worldhealth organization memorandum classification...

WORLD HEALTH ORGANIZATIONMEMORANDUM

Classification of Hyperlipidemiasand Hyperlipoproteinemias

M ANY STUDIES OF atherosclerosis haveindicated hyperlipidemia as a predis-

posing factor to vascular disease. The relation-ship holds even for mild degrees of hyperlipi-demia, a fact that underlines the importanceof this category of disorders. Both primaryand secondary hyperlipidemias represent sucha variety of abnormalities that an internation-ally acceptable provisional classification ishighly desirable in order to facilitate commun-ication between scientists with different back-grounds.The present memorandum presents such a

classification; it briefly describes the criteriafor diagnosis of the main types of hyperlipide-mia as well as the methods of their determina-tion. Because lipoproteins offer more informa-tion than analysis of plasma lipids (most ofthe plasma lipids being bound to variousproteins), the classification is based on lipo-protein analyses by electrophoresis and ultra-centrifugation. Simpler methods, however,such as the observation of plasma andmeasurements of cholesterol and triglycerides,are used to the fullest possible extent indetermining the lipoprotein patterns.The plasma lipids circulate in lipoproteins;

each of the four main lipoprotein families,chylomicrons, pre-/3 (VLDL), ,8 (LDL), anda (HDL) contains cholesterol, triglycerides,and phospholipids; and the metabolism of thefour lipoprotein families is different. Thesefacts provide keys to the classification ofhyperlipidemias, because they indicate that

(1) hyperlipoproteinemia very seldom occurs

without hyperlipidemia and, consequently,hyperllpidemia may be used to detect hyper-lipoproteinemia; (2) a classification based on

lipoproteins offers more information than one

based on lipids alone; (3) a classificationshould distinguish between disorders in themetabolism of lipoproteins as well as lipids.The proposed classification described here

includes, step by step, the use of lipidanalyses, lipoprotein analyses, and other clini-cal and biologic data. It provides an approachto the etiologic and to the pathogenicclassification by which the former will ulti-mately be replaced. The classification forgenetic purposes is based on the assumptionthat the patient has been on a standard dietprior to the analyses.

HyperlipidemiaCholesterol (Chol) and triglyceride (TG)

analyses are the simplest means for detectinghyperlipoproteinemia. They also provide some

information about the type of hyperlipopro-teinemia because the proportion of theselipids varies from one lipoprotein family toanother.Knowledge of the concentrations of choles-

terol and triglycerides permits the distinctionof three general types of hyperlipidemia thatroughly correspond to certain types of hyper-lipoproteinemias:

(1) High cholesterol concentrations andnormal triglyceride concentrations-this group,

sometimes called "pure hypercholesterolemia,"usually corresponds to hyper-,8-1ipoprotein-emia.

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WHO MEMORANDUM

(2) High triglyceride and normal choles-terol concentrations-this group usually cor-responds to either "pure hyperchylomicrone-mia" or hyperpre-/3-lipoproteinemia.

(3) High cholesterol and high triglycerideconcentrations-all of the major types ofhyperlipoproteinemia, except "pure" hyper-,3-lipoproteinemia, may occur in this group.The heterogeneity of the third group

particularly emphasizes the need for a classifi-cation based on lipoproteins.

It is possible to refine a little the classifica-tions of hyperlipidemias by adding a totalphospholipid (PL) measurement and also bycalculating the following ratios: Chol/TG andChol/PL.The ratio Chol/TG indicates vhether the

predominant elevation is in cholesterol or intriglyceride. The ratio Chol/PL often indi-cates elevation of HDL (a-lipoproteins)when it falls under 0.5. These refinements arenot necessary to detect hyperlipidemia but dooffer some assistance in classification if lipo-proteins are not determined.

HyperlipoproteinemiaHyperlipidemia can usually be resolved into

one of the abnormal lipoprotein patternssummarized in table 1. For the sake ofsimplicity, these patterns or types can benumbered according to the system of Fred-rickson and his colleagues. These patterns arenot to be equated with single diseases andeach may have multiple causes. Most, but notall, hyperlipidemia is represented by the six

Table 1Major Abnormal Lipoprotein Patterns* and TheirType Numrzbers

LDL VLDL FloatingType Chylomicrons (W-lp) (pre-,8-1p) d-lipoproteinst

I +Ila +IIb + +III +Iv +V + +

*+ indicates which lipoprotein "family" (families)occurs in concentration above "normal" in the dif-ferent abnormal patterns.

tAlso known as "broad $-lipoproteins."

patterns described. The methods of diagnosisdescribed are arranged in the order ofpracticality. Some tests are diagnostic (defini-tive) of a given type; others are not.

