`MEMORANDUM
`
`Classification of Hyperlipidemias
`and Hyperlipoproteinemias
`
`M ANY STUDIES OF atherosclerosis have
`indicated 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 importance
`of this category of disorders. Both primary
`and secondary hyperlipidemias represent such
`a variety of abnormalities that an internation-
`ally acceptable provisional
`classification
`is
`highly desirable in order to facilitate commun-
`ication between scientists with different back-
`grounds.
`The present memorandum presents such a
`classification; it briefly describes the criteria
`for 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 of
`the plasma lipids being bound to various
`proteins), the classification is based on lipo-
`protein analyses by electrophoresis and ultra-
`Simpler methods,
`however,
`centrifugation.
`and
`of plasma
`observation
`the
`such
`as
`measurements of cholesterol and triglycerides,
`are used to the fullest possible extent in
`determining the lipoprotein patterns.
`The plasma lipids circulate in lipoproteins;
`each of the four main lipoprotein families,
`chylomicrons, pre-/3 (VLDL), ,8 (LDL), and
`a (HDL) contains cholesterol, triglycerides,
`and phospholipids; and the metabolism of the
`four lipoprotein families is different. These
`of
`facts provide keys to the classification
`hyperlipidemias, because they indicate that
`
`Reprinted from the Bulletin of the World Health
`Organization 43: 891, 1970, by permission.
`Circulation, Volume XLV, February 1972
`
`501
`
`(1) hyperlipoproteinemia very seldom occurs
`consequently,
`and,
`without hyperlipidemia
`hyperllpidemia may be used to detect hyper-
`lipoproteinemia; (2) a classification based on
`lipoproteins offers more information than one
`a classification
`(3)
`based on lipids alone;
`should distinguish between disorders in the
`metabolism of lipoproteins as well as lipids.
`The proposed classification described here
`of
`lipid
`the use
`step by step,
`includes,
`analyses, lipoprotein analyses, and other clini-
`cal and biologic data. It provides an approach
`pathogenic
`the
`and to
`etiologic
`the
`to
`classification by which the former will ulti-
`for
`mately be replaced. The classification
`genetic purposes is based on the assumption
`that the patient has been on a standard diet
`prior to the analyses.
`
`Hyperlipidemia
`Cholesterol (Chol) and triglyceride (TG)
`analyses are the simplest means for detecting
`hyperlipoproteinemia. They also provide some
`information about the type of hyperlipopro-
`teinemia because the proportion of these
`lipids varies from one lipoprotein family to
`another.
`Knowledge of the concentrations of choles-
`terol and triglycerides permits the distinction
`of three general types of hyperlipidemia that
`roughly correspond to certain types of hyper-
`lipoproteinemias:
`concentrations and
`(1) High cholesterol
`normal triglyceride concentrations-this group,
`sometimes called "pure hypercholesterolemia,"
`usually corresponds to hyper-,8-1ipoprotein-
`emia.
`
`Downloaded from http://ahajournals.org by on November 19, 2021
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1034, p. 1 of 8
`
`
`
`5-02
`
`(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 triglyceride
`of
`the major types
`concentrations-all
`of
`hyperlipoproteinemia, 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 total
`phospholipid (PL) measurement and also by
`calculating the following ratios: Chol/TG and
`Chol/PL.
`vhether the
`The ratio Chol/TG indicates
`predominant elevation is in cholesterol or in
`triglyceride. The ratio Chol/PL often indi-
`of HDL (a-lipoproteins)
`elevation
`cates
`when it falls under 0.5. These refinements are
`not necessary to detect hyperlipidemia but do
`offer some assistance in classification if lipo-
`proteins are not determined.
`Hyperlipoproteinemia
`Hyperlipidemia can usually be resolved into
`one of the abnormal lipoprotein
`patterns
`summarized in
`table
`1. For the sake of
`simplicity, these patterns or types can be
`numbered according to the system of Fred-
`rickson and his colleagues. These patterns are
`not to be equated with single diseases and
`each may have multiple causes. Most, but not
`all, hyperlipidemia is represented by the six
`
`Table 1
`Major Abnormal Lipoprotein Patterns* and Their
`Type Numrzbers
`
`Type
`I
`Ila
`IIb
`III
`Iv
`V
`
`Chylomicrons
`+
`
`+
`
`LDL
`(W-lp)
`
`VLDL
`(pre-,8-1p)
`
`Floating
`d-lipoproteinst
`
`+
`+
`
`+
`
`+
`+
`
`+
`
`*+ indicates which lipoprotein "family" (families)
`occurs in concentration above "normal" in the dif-
`ferent abnormal patterns.
`tAlso known as "broad $-lipoproteins."
`
`WHO MEMORANDUM
`
`patterns described. The methods of diagnosis
`arranged
`described
`the
`order
`of
`in
`are
`practicality. 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 (diagnostic
`test).
`(2) Plasma cholesterol usually increased;
`plasma triglyceride increased; Chol/TG less
`than 0.2; a ratio of less than 0.1 occurs only in
`type I.
`(3) Electrophoresis-a heavy chylomicron
`distinct from any
`band is present and is
`lipoproteins trailing from the pre-/3 region;
`sometimes a- (HDL) and /3- (LDL) lipo-
`pre-/3
`visible;
`bands
`protein
`a
`are
`not
`(VLDL) baud may be absent or it may
`appear with diminished, normal, or slightly
`increased intensity and with trailing into the
`massive chylomicron band (usually diagnos-
`tic).
`(4) Ultracentrifugation-chylomicrons, mark-
`increased; VLDL, usually
`edly
`increased
`(separation from chylomicrons incomplete);
`LDL markedly decreased; HDL markedly
`decreased.
`Comment. It must be noted that, in type I,
`chylomicrons may sometimes be accompanied
`by an apparent modest increase in VLDL
`(pre-,3). This is partly due to the difficulty of
`separating these two lipoprotein families. The
`amount of excess VLDL, however, is always
`far less than the overwhelming amount of
`chylomicrons.
`
`Recommended Tests for Diagnosis
`(1) Examination of standing plasma.
`(2) Electrophoresis.
`Type II-Hyper-p-lipoproteinemia
`Criterion
`Abnormal increase in LDL (,8) concentra-
`tion.
`
`Circulation, Volume XLV, February 1972
`
`Downloaded from http://ahajournals.org by on November 19, 2021
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1034, p. 2 of 8
`
`
`
`HYPERLIPIDEMIAS, HYPERLIPOPROTEINEMIAS
`
`503
`
`it may be
`For some purposes
`Note.
`convenient to distinguish between two sub-
`types of this pattern. These are referred to
`here as lla and lIb. In both, the criterion for
`type II, an increase in LDL (,/3), is present,
`but in one (IIb)
`in VLDL
`an increase
`(pre-,8)
`of
`also
`Recognition
`present.
`is
`is important because it may require
`Ilb
`for
`that required
`to
`treatment additional
`"pure" hypercholesterolemia.
`Both patterns
`may occur in the same kindreds affected with
`familial hyper-/3-lipoproteinemia; it is mainly
`for this reason that they must at present be
`considered 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;
`normal; Chol/TG al-
`plasma triglycerides
`ways > 1.5.
`intensely
`stained
`(3) Electrophoresis-an
`,8-lipoprotein band is present; a pre-,3 band is
`either not present or, if present, is of normal
`intensity. Chylomicrons are not visible; a-
`lipoproteins are usually normal (diagnostic
`only if accompanied by estimation of LDL
`concentration) .
`(4) Ultracentrifugation-LDL (Sf 0-20) is
`increased. VLDL (Sf 20-400) is normal, HDL
`is usually normal, and chylomicrons are not
`increased (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 is
`intensely stained; pre-,B band is increased in
`intensity. Chylomicrons are not visible; a-
`lipoproteins are usually normal (diagnostic
`only if accompanied by estimations of LDL
`and VLDL concentrations).
`(4) Ultracentrifugation-LDL (Sf 0-20) is
`increased; VLDL (Sf 20-400) is increased;
`chylomicrons
`increased; HDL is
`not
`are
`usually normal (diagnostic).
`Comment. Definite determination of type II
`depends upon the establishment of an abnor-
`mal increase in LDL (,8) concentrations. This
`is most precisely obtained by analytical or
`preparative ultracentrifugation. It may also be
`estimated 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 infranatant
`fractions using anti-LDL sera. (Such antisera
`also react with VLDL and therefore do not
`accurate LDL determinations
`on
`permit
`whole plasma.)
