electrophoresis, and it is always elevated
agarose, or cellulose acetate should be com- in type IV. Conversely, an apparent increase
pared. Absence of /3-migrating lipoproteins on in pre-,8 lipoproteins on electrophoresis will
PGE and their presence on the other systems not be accompanied by an increase in plasma
permits a presumptive diagnosis. TG if most of the pre-,8 represents "sinking
(2) When possible, confirmation of "float- pre-,/3 (see above). This is a normal phenom-
ing /3" (or VLDL having a high Chol/TG e'ion and its frequent occurrence emphasizes
ratio) should be made after preparative the need for TG concentrations to monitor
ultracentrifugation. electrophoresis. One should look for signs of
the "type III anomaly"; it is not necessary to
Type IV-Hyperpre-g-lipoproteinemia
exclude the anomaly by specific tests in most
Criteria instances of type IV.
(1) Increased VLDL (pre-,8).
(2) No increase in LDL (,3). Recommended Tests
(3) Chylomicrons absent. (1) For most samples, Chol plus TG plus
observation of plasma plus electrophoresis
Methods of Diagnosis permits a diagnosis.
(1) Standing plasma clear or turbid (2) Estimate LDL and exclude type III in
throughout with no overlying chylomicron doubtful cases.
layer (helpful but not diagnostic). (3) The ultracentrifuge can be very helpful
(2) Plasma cholesterol normal or increased;
plasma triglycerides increased; plasma in certain cases.
Chol/TG, variable (very helpful, sometimes Type V-Hyperpre-,3-lipoproteinemia and
diagnostic). Chylomicronemia
(3) Electrophoresis-increased intensity of Criteria
pre-,8-lipoprotein band; /3 band normal or (1) VLDL increased.
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decreased; a band may be normal, often (2) Chylomicrons present.

decreased; chylomicrons not visible. There
may be trailing of lipoproteins from the pre-/3 Methods of Diagnosis
region to the origin (helpful, but not diagnos- (1) Standing plasma-chylomicron ("cream")
tic without some quantification; see Com- layer overlying a turbid infranatant layer
ments, below). (diagnostic, if type III anomaly is excluded).
All of the isolated VLDL on starch-block (2) Plasma cholesterol increased; plasma
electrophoresis has the usual a2 mobility ( a2- triglyceride increased; plasma Chol/TG usual-
VLDL). There is no /3-VLDL, or "floating ,/," ly > 0.15 and <0.6 (helpful but not diagnos-
and VLDL has usual Chol/ TG ratio of 0.2 or tic) .
less. (3) Electrophoresis-pre-,/ band is in-
(4) Ultracentrifugation-VLDL (Sf 20-400) creased and frequently trails to origin where a
is increased; LDL (Sf 0-20) is normal or distinct accentuation indicates concomitant
decreased; HDL is normal or decreased; and presence of chylomicrons: /3- and a-lipopro-
chylomicrons are not increased (diagnostic). tein bands are usually decreased, often
Comments. If the plasma cholesterol is
definitely normal, triglycerides are clearly markedly so. There is no "floating /3" (can be
increased, and there are no chylomicrons diagnostic, if trailing pre-,/ does not obscure a
visible on standing plasma, then the determi- chylomicron band).
nation of type IV is fairly certain. The (4) Ultracentrifugation-chylomicrons and
accuracy of assignment is enhanced if electro- VLDL (Sf 20-400) increased. LDL, particular-
phoresis reveals a distinct pre-,3 band and a ly subclass Sf 0-12, and HDL are usually
distinct and diminished ,3 band. Plasma TG is decreased (diagnostic).
Circulation, Volume XLV, February 1972
 506 WHO MEMORANDUM
Comments. The major diagnostic problem, Xanthelasma is frequent in type II and
that of discerning chylomicrons by electro- sometimes occurs in type III, but often may
phoresis when pre-/3 (VLDL) concentrations be seen in the absence of hyperlipidemia or
are extremely high, can usually be overcome hyperlipoproteinemia.
by observation of standing plasma. The latter Arcus corneae (arcus senilis) is significant
is a very good test for type V. only when it appears before the age of 40
Recommended Test years. In younger people it usually implies
familial type II hyperlipoproteinemia.
(1) Examine standing plasma and measure
Chol plus TG. The typical appearance in type Other Clinical Signs
V may be imitated in two situations. One is a Pancreatitis or recurrent abdominal pain
type I pattern with enough VLDL to impart should lead to a suspicion of severe hyper-
faint turbidity to the infranatant layer. The glyceridemia (type I or V).
Chol/TG ratio is usually below 0.15 in type I
and usually above this in type V. The other Family History
situation is type III. Here the Chol/TG ratio is The family history often leads to the
often close to 1 but may be as low as 0.3. Test detection of hyperlipidemia: Ischemic heart
for "floating /3" should be done if any disease and other vascular accidents in young
uncertainty remains. relatives are usual in familial type II or type
IV hyperlipoproteinemia.
Additional Useful Clinical Data Diabetes is often seen in families of patients
Certain clinical signs, and other information with type IV or type V hyperlipoproteinemia,
that is relatively easy to obtain, are valuable even if the patient himself is not the
for the detection of hyperlipidemia and can diabetic.
sometimes be used to predict the type of
hyperlipoproteinemia that is present. Xan- Other Useful Laboratory Data
thomas and other lipid deposits and the These include some common laboratory
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familial history are the most valuable. tests, such as those for: thyroid function,
glucose tolerance, urinary protein, plasma
Lipid Deposits-Xanthcmas protein electrophoresis, immunoglobulin
Tendon xanthomas are not rare; they are quantification, liver function, and uric acid.
easy to detect, and are especially informative Certain special analyses may also be useful
because they almost invariably indicate hyper- and include: plasma postheparin lipolytic
lipoproteinemia of long duration. They usually activity, proportion of plasma cholesterol in
indicate hyper-,l-lipoproteinemia and almost the esterified form, lecithin cholesterol acyl-
always imply familial type II. transferase activity (LCAT), fat tolerance,
Tuberous xanthomas occur with type II and and vitamin A tolerance.
type III hyperlipoproteinemia. Somewhat sim-
ilar "tuberoeruptive" lesions appear with types Etiology of Hyperlipoproteinemia
III and IV. Eruptive xanthomas always Once the type pattern of hyperlipopro-
indicate severe hyperglyceridemia (usually teinemia has been established, it is necessary
type I or V). to consider etiology. One approach is to
Planar xanthomas occur with several kinds consider etiology as falling into two main
of hyperlipoproteinemia. In the familial dis- categories, secondary and primary hyperlipo-
orders, they occur on the palms of the hands proteinemias.
in type III and in homozygotes for type II.
They also may occur with obstructive liver Secondary to Known Diseases
disease. More widely distributed planar le- Common diseases that are often associated
sions, on the trunk and elsewhere, are rare and with hyperlipoproteinemia and that must
occur especially in hyperlipoproteinemia asso- always be excluded in considering etiology
ciated with dysglobulinemias. are: (1) hypothyroidism, (2) diabetes, (3)
Circulation, Volume XLV. February 1972
 HYPERLIPIDEMIAS, HYPERLIPOPROTEINEMIAS 507