Type 1-Hyperchylomicronemia

Criteria(1) Chylomicrons present.(2) VLDL (pre-/3-lipoproteins) normal or

only slightly increased.

Methods of Diagnosis(1) Standing plasma contains a "cream"

layer over a clear infranatant layer (diagnostictest) .

(2) Plasma cholesterol usually increased;plasma triglyceride increased; Chol/TG lessthan 0.2; a ratio of less than 0.1 occurs only intype I.

(3) Electrophoresis-a heavy chylomicronband is present and is distinct from anylipoproteins trailing from the pre-/3 region;sometimes a- (HDL) and /3- (LDL) lipo-protein bands are not visible; a pre-/3(VLDL) baud may be absent or it mayappear with diminished, normal, or slightlyincreased intensity and with trailing into themassive chylomicron band (usually diagnos-tic) .

(4) Ultracentrifugation-chylomicrons, mark-edly increased; VLDL, usually increased(separation from chylomicrons incomplete);LDL markedly decreased; HDL markedlydecreased.Comment. It must be noted that, in type I,

chylomicrons may sometimes be accompaniedby an apparent modest increase in VLDL(pre-,3). This is partly due to the difficulty ofseparating these two lipoprotein families. Theamount of excess VLDL, however, is alwaysfar less than the overwhelming amount ofchylomicrons.

Recommended Tests for Diagnosis

(1) Examination of standing plasma.(2) Electrophoresis.

Type II-Hyper-p-lipoproteinemiaCriterionAbnormal increase in LDL (,8) concentra-

tion.Circulation, Volume XLV, February 1972

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HYPERLIPIDEMIAS, HYPERLIPOPROTEINEMIAS

Note. For some purposes it may beconvenient to distinguish between two sub-types of this pattern. These are referred tohere as lla and lIb. In both, the criterion fortype II, an increase in LDL (,/3), is present,but in one (IIb) an increase in VLDL(pre-,8) is also present. Recognition ofIlb is important because it may requiretreatment additional to that required for"pure" hypercholesterolemia. Both patternsmay occur in the same kindreds affected withfamilial hyper-/3-lipoproteinemia; it is mainlyfor this reason that they must at present beconsidered under the main rubric of type II.

Type Ila

Criteria

(1) IncreaseinsLDL (/).

(2) Normal VLDL (pre-/3)

tions.

concentra-

Methods of Diagnosis

(1) Standing plasma clear (very helpful;not always diagnostic).

(2) Plasma cholesterol usually increased;plasma triglycerides normal; Chol/TG al-ways > 1.5.

(3) Electrophoresis-an intensely stained,8-lipoprotein band is present; a pre-,3 band iseither not present or, if present, is of normalintensity. Chylomicrons are not visible; a-

lipoproteins are usually normal (diagnosticonly if accompanied by estimation of LDLconcentration) .

(4) Ultracentrifugation-LDL (Sf 0-20) isincreased. VLDL (Sf 20-400) is normal, HDLis usually normal, and chylomicrons are notincreased (diagnostic).

Type IIb

Criteria

(1) Increase in LDL (/3).(2) Increase in VLDL (pre-,8).

Methods of Diagnosis(1) Standing plasma either clear or faintly

turbid throughout, without a chylomicron("cream") layer on the top (not diagnos-tic).Circulation, Volume XLV, February 1972

(2) Plasma cholesterol usually increased;plasma triglyceride always increased; Chol/TG is variable (not diagnostic).

(3) Electrophoresis-,3-lipoprotein band isintensely stained; pre-,B band is increased inintensity. Chylomicrons are not visible; a-lipoproteins are usually normal (diagnosticonly if accompanied by estimations of LDLand VLDL concentrations) .

(4) Ultracentrifugation-LDL (Sf 0-20) isincreased; VLDL (Sf 20-400) is increased;chylomicrons are not increased; HDL isusually normal (diagnostic).Comment. Definite determination of type II

depends upon the establishment of an abnor-mal increase in LDL (,8) concentrations. Thisis most precisely obtained by analytical orpreparative ultracentrifugation. It may also beestimated from the cholesterol, triglyceride,and HDL-cholesterol concentrations, as de-scribed above.LDL can also be measured by immuno-

chemical analysis of the 1.006 infranatantfractions using anti-LDL sera. (Such antiseraalso react with VLDL and therefore do notpermit accurate LDL determinations onwhole plasma.)The type IIa pattern can usually be

ascertained by the cholesterol and triglycerideanalyses alone, especially when the Chol/TGratio is > 2. The exceptions are those patientswho may have abnormally increased LDLconcentrations in the presence of a normalplasma cholesterol concentration.The type IIb pattern is difficult to ascertain

from plasma lipids alone.

Recommended Tests(1) Chol plus TG plus electrophoresis,

when Chol/TG > 2.(2) Chol plus TG plus HDL (cholesterol

measurements after precipitation) for calcu-lation of LDL (applicable only when type IIIis excluded and TG < 400). If estimated LDLis increased, assignment of subtypes is: llawhen TG is normal; JIb when TG isincreased.

(3) Ultracentrifugal analyses.

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WHO MEMORANDUM

Type III-"Floating /" or "Broad /3" Pattern

Criterion

Presence of VLDL having abnormally highcholesterol content and abnormal electropho-retic mobility ("floating-/3"; ",/-VLDL").Methods of Diagnosis

(1) Standing plasma usually turbid, fre-quently with a faint chylomicron "cream"layer (helpful but not diagnostic).

(2) Plasma cholesterol nearly always in-creased; plasma triglycerides nearly alwaysincreased; Chol/TG frequently about 1, butmay vary from 0.3 to > 2.0.

(3) Electrophoresis-on paper, agarose, or

cellulose acetate, there is usually a "broad /3"

band extending from the position into thepre-,e position. This occurs in about two thirdsof plasma containing "floating /3." A distinctpre-/3 band is sometimes present and may beincreased in intensity: a-lipoproteins usuallyappear normal. A faint chylomicron band isoften present even during periods of very lowfat intake (helpful but not diagnostic). Onpolyacrylamide gel electrophoresis (PGE) a

broadened pre-/3 (VLDL) band is present,and no lipoproteins are seen in the usualposition occupied by /-lipoproteins (LDL)on this medium. The concomitant presence of,3-migrating lipoproteins on paper, agarose, or

cellulose acetate and their absence on poly-acrylamide gel is a presumptive test for thetype III anomaly and is about 95% accurate.(The combination electrophoretic test is con-

sidered diagnostic.)On starch-block electrophoresis of isolated

VLDL, two bands are obtained, one in theusual a2 position (sometimes called "a(-VLDL") and one in an abnormal position(",3-VLDL") (diagnostic).Paper, agarose, cellulose acetate, or starch

electrophoresis of the supernatant fraction ofplasma after ultracentrifugation at its unadjust-ed salt density of 1.006 reveals /8-migratinglipoproteins. Normally only pre-/3 migratinglipoproteins are present in the lipoproteinfraction of density <1.006. (The demonstra-tion of "floating is at present the definitivestandard against which other diagnostic testsmust be compared.)

(4) Ultracentrifugation-in the analyticalultracentrifuge the normally predominatingLDL subclass of density 1.010-1.063 (Sf 0-12)is greatly decreased and the LDL subclass ofdensity 1.006-1.019 (Sf 12-20) is disproportion-ately increased. The VLDL subclass (Sf100-400) is also increased. Chylomicrons maybe increased. This inversion of the usualconcentrations of LDL and VLDL usuallyprovides a characteristic pattern in type III;however, it is possible to have similar changesin total Sf 0-20 and Sf 20-400 subclasses inother types (very helpful but not alwaysdiagnostic).The combination of preparative ultracentri-

fugation and electrophoresis described abovemay be augmented by a measurement ofcholesterol and triglycerides in the VLDL(density < 1.006) ultracentrifuge fraction(the latter may possibly be substituted for theformer). Normally, the Chol/TG ratio inVLDL is 0.2 or less. Significantly higher ratios( >0.4) are indicative of type III (probablydiagnostic).Comment. The type III anomaly indicates