`usually be
`The type
`can
`pattern
`IIa
`ascertained by the cholesterol and triglyceride
`analyses alone, especially when the Chol/TG
`ratio is > 2. The exceptions are those patients
`who may have abnormally increased LDL
`concentrations in the presence of a normal
`plasma cholesterol concentration.
`The type IIb pattern is difficult to ascertain
`from plasma lipids alone.
`
`electrophoresis,
`
`Recommended Tests
`(1) Chol plus TG plus
`when Chol/TG > 2.
`(2) Chol plus TG plus HDL (cholesterol
`measurements after precipitation) for calcu-
`lation of LDL (applicable only when type III
`is excluded and TG < 400). If estimated LDL
`is increased, assignment of subtypes is: lla
`JIb when TG is
`normal;
`when TG is
`increased.
`(3) Ultracentrifugal analyses.
`
`Downloaded from http://ahajournals.org by on November 19, 2021
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1034, p. 3 of 8
`
`
`
`504
`
`Type III-"Floating /" or "Broad /3" Pattern
`Criterion
`Presence of VLDL having abnormally high
`cholesterol 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 always
`increased; Chol/TG frequently about 1, but
`may 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 the
`position. This occurs in about two thirds
`pre-,e
`of plasma containing "floating /3." A distinct
`pre-/3 band is sometimes present and may be
`increased in intensity: a-lipoproteins usually
`appear normal. A faint chylomicron band is
`often present even during periods of very low
`fat intake (helpful but not diagnostic). On
`polyacrylamide gel electrophoresis (PGE) a
`broadened pre-/3 (VLDL) band is present,
`and no lipoproteins are seen in the usual
`position 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 the
`type 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 the
`(sometimes
`usual
`called
`"a(-
`position
`VLDL") and one in an abnormal
`position
`(",3-VLDL") (diagnostic).
`Paper, agarose, cellulose acetate, or starch
`electrophoresis of the supernatant fraction of
`plasma after ultracentrifugation at its unadjust-
`ed salt density of 1.006 reveals /8-migrating
`lipoproteins. Normally only pre-/3
`migrating
`lipoproteins are present in the lipoprotein
`fraction of density <1.006. (The demonstra-
`tion of "floating
`is at present the definitive
`standard against which other diagnostic tests
`must be compared.)
`
`a2
`
`WHO MEMORANDUM
`
`(4) Ultracentrifugation-in
`the analytical
`ultracentrifuge the normally predominating
`LDL subclass of density 1.010-1.063 (Sf 0-12)
`is greatly decreased and the LDL subclass of
`density 1.006-1.019 (Sf 12-20) is disproportion-
`ately
`increased. The VLDL subclass
`(Sf
`100-400) is also increased. Chylomicrons may
`be increased. This inversion of the usual
`concentrations of LDL and VLDL usually
`provides a characteristic pattern in type III;
`however, it is possible to have similar changes
`in total Sf 0-20 and Sf 20-400 subclasses in
`other types
`(very helpful but not always
`diagnostic).
`The combination of preparative ultracentri-
`fugation and electrophoresis described above
`may be augmented by a measurement of
`cholesterol and triglycerides in the VLDL
`(density < 1.006)
`ultracentrifuge
`fraction
`(the latter may possibly be substituted for the
`former). Normally, the Chol/TG ratio
`in
`VLDL is 0.2 or less. Significantly higher ratios
`( >0.4) are indicative of type III (probably
`diagnostic).
`Comment. The type III anomaly indicates
`the presence of abnormal VLDL or, more
`precisely, of abnormal LDL in the VLDL
`fraction of plasma lipoproteins. It may be
`suspected
`from
`a Chol/TG ratio
`1,
`of
`especially when repeated
`analyses
`show
`marked lability of both Chol and TG concen-
`trations, and a "broad 83', band appears on
`conventional electrophoresis. This combina-
`tion may permit a presumptive diagnosis;
`however, the diagnosis should never be made
`alone from conventional electrophoresis on a
`single medium.
`The definitive test is the demonstration of
`"floating /,," but an analysis of equivalent
`value may prove to be the measurement of
`cholesterol and triglyceride in VLDL; com-
`bining electrophoresis on PGE and one other
`medium permits a presumptive diagnosis. A
`simpler, accurate diagnostic test is
`still de-
`sired.
`Recommended Tests
`When the plasma Chol/TG ratio is close to
`1 and a "broad /3" band is suspected on
`electrophoresis:
`
`Circulation, Volume XLV, February 1972
`
`Downloaded from http://ahajournals.org by on November 19, 2021
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1034, p. 4 of 8
`
`
`
`HYPERLIPIDEMIAS, HYPERLIPOPROTEINEMIAS
`
`50S
`
`(1) Plasma lipoprotein patterns obtained
`on polyacrylamide gel and on either paper,
`agarose, or cellulose acetate should be com-
`pared. Absence of /3-migrating lipoproteins on
`PGE and their presence on the other systems
`permits a presumptive diagnosis.
`(2) When possible, confirmation of "float-
`ing /3" (or VLDL having a high Chol/TG
`should be made after
`ratio)
`preparative
`ultracentrifugation.
`
`Type IV-Hyperpre-g-lipoproteinemia
`Criteria
`(1) Increased VLDL (pre-,8).
`(2) No increase in LDL (,3).
`(3) Chylomicrons absent.
`
`Methods of Diagnosis
`plasma
`(1) Standing
`clear
`turbid
`or
`throughout with no overlying chylomicron
`layer (helpful but not diagnostic).
`(2) Plasma cholesterol normal or increased;
`plasma
`triglycerides
`increased;
`plasma
`Chol/TG, variable (very helpful, sometimes
`diagnostic).
`(3) Electrophoresis-increased intensity of
`pre-,8-lipoprotein band; /3 band normal or
`decreased; a band may be normal, often
`decreased; chylomicrons not visible. There
`may be trailing of lipoproteins from the pre-/3
`region to the origin (helpful, but not diagnos-
`tic without some quantification;
`see Com-
`ments, below).
`All of the isolated VLDL on starch-block
`electrophoresis has the usual a2 mobility ( a2-
`VLDL). There is no /3-VLDL, or "floating ,/,"
`and VLDL has usual Chol/ TG ratio of 0.2 or
`less.
`(4) Ultracentrifugation-VLDL (Sf 20-400)
`is increased; LDL (Sf 0-20) is normal or
`decreased; HDL is normal or decreased; and
`chylomicrons are not increased (diagnostic).
`Comments. If the plasma cholesterol is
`definitely normal,
`clearly
`triglycerides
`are
`increased, and there are no chylomicrons
`visible on standing plasma, then the determi-
`nation of type IV is
`fairly
`certain. The
`accuracy of assignment is enhanced if electro-
`phoresis reveals a distinct pre-,3 band and a
`distinct and diminished ,3 band. Plasma TG is
`Circulation, Volume XLV, February 1972
`
`always used to assess pre-/3 concentrations
`with electrophoresis, and it is always elevated
`in type IV. Conversely, an apparent increase
`in pre-,8 lipoproteins on electrophoresis will
`not be accompanied by an increase in plasma
`TG if most of the pre-,8 represents "sinking
`pre-,/3
`(see above). This is a normal phenom-
`e'ion and its frequent occurrence emphasizes
`the need for TG concentrations to monitor
`electrophoresis. One should look for signs of
`the "type III anomaly"; it is not necessary to
`exclude the anomaly by specific tests in most
`instances of type IV.
`
`Recommended Tests
`(1) For most samples, Chol plus TG plus
`observation of plasma plus electrophoresis
`permits a diagnosis.
`(2) Estimate LDL and exclude type III in
`doubtful cases.
`(3) The ultracentrifuge can be very helpful
`in certain cases.
`
`Type V-Hyperpre-,3-lipoproteinemia and
`Chylomicronemia
`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; plasma
`triglyceride increased; plasma Chol/TG usual-
`ly > 0.15 and <0.6 (helpful but not diagnos-
`tic).
`Electrophoresis-pre-,/
`(3)
`band is
`in-
`creased and frequently trails to origin where a
`distinct accentuation indicates concomitant
`presence of chylomicrons: /3- and a-lipopro-
`decreased,
`often
`usually
`tein bands
`are
`markedly so. There is no "floating /3" (can be
`diagnostic, if trailing pre-,/ does not obscure a
`chylomicron band).
`(4) Ultracentrifugation-chylomicrons and
`VLDL (Sf 20-400) increased. LDL, particular-
`ly subclass Sf 0-12, and HDL are usually
`decreased (diagnostic).
`
`Downloaded from http://ahajournals.org by on November 19, 2021
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1034, p. 5 of 8
`
`
`
`506
`
`Comments. The major diagnostic problem,
`that of discerning chylomicrons by electro-
`phoresis when pre-/3 (VLDL) concentrations
`are extremely high, can usually be overcome
`by observation of standing plasma. The latter
`is a very good test for type V.
`Recommended Test
`(1) Examine standing plasma and measure
`Chol plus TG. The typical appearance in type
`V may be imitated in two situations. One is a
`type I pattern with enough VLDL to impart
`faint turbidity to the infranatant layer. The
`Chol/TG ratio is usually below 0.15 in type I
`and usually above this in type V. The other
`situation is type III. Here the Chol/TG ratio is
`often close to 1 but may be as low as 0.3. Test
`should be done if any
`"floating
`/3"
`for
`uncertainty remains.
`Additional Useful Clinical Data
`Certain clinical signs, and other information
`that is relatively easy to obtain, are valuable
`for the detection of hyperlipidemia and can
`sometimes be used to predict the type of
`hyperlipoproteinemia that is
`present. Xan-
`deposits and the
`thomas and other lipid
`familial history are the most valuable.
`Lipid Deposits-Xanthcmas
`Tendon xanthomas are not rare; they are
`easy to detect, and are especially informative
`because they almost invariably indicate hyper-
`lipoproteinemia of long duration. They usually
`indicate hyper-,l-lipoproteinemia and almost
`always imply familial type II.
`Tuberous xanthomas occur with type II and
`type III hyperlipoproteinemia. Somewhat sim-
`ilar "tuberoeruptive" lesions appear with types
`Eruptive xanthomas
`and IV.
`always
`III
`indicate
`severe hyperglyceridemia
`(usually
`type I or V).
`Planar xanthomas occur with several kinds
`of hyperlipoproteinemia. In the familial dis-
`orders, they occur on the palms of the hands
`in type III and in homozygotes for type II.
`They also may occur with obstructive liver
`disease. More widely distributed planar le-
`sions, on the trunk and elsewhere, are rare and
`occur especially in hyperlipoproteinemia asso-
`ciated with dysglobulinemias.
`
`WHO MEMORANDUM
`
`Xanthelasma is frequent in type II and
`sometimes occurs in type III, but often may
`be seen in the absence of hyperlipidemia or
`hyperlipoproteinemia.
`Arcus corneae (arcus senilis) is significant
`only when it appears before the age of 40
`years. In younger people it usually implies
`familial type II hyperlipoproteinemia.
`
`Other Clinical Signs
`Pancreatitis or recurrent abdominal pain
`should lead to a suspicion of severe hyper-
`glyceridemia (type I or V).
`
`Family History
`The family
`history
`leads
`often
`the
`to
`detection of hyperlipidemia: Ischemic heart
`disease and other vascular accidents in young
`relatives are usual in familial type II or type
`IV hyperlipoproteinemia.
`Diabetes is often seen in families of patients
`with type IV or type V hyperlipoproteinemia,
`himself
`if
`the
`the
`patient
`even
`is
`not
`diabetic.
`
`Other Useful Laboratory Data
`These include some common laboratory
`tests, such as those for:
`thyroid function,
`glucose tolerance,
`protein, plasma
`urinary
`electrophoresis,
`immunoglobulin
`protein
`quantification, liver function, and uric acid.
`Certain special analyses may also be useful
`plasma postheparin
`and include:
`lipolytic
`activity, proportion of plasma cholesterol in
`the esterified form, lecithin cholesterol acyl-
`transferase activity (LCAT), fat tolerance,
`and vitamin A tolerance.