nephrotic syndrome, (4) biliary obstruction, -lp . .Lipoproteins having /3-mobility

(5) pancreatitis, and (6) dysglobulinemia on elect.rophoresis band (same
as LDL)
(including autoimmune hyperlipoproteine- "/3-VLDL" .... . Lipoproteins of P-mobility float-
mia). The lipoprotein patterns that may be ing at density 1.006 (same as
associated with these diseases are shown in "floating /3-1p")
table 2. Broad 3-lp..... Same as "floating /3-1p"
Floating /3-lp.. Lipoproteins of P-mobility float-
Primary ing at density 1.006 (same as
These are hyperlipoproteinemias that are "broad /3-lp")
HDL ........ High-density lipoproteins, iso-
due to genetically determined defects in lipid lated between density 1.063
or lipoprotein metabolism or are caused by and 1.21 (same as a-lp)
some environmental factors through an un- Hyperlipemia. A lactescent appearance of plas-
known mechanism. ma due to increased concen-
trations of glycerides in either
All five major types of hyperlipoproteinemia VLDL or chylomicrons
may be familial and probably represent many Hyperlipidemia. An increase in concentration of
different mutations. any plasma lipid constituent;
Environmental factors that may cause pri- for practical purposes usually
confined to cholesterol or tri-
mary hyperlipoproteinemia include: (1) diet, glycerides, or both
including alcohol intake; and (2) drugs. Many Hyperlipoproteinemia An increase in plasma concen-
drugs cause hyperlipidemia, particularly the tration of one or more lipo-
estrogens as contained in contraceptive medi- protein families; nearly always
accompanied by hyperlipi-
cations, and steroid hormones. demia
A proper classification of hyperlipopro- LDL.......... Low-density lipoproteins (same
teinemia should include reference to both as P-lp)
lipoprotein pattern and etiology. Lp antigen (Berg) A form of genetic polymorphism
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of lipoprotein
Glossary of Relevant Terms Lp-X .......... Lipoprotein-X (complexes main-
Abetalipoproteinemia Absence of /-lipoprotein ly of phospholipid, unesteri-
a-lp (a 1-lp) Lipoproteins appearing in the a fled cholesterol, and VLDL
(a1) electrophoresis band apoprotein seen in obstructive
(same as HDL) liver disease)
Pre-/3-lp .......... Lipoproteins appearing in the
Table 2 pre-p electrophoresis band
(same as VLDL)
Types of Hyperlipoproteinemnia Associated with Sf value .......... Svedberg unit of flotation
Selected Comrmon Diseases* "Sinking" pre-/3-lp.. Pre-js lipoproteins that sediment
Types of at density 1.006
Disorder hyperlipoproteinemia Tangier disease ..... Familial deficiency of HDL
Hypothyroidism II, IV VLDL ........ Very low-density lipoproteins
Insulin-dependent diabetes I, IV, V (II, III)* (pre-p3-lipoproteins)
(uncontrolled)
Nephrotic syndrome II, IV, V J. L. BEAUMONT, Doyen de la Faculte de
Biliary obstruction Does not conform Medecine de Creteil, Unite de Recherches
predictably to sur l'Atherosclerose, Hopital Henri Mondor,
any of the Creteil, France
major types L. A. CARLSON, Professor of Medicine, De-
Pancreatitis IV, V
Dysglobulinemia I, II, IV, V (III)* partment of Geriatrics, Uppsala University,
Autoimmune Uppsala, Sweden
hyperlipoproteinemia 1, III, IV, V (II)* G. R. COOPER, Medical Director, Chief,
*Secondary hyperlipoproteinemias are shown in Clinical Chemistry and Hematology Branch,
parentheses. Center for Disease Control, Atlanta, Georgia
Circulation, Volume XLV, February 1972
 5()8 WHO MEMORANDUM

Z. FEJFAR, Chief, Cardiovascular Diseases, JB, Fredrickson DS. New York, McGraw-Hill Book
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T. STRASSER, Medical Officer, Cardiovascular Analysis, edited by Glick D. New York, Interscience
Diseases, World Health Organization, Ge- Publishers, Inc., 1954, vol 1
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Circulation, Volume XLV, February 1972