the presence of abnormal VLDL or, moreprecisely, of abnormal LDL in the VLDLfraction of plasma lipoproteins. It may besuspected from a Chol/TG ratio of 1,especially when repeated analyses showmarked lability of both Chol and TG concen-trations, and a "broad 83', band appears onconventional electrophoresis. This combina-tion may permit a presumptive diagnosis;however, the diagnosis should never be madealone from conventional electrophoresis on asingle medium.The definitive test is the demonstration of

"floating /,," but an analysis of equivalentvalue may prove to be the measurement ofcholesterol and triglyceride in VLDL; com-bining electrophoresis on PGE and one othermedium permits a presumptive diagnosis. Asimpler, accurate diagnostic test is still de-sired.

Recommended TestsWhen the plasma Chol/TG ratio is close to

1 and a "broad /3" band is suspected onelectrophoresis:


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(1) Plasma lipoprotein patterns obtainedon polyacrylamide gel and on either paper,agarose, or cellulose acetate should be com-pared. Absence of /3-migrating lipoproteins onPGE and their presence on the other systemspermits a presumptive diagnosis.

(2) When possible, confirmation of "float-ing /3" (or VLDL having a high Chol/TGratio) should be made after preparativeultracentrifugation.

Type IV-Hyperpre-g-lipoproteinemia

Criteria

(1) Increased VLDL (pre-,8).(2) No increase in LDL (,3).(3) Chylomicrons absent.

Methods of Diagnosis(1) Standing plasma clear or turbid

throughout with no overlying chylomicronlayer (helpful but not diagnostic).

(2) Plasma cholesterol normal or increased;plasma triglycerides increased; plasmaChol/TG, variable (very helpful, sometimesdiagnostic).

(3) Electrophoresis-increased intensity ofpre-,8-lipoprotein band; /3 band normal ordecreased; a band may be normal, oftendecreased; chylomicrons not visible. Theremay be trailing of lipoproteins from the pre-/3region to the origin (helpful, but not diagnos-tic without some quantification; see Com-ments, below).

All of the isolated VLDL on starch-blockelectrophoresis has the usual a2 mobility ( a2-VLDL). There is no /3-VLDL, or "floating ,/,"and VLDL has usual Chol/TG ratio of 0.2 orless.

(4) Ultracentrifugation-VLDL (Sf 20-400)is increased; LDL (Sf 0-20) is normal ordecreased; HDL is normal or decreased; andchylomicrons are not increased (diagnostic).Comments. If the plasma cholesterol is

definitely normal, triglycerides are clearlyincreased, and there are no chylomicronsvisible on standing plasma, then the determi-nation of type IV is fairly certain. Theaccuracy of assignment is enhanced if electro-phoresis reveals a distinct pre-,3 band and adistinct and diminished ,3 band. Plasma TG is


always used to assess pre-/3 concentrationswith electrophoresis, and it is always elevatedin type IV. Conversely, an apparent increasein pre-,8 lipoproteins on electrophoresis willnot be accompanied by an increase in plasmaTG if most of the pre-,8 represents "sinkingpre-,/3 (see above). This is a normal phenom-e'ion and its frequent occurrence emphasizesthe need for TG concentrations to monitorelectrophoresis. One should look for signs ofthe "type III anomaly"; it is not necessary toexclude the anomaly by specific tests in mostinstances of type IV.

Recommended Tests(1) For most samples, Chol plus TG plus

observation of plasma plus electrophoresispermits a diagnosis.

(2) Estimate LDL and exclude type III indoubtful cases.

(3) The ultracentrifuge can be very helpfulin certain cases.

Type V-Hyperpre-,3-lipoproteinemia andChylomicronemia

Criteria

(1) VLDL increased.(2) Chylomicrons present.

Methods of Diagnosis(1) Standing plasma-chylomicron ("cream")

layer overlying a turbid infranatant layer(diagnostic, if type III anomaly is excluded).

(2) Plasma cholesterol increased; plasmatriglyceride increased; plasma Chol/TG usual-ly > 0.15 and <0.6 (helpful but not diagnos-tic) .

(3) Electrophoresis-pre-,/ band is in-creased and frequently trails to origin where adistinct accentuation indicates concomitantpresence of chylomicrons: /3- and a-lipopro-tein bands are usually decreased, oftenmarkedly so. There is no "floating /3" (can bediagnostic, if trailing pre-,/ does not obscure achylomicron band).

(4) Ultracentrifugation-chylomicrons andVLDL (Sf 20-400) increased. LDL, particular-ly subclass Sf 0-12, and HDL are usuallydecreased (diagnostic).

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WHO MEMORANDUM

Comments. The major diagnostic problem,that of discerning chylomicrons by electro-phoresis when pre-/3 (VLDL) concentrationsare extremely high, can usually be overcomeby observation of standing plasma. The latteris a very good test for type V.

Recommended Test(1) Examine standing plasma and measure

Chol plus TG. The typical appearance in typeV may be imitated in two situations. One is atype I pattern with enough VLDL to impartfaint turbidity to the infranatant layer. TheChol/TG ratio is usually below 0.15 in type Iand usually above this in type V. The othersituation is type III. Here the Chol/TG ratio isoften close to 1 but may be as low as 0.3. Testfor "floating /3" should be done if anyuncertainty remains.

Additional Useful Clinical Data

Certain clinical signs, and other informationthat is relatively easy to obtain, are valuablefor the detection of hyperlipidemia and cansometimes be used to predict the type ofhyperlipoproteinemia that is present. Xan-thomas and other lipid deposits and thefamilial history are the most valuable.Lipid Deposits-XanthcmasTendon xanthomas are not rare; they are

easy to detect, and are especially informativebecause they almost invariably indicate hyper-lipoproteinemia of long duration. They usuallyindicate hyper-,l-lipoproteinemia and almostalways imply familial type II.Tuberous xanthomas occur with type II and

type III hyperlipoproteinemia. Somewhat sim-ilar "tuberoeruptive" lesions appear with typesIII and IV. Eruptive xanthomas alwaysindicate severe hyperglyceridemia (usuallytype I or V).

Planar xanthomas occur with several kindsof hyperlipoproteinemia. In the familial dis-orders, they occur on the palms of the handsin type III and in homozygotes for type II.They also may occur with obstructive liverdisease. More widely distributed planar le-sions, on the trunk and elsewhere, are rare andoccur especially in hyperlipoproteinemia asso-ciated with dysglobulinemias.

Xanthelasma is frequent in type II andsometimes occurs in type III, but often maybe seen in the absence of hyperlipidemia orhyperlipoproteinemia.Arcus corneae (arcus senilis) is significant

only when it appears before the age of 40years. In younger people it usually impliesfamilial type II hyperlipoproteinemia.

Other Clinical SignsPancreatitis or recurrent abdominal pain

should lead to a suspicion of severe hyper-glyceridemia (type I or V).

Family History

The family history often leads to thedetection of hyperlipidemia: Ischemic heartdisease and other vascular accidents in youngrelatives are usual in familial type II or typeIV hyperlipoproteinemia.

Diabetes is often seen in families of patientswith type IV or type V hyperlipoproteinemia,even if the patient himself is not thediabetic.

Other Useful Laboratory DataThese include some common laboratory

tests, such as those for: thyroid function,glucose tolerance, urinary protein, plasmaprotein electrophoresis, immunoglobulinquantification, liver function, and uric acid.

Certain special analyses may also be usefuland include: plasma postheparin lipolyticactivity, proportion of plasma cholesterol inthe esterified form, lecithin cholesterol acyl-transferase activity (LCAT), fat tolerance,and vitamin A tolerance.

Etiology of HyperlipoproteinemiaOnce the type pattern of hyperlipopro-

teinemia has been established, it is necessaryto consider etiology. One approach is toconsider etiology as falling into two maincategories, secondary and primary hyperlipo-proteinemias.

Secondary to Known DiseasesCommon diseases that are often associated

with hyperlipoproteinemia and that mustalways be excluded in considering etiologyare: (1) hypothyroidism, (2) diabetes, (3)

Circulation, Volume XLV. February 1972

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nephrotic syndrome, (4) biliary obstruction,(5) pancreatitis, and (6) dysglobulinemia(including autoimmune hyperlipoproteine-mia). The lipoprotein patterns that may beassociated with these diseases are shown intable 2.

Primary

These are hyperlipoproteinemias that aredue to genetically determined defects in lipidor lipoprotein metabolism or are caused bysome environmental factors through an un-known mechanism.

All five major types of hyperlipoproteinemiamay be familial and probably represent manydifferent mutations.

Environmental factors that may cause pri-mary hyperlipoproteinemia include: (1) diet,including alcohol intake; and (2) drugs. Manydrugs cause hyperlipidemia, particularly theestrogens as contained in contraceptive medi-cations, and steroid hormones.A proper classification of hyperlipopro-

teinemia should include reference to bothlipoprotein pattern and etiology.

Glossary of Relevant TermsAbetalipoproteinemiaa-lp (a 1-lp)

Absence of /-lipoproteinLipoproteins appearing in the a

(a1) electrophoresis band(same as HDL)

Table 2

Types of Hyperlipoproteinemnia Associated withSelected Comrmon Diseases*

Types ofDisorder hyperlipoproteinemia

Hypothyroidism II, IVInsulin-dependent diabetes I, IV, V (II, III)*

(uncontrolled)Nephrotic syndrome II, IV, VBiliary obstruction Does not conform

predictably toany of themajor types

Pancreatitis IV, VDysglobulinemia I, II, IV, V (III)*Autoimmune

hyperlipoproteinemia 1, III, IV, V (II)*

*Secondary hyperlipoproteinemias are shown inparentheses.Circulation, Volume XLV, February 1972

-lp . .Lipoproteins having /3-mobilityon elect.rophoresis band (same

"/3-VLDL" ....

Broad 3-lp.....Floating /3-lp..

HDL ........

Hyperlipemia.

Hyperlipidemia.

as LDL). Lipoproteins of P-mobility float-

ing at density 1.006 (same as"floating /3-1p")

Same as "floating /3-1p"Lipoproteins of P-mobility float-

ing at density 1.006 (same as"broad /3-lp")

High-density lipoproteins, iso-lated between density 1.063and 1.21 (same as a-lp)

A lactescent appearance of plas-ma due to increased concen-trations of glycerides in eitherVLDL or chylomicrons

An increase in concentration ofany plasma lipid constituent;for practical purposes usuallyconfined to cholesterol or tri-glycerides, or both

Hyperlipoproteinemia An increase in plasma concen-tration of one or more lipo-protein families; nearly alwaysaccompanied by hyperlipi-demia

LDL.......... Low-density lipoproteins (sameas P-lp)

Lp antigen (Berg) A form of genetic polymorphismof lipoprotein

Lp-X .......... Lipoprotein-X (complexes main-ly of phospholipid, unesteri-fled cholesterol, and VLDLapoprotein seen in obstructiveliver disease)

Pre-/3-lp .......... Lipoproteins appearing in thepre-p electrophoresis band(same as VLDL)

Sf value.......... Svedberg unit of flotation"Sinking" pre-/3-lp.. Pre-js lipoproteins that sediment

at density 1.006Tangier disease ..... Familial deficiency of HDLVLDL ........ Very low-density lipoproteins

(pre-p3-lipoproteins)J. L. BEAUMONT, Doyen de la Faculte deMedecine de Creteil, Unite de Recherchessur l'Atherosclerose, Hopital Henri Mondor,Creteil, France

L. A. CARLSON, Professor of Medicine, De-partment of Geriatrics, Uppsala University,Uppsala, Sweden

G. R. COOPER, Medical Director, Chief,Clinical Chemistry and Hematology Branch,Center for Disease Control, Atlanta, Georgia

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WHO MEMORANDUM

Z. FEJFAR, Chief, Cardiovascular Diseases,World Health Organization, Geneva, Swit-zerland

D. S. FREDRICKSON, Chief, Molecular DiseaseBranch and Director of Intramural Re-search, National Heart and Lung Institute,National Institutes of Health, Bethesda,Maryland

T. STRASSER, Medical Officer, CardiovascularDiseases, World Health Organization, Ge-neva, Switzerland

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Classification of Hyperlipidemias and Hyperlipoproteinemias

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