`
`Etiology of Hyperlipoproteinemia
`Once the type pattern of hyperlipopro-
`teinemia has been established, it is necessary
`consider etiology. One approach is
`to
`to
`consider etiology as falling into two main
`categories, secondary and primary hyperlipo-
`proteinemias.
`
`Secondary to Known Diseases
`Common diseases that are often associated
`hyperlipoproteinemia and that must
`with
`always be excluded in considering etiology
`(1) hypothyroidism, (2) diabetes, (3)
`are:
`Circulation, Volume XLV. February 1972
`
`Downloaded from http://ahajournals.org by on November 19, 2021
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1034, p. 6 of 8
`
`
`
`HYPERLIPIDEMIAS, HYPERLIPOPROTEINEMIAS
`
`507
`
`nephrotic syndrome, (4) biliary obstruction,
`dysglobulinemia
`(5)
`pancreatitis, and (6)
`(including
`hyperlipoproteine-
`autoimmune
`mia). The lipoprotein patterns that may be
`associated with these diseases are shown in
`table 2.
`
`Primary
`These are hyperlipoproteinemias that are
`due to genetically determined defects in lipid
`or lipoprotein metabolism or are caused by
`some environmental factors through an un-
`known mechanism.
`All five major types of hyperlipoproteinemia
`may be familial and probably represent many
`different mutations.
`Environmental factors that may cause pri-
`mary hyperlipoproteinemia include: (1) diet,
`including alcohol intake; and (2) drugs. Many
`drugs cause hyperlipidemia, particularly the
`estrogens as contained in contraceptive medi-
`cations, and steroid hormones.
`hyperlipopro-
`A proper classification
`of
`teinemia should include reference to both
`lipoprotein pattern and etiology.
`
`Glossary of Relevant Terms
`Abetalipoproteinemia
`Absence of /-lipoprotein
`Lipoproteins appearing in the a
`a-lp (a 1-lp)
`(a1)
`electrophoresis
`band
`(same as HDL)
`
`Table 2
`Types of Hyperlipoproteinemnia Associated with
`Selected Comrmon Diseases*
`
`Disorder
`Hypothyroidism
`Insulin-dependent diabetes
`(uncontrolled)
`Nephrotic syndrome
`Biliary obstruction
`
`Types of
`hyperlipoproteinemia
`II, IV
`I, IV, V (II, III)*
`
`II, IV, V
`Does not conform
`predictably to
`any of the
`major types
`IV, V
`I, II, IV, V (III)*
`
`Pancreatitis
`Dysglobulinemia
`Autoimmune
`hyperlipoproteinemia
`
`1, III, IV, V (II)*
`*Secondary hyperlipoproteinemias
`parentheses.
`Circulation, Volume XLV, February 1972
`
`are shown in
`
`-lp
`
`.
`
`"/3-VLDL" ....
`
`Broad 3-lp.....
`Floating /3-lp..
`
`HDL ........
`
`Hyperlipemia.
`
`Hyperlipidemia.
`
`LDL..........
`
`Lp antigen (Berg)
`
`Sf value ..........
`"Sinking" pre-/3-lp..
`
`.Lipoproteins having /3-mobility
`on elect.rophoresis band (same
`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 1.063
`and 1.21 (same as a-lp)
`A lactescent appearance of plas-
`ma due to increased concen-
`trations of glycerides in either
`VLDL or chylomicrons
`An increase in concentration of
`any plasma lipid constituent;
`for practical purposes usually
`confined to cholesterol or tri-
`glycerides, or both
`Hyperlipoproteinemia An increase in plasma concen-
`tration of one or more lipo-
`protein families; nearly always
`accompanied
`by
`hyperlipi-
`demia
`Low-density lipoproteins (same
`as P-lp)
`A form of genetic polymorphism
`of lipoprotein
`Lp-X .......... Lipoprotein-X (complexes main-
`ly of phospholipid, unesteri-
`fled cholesterol, and VLDL
`apoprotein seen in obstructive
`liver disease)
`Pre-/3-lp .......... Lipoproteins appearing in the
`electrophoresis
`pre-p
`band
`(same as VLDL)
`Svedberg unit of flotation
`Pre-js lipoproteins that sediment
`at density 1.006
`Tangier disease ..... Familial deficiency of HDL
`low-density
`lipoproteins
`VLDL ........
