J. Streicher et al., Up-regulation of LDL-receptor expression by LDL-immunoapheresis in patients with familial hypercholesterolemia, J INVES MED, 47(8), 1999, pp. 378-387
Citations number
50
Categorie Soggetti
General & Internal Medicine","Medical Research General Topics
Background: Familial hypercholesterolemia (FH) is characterized by an autos
omal dominantly inherited deficiency of LDL-receptor expression on the cell
surface, leading to excess plasma LDL-cholesterol and severe premature ath
erosclerosis, In patients with heterozygous FH, a major therapeutic objecti
ve of conventional drug therapy is to stimulate maximally the residual cell
ular capacity to produce LDL-receptors via inhibition of endogenous cholest
erol synthesis, in contrast, LDL-immunoapheresis aims at reducing the plasm
a LDL-cholesterol level by extracorporeal elimination of LDL particles. The
present study investigates whether LDL-immunoapheresis applied in addition
to conventional drug therapy is able to further stimulate residual LDL-rec
eptor expression capacity in patients with heterozygous FB via the withdraw
al of external cholesterol supply, thereby exerting a second accessory lipi
d lowering effect.
Methods: LDL-receptor expression-calculated by transforming mean fluorescen
ce intensities into numbers of antibody binding sites per cell (S/C)-was de
termined flow-cytometrically on peripheral blood monocytes before and after
LDL-apheresis, For a comparison with the maximum obtainable receptor expre
ssion capacity, in vitro stimulation experiments under completely LDL defic
ient conditions were performed.
Results: Prior to LDL-apheresis, LDL-receptor density was comparable in pat
ients (N=7; 2014 +/- 359 S/C) and controls (N=10; 1782 +/- 252 S/C), Under
in vitro conditions LDL-receptor expression of controls exceeded that of pa
tients with FH by 1.6 times, Immediately after apheresis, LDL-receptor expr
ession significantly increased to almost the same level as obtained by in v
itro stimulation (3640 +/- 423 S/C and 3632 +/- 572 S/C), The LDL-receptor
expression in FH subsequent to LDL-apheresis exhibited two patterns of kine
tics [Type I: maximal receptor stimulation (288 +/- 70%; P<0.07) already du
ring apheresis; Type 2: highest receptor density 24 hours after treatment (
149 +/- 11%; P<0.01)].
Conclusions: These results demonstrate that despite drug therapy, LDL-apher
esis significantly stimulates the residual LDL-receptor expression in FH vi
a the reduction of available extracellular cholesterol resulting in delayed
reappearance of hypercholesterolemia in between treatments.