Beruflich Dokumente
Kultur Dokumente
FAMILIAL HYPERCHOLESTEROLEMIA
I. Introduction
I. INTRODUCTION
References
3. Harlan, W.R., Jr., Graham, J.B., and Estes, E.H. Familial hyper-
cholesterolemia: A genetic and metabolic study, Medicine 45: 77,
1966.
Case Report
I
193
li
2.or J.?r z.z,f tvo . '/Z1 Z.lf 3S'a. ''' z.f J" zt&
D UNAFFECTED
ill [I HETEROZYGOTE
2.2S ld 3l3jtool e HOMOZYGOTE
Fig. 2 - Distribution
of serum cholesterol
DISTRIBUTION OF PLASMA CHOLESTEROL levels in controls and
in members of the M
IN CONTROLS AND IN .MEMBERS OF M FAMILY family, a single large
kindred with familial
20 hypercholesterolemia.
(Data of Schrott,
Goldstein, Hazzard,
et al. {8}).
Controls, n =455
0
20
M Family, n=85
(f)
~
..J
0
- 1-
~
::c
u
<
400 - .. . ...
-
':.
2E
(f)
<
..J
a.
1- -
=
'::: ~
200
1-
-
-
1-
t
Mean2S.D.
0
- 5-
Natural History
- - -~//
different ages
in the affected
~embers (heterozy-
gotes) of a single
I II I
large family with
.Arcus Corneae
-
familial hyper-
-~-.1,1
cholesterolemia.
(Data of Schrott, 0.., I
Goldstein,
Hazzard, et al.
{ 8}) Xanthomas
M n
- -~On If
[U] r= n&
10 20
0 CJ
Aqe in years
.,
30
r:w ~ n,/
40
60
-6-
Table 1
Table 2
Xanthomata
Type Tendinous Cutaneous Planar
Xanthelasma Tendinous
Heart Disease
Type CHD CHDi Valvular Aortic
Stenosis
Onset After age 30 Before age 15
- 8-
Frequency
15. Patterson, D., and Slack, J.: Lipid abnormalities in male and
female survivors of myocardial infarction and their first-degree
relatives, The Lancet i: 393, 1972.
17. Nikkila, E.A., and Aro, A.: Family study of serum lipids and
lipoproteins in coronary heart-disease, The Lancet ~: 954, 1973.
Table 3
I Primary Disorders
1. Familial Hypercholesterolemia
3. Polygenic Hypercholesterolemia
II Secondary Disorders
19. Fredrickson, D.S., Levy, R.I., and Lees, R.S. : Fat transport
in lipoproteins: an integrated approach to mechanisms and
disorders, New Eng. ~ Med. 276: 32, 94, 148, 215, 273, 1967.
22. Glueck, C.J., Fallat, R., and Buncher, C.R.: Familial combined
hyperlipoproteinemia: Studies of 91 adults and 95 children
from 33 kindreds. Metabolism. 22: 1403, 1973.
27. Gotto, A.M., Brown, W.V., Levy, R.I., Birnbaumer, M.E., and
Fre drickson, D.S.: Evidence for the identity of the major
apoprotein in low density and very low density lipoproteins
in normal subjects and patients with familial hyperlipoprotein-
emia, ~ Clin. Invest . 51: 1486, 1972.
Cholesterol Absorption
Cholesterol Excretion
Cholesterol Synthesis
33. Lewis, B., and Myant, N.G.: Studies in the metabolism of cholesterol
in subjects with normal plasma cholesterol levels and in patients
with essential hypercholesterolaemia, Clin. Sci. 32: 201, 1967.
35 . Langer, T., Strober, W., and Levy, R.I.: The metabolism of low
density lipoprotein in familial type II hyperlipoproteinemia,
J. Clin . Invest. ~: 1528, 1972.
40. Quintao, E., Grundy, S.M., and Ahrens, E. H., Jr.: Effects of
dietary cholesterol on the regulation of total body cholesterol
in man, ~- Lipid Res. ~: 233, 1971.
41. Grundy, S.M., Ahrens, E.H., Jr., and Salen, G.: Interruption
of the enterohepatic circulation of bile acids in man:
Comparative effects of cholestyramine and ileal exclusion on
cholesterol metabolism, ~- Lab. Clin. Med. 78: 94, 1971.
42 . Grundy, S.M., Ahrens, E.H., Jr., and Davignon, J.: The inter-
action of cholesterol absorption and cholesterol synthesis in
man, ~- Lipid Res. ~: 304, 1969.
Fig. 5 - Pathway
of cholesterol
Acetyl CoA 2TPNH 2TPN
synthesis from
acetyl CoA in
mammalian
f
Acetoacetyl Co A \ HMG CoA
J
tissues, showing
the site of feed- f Reductase
back regulation 3- Hydroxy- 3- Methylglutoryl Co A - - Mevolonote
by cholesterol.
(HMG Co A} ~ t
\ Squalene
', t
' 'Cholesterol
t
-16-
c
~ 100
0
E
.f!,
-~
-~
B
I I I
4 12
0 " 24 32
HOURS HOURS
50. Williams, C.D., and Avigan, J.: In vitro effects of serum proteins
and lipids on lipid synthesis in human skin fibroblasts and
leukocytes grown in culture, Biochim. Biophys. Acta. 260: 413, 1972.
Table 4
~fi~i~~t ~~UBindingj
F~k ~---
l impaired
Regulation of
~~G CoA Reductase
~~~ - - - - -- - ,1
Defective Degradation !
of LDL
- - --- - -
--- -- - ------- - -~
IV THERAPEUTIC CONSIDERATIONS
Table 5
In our view and in the opinion of Myant and Slack (51), the need
to treat all heterozygous females is considerably less compelling
than that for heterozygous males since many hypercholesterolemic
females live a normal life span without symptoms (12,13). Therefore,
-20-
Diet
Table 6
Egg Yolk
Shellfish
Butter
Milk
Chocolate
Coconut
Drugs
56. G-lueck, C.J., Ford, S., Scheel, D., and Steiner, P.: Colestipol
and cholestyramine resin: comparative effects in familial
type II hyperlipoproteinemia, JAMA 222: 676, 1972.
58. Buchwald, H., Moore, R.B., Lee, G.B., Frantz, I.D., Jr., and
Varco, R.L.: Treatment of hypercholesterolemia, Arch. Surg.
(Chicago) 97: 275, 1968.
60. Thompson, G.R., and Gotto, A.M., Jr.: Ileal bypass in the
treatment of hyperlipoproteinemia, The Lancet ii: 35, 1973.
-23-
61. Starzl, T.E., Chase, H.P., Putram, C.W., and Porter, K.A.
Portacaval shunt in hyperlipoproteinemia. The Lancet ii:
940, 1973.
The recent studies of Lloyd (63,64) and Glueck (65) indicate that
cholestyramine in a daily dosage of 8 to 24 g is tolerated well by
children and is very effective. In Lloyd's series, the serum
cholesterol concentration was reduced by a mean of 30% (rang e 27 to
47%) in 19 heterozygous children and the effect was maintained for
periods up to 20 months without any dietary modifications (64). The
only long-term side effect of the resin in children was a lowering
of the serum folate in all patients; this was due to binding of the
folate anion by the resin in the intestine.
63. Segall, M.M., Fosbrooke, A.S., Lloyd, J.K., and Wolff, O.H.:
Treatment of familial hypercholesterolemia in children, The
Lancet ~: 641, 1970.
65 . G 1 u e c k , C . J . , Fa 11 at , R. , and T so r g , R. : Pediatric fa rn i 1 i a 1
type II hyper1ipoproteinernia: therapy with diet and cho1estyrarnine
resin, Pediatrics 52: 669, 1973.