`Very
`(pre-p3-lipoproteins)
`J. L. BEAUMONT, Doyen de la Faculte de
`Medecine de Creteil, Unite de Recherches
`sur l'Atherosclerose, Hopital Henri Mondor,
`Creteil, France
`L. A. CARLSON, Professor of Medicine, De-
`partment of Geriatrics, Uppsala University,
`Uppsala, Sweden
`Chief,
`COOPER,
`Medical Director,
`R.
`Clinical Chemistry and Hematology Branch,
`Center for Disease Control, Atlanta, Georgia
`
`G.
`
`Downloaded from http://ahajournals.org by on November 19, 2021
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1034, p. 7 of 8
`
`
`
`5()8
`
`Z. FEJFAR, Chief, Cardiovascular Diseases,
`World Health Organization, Geneva, Swit-
`zerland
`D. S. FREDRICKSON, Chief, Molecular Disease
`Branch and Director of Intramural Re-
`search, National Heart and Lung Institute,
`Bethesda,
`of Health,
`National Institutes
`Maryland
`T. STRASSER, Medical Officer, Cardiovascular
`Diseases, World Health Organization, Ge-
`neva, Switzerland
`
`References
`ABELL LL, LEVY BB, BRODIE BB, KENDALL FE: J Biol
`Chem 195: 357, 1952
`BEAUMONT JL: C R Acad Sci [D] (Paris) 261: 4563,
`1965
`BEAUMONT JL: Ann Biol Clin (Paris) 27: 611, 1969
`BRODY S, CARLSON LA: Clin Chim Acta 7: 694, 1962
`CARLSON LA: Acta Med Scand 167: 377, 399, 1960
`CARLSON LA, LINDSTEDT S: Acta Med Scand (suppl)
`493: 1, 1969
`EWING AM, FIREEMAN NK, LINDCREN FT: Advances
`Lipid Res 3: 25, 1965
`FREDRICKSON DS, LEVY RI:
`Familial hyperlipopro-
`teinemia. In The Metabolic Basis of Inherited Dis-
`ease, 3rd ed, edited by Stanbury JB, Wyngaarden
`
`WHO MEMORANDUM
`
`JB, Fredrickson DS. New York, McGraw-Hill Book
`Co. In press
`FREDRICKSON DS, LEVY RI, LEES RS: New Eng J Med
`276: 34, 94, 148, 215, 273, 1967
`HATCH FT, LEES RS: Advances Lipid Res 6: 1, 1968
`HAVEL RJ, CARLSON LA: Metabolism 11: 195, 1962
`KOERSELMAN HB, LEwIS B, PILKINC.TON TRE: J Athe-
`roscler Res 1: 85, 1961
`DE LALLA OF, GOFMIAN JW: Ultracentrifugal analysis
`of serum lipoproteins. In Methods of Biochemical
`Analysis, edited by Glick D. New York, Interscience
`Publishers, Inc., 1954, vol 1
`SCHUMAKER VN, ADAMS CH: Ann Rev Biochem 38:
`113, 1969
`SEIDEL D, ALAUPOVIC P, FURIMAN RH: J Clin Invest
`48: 1211, 1969
`TRIA E, SCANU AM: Structural and Functional Aspects
`of Lipoproteins in Liviing Systems, New York, Aca-
`demic Press, 1969
`WILLIAMS JH, KUCH-MAK M, WITTER RF: Clin Chem
`16: 423, 1970
`WILLIAMIS JH, TAYLOR L, KUCHMAK M, WITTEiR RF:
`Clin Chiim Acta 28: 247, 1970
`WITTER RF, KUCHMAK M, WILLIAMS JH, WHITNER
`VS, WINN CL: Clin Chem. In press
`WITTER RF, WHITNER VS: Determination of serum or
`plasma triglycerides. In Blood Lipids and Lipopro-
`teins, edited by Nelson GL, Rouser G. New York,
`John Wiley and Sons, Inc. In press
`
`Circulation, Volume XLV, February 1972
`
`Downloaded from http://ahajournals.org by on November 19, 2021
`
`Hikma Pharmaceuticals
`
`IPR2022-00215
`
`Ex. 1034, p. 8 of 8
`
`