throbber
WORLD HEALTH ORGANIZATION
`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
`
`

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket