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Xanthomatoses and
Lipoprotein Disorders
Ernst J. Schaefer & Raul D. Santos
cholesterol. Patients with familial combined hyperlipidemia may have altered cholesterol metabolism.
The final steps in the cholesterol synthesis pathway
are where squalene is converted to lanosterol and
then either to desmosterol or lathosterol, both of
which are converted to cholesterol. Recently, we
have documented that patients with familial combined hyperlipidemia have normal squalene levels,
but elevated lathosterol and cholesterol levels
indicating altered sterol metabolism and enhanced
conversion of squalene to lathosterol (measured
by gas chromatography).41 Patients with markedly
elevated levels of LDL cholesterol and triglycerides
due to familial combined hyperlipidemia may very
occasionally develop tendinous or tubo-eruptive
xanthomas. They are at high risk for CHD and ideal
therapy for these patients in addition to dietary
modification is statin therapy.
Familial Dyslipidemia
About 15% of patient with premature CHD have
familial dyslipidemia, characterized by elevated
triglyceride levels, and decreased HDL cholesterol
levels.38 These patients also usually have normal
LDL cholesterol levels, but increased small LDL, and
decreased large HDL particles. These patients often
have delayed clearance of VLDL and enhanced
clearance of HDL, but some may also have overproduction of VLDL.3 In contrast to patients with
familial combined hyperlipidemia (see previous
section), these patients do not have any evidence
of enhanced conversion of squalene to lathosterol
and cholesterol. These patients also are often
overweight and may be insulin resistant or have
diabetes. Patients with elevated levels of triglycerides (>400 mg/dL) and low HDL cholesterol (<40
mg/dL) may occasionally develop tubo-eruptive
xanthomas. Restriction of calories and simple
carbohydrates, along with exercise, optimization of
plasma glucose levels, and either niacin or fibrate
therapy are the treatments of choice. Such patients,
if severely affected, may occasionally develop eruptive xanthomas.
Familial
Hypoalphalipoproteinemia
This familial lipoprotein disorder characterized by
isolated HDL deficiency (HDL cholesterol <40 mg/
dL) is found in about 5% of families with premature
CHD, and is associated with decreased HDL apoA-I
production.38 Patients with marked HDL deficiency
may occasionally develop tubo-eruptive xanthomas, and can be treated with niacin therapy. Some
patients may have mutations in ABCA1 and technically be heterozygotes for Tangier Disease.
Tangier Disease
Tangier disease is caused by defects in the gene
ABCA1, which transports cellular cholesterol to the
cell surface for delivery to circulating HDL.31 A defect in the transmembrane transporter causes HDL
to be cleared from the circulation and an accumulation of cholesterol in peripheral tissues due to the
inability to perform reverse transport via the HDL
particles. Plasma HDL cholesterol is less than 5 mg/
dL. Tangier homozygotes accumulate cholesterol
esters in tonsils, spleen, lymph nodes, bone narrow,
thymus, and intestinal mucosa, leading to yellow/
orange hyperplastic tonsils, mild lymphadenopathy,
and splenomegaly. Patients with Tangier disease
have low plasma HDL cholesterol and apo-A1 levels.
They can have low LDL levels and a lower risk of
atherosclerosis.
TREATMENT OF
HYPERLIPIDEMIAS
Pharmacologic Agents
STATINS.
Statins are the cornerstone of therapy for LDL
control after lifestyle change, and have clearly been
shown to reduce CHD risk and stroke risk.1,2,6163 In
addition to lowering LDL and triglyceride, these
agents have a very beneficial effect on HDL particles. Statins inhibit HMG-CoA reductase, the
rate-limiting step in cholesterol biosynthesis Statins
induce cellular inhibition of cholesterol synthesis
and upregulation of LDL receptor activity, with
enhanced clearance of LDL apoB-100, VLDL apoB100, and chylomicron apoB-48.63 Statins can lower
LDL cholesterol by up to 60%, and triglyceride
levels by up to 30%. In addition, statins are known
to decrease cholesteryl ester transfer protein
activity, resulting in larger HDL particles because
of less cholesteryl ester transfer to triglyceride-rich
lipoproteins under these circumstances.63 Their use
decreases xanthomas in patients with elevated LDL
cholesterol levels. Statins are well tolerated, but
have been associated with side effects including
dyspepsia, headaches, muscle or joint aches. Rarely,
they have the potential to induce severe myopathy
leading to rhabdomyolysis. They may also cause
Chapter 135:
We have recently documented that niacin enhances the clearance of triglyceride-rich lipoprotein apoB-100 and apoB-48, while increasing the
production of HDL apoA-I.78 Large scale studies are
currently underway to determine whether niacin
will reduce CHD risk above and beyond the effects
of a statin. Niaspan, an extended release formulation, is currently being tested versus placebo in a
trial of over 3,000 heart disease patients with HDL
cholesterol below 40 mg/dL all on simvastatin
therapy. Niacin, together with a flushing inhibitor
laropiprant, is currently also being tested versus
placebo in a trial of over 20,000 patients all on
simvastatin therapy. These trials will be completed
within the next several years, and in our opinion
will provide hard evidence for the benefits of niacin
in HDL cholesterol raising and Lp(a) lowering.
EZETIMIBE.
Ezetimibe is a second-line agent for cholesterol lowering, and blocks intestinal cholesterol absorption,
and lowers LDL C by 18%.34,35 This agent is generally
well tolerated, and is especially helpful in hyporesponders to statins. It has minimal effects on HDL
cholesterol, but potentiates the effects of statins
not only for LDL lowering, but also for the lowering
of CRP.35 No prospective studies have clearly shown
clinical benefit at this point. A large clinical trial testing ezetimibe plus simvastatin versus simvastatin
alone in over 18,000 patients with acute coronary
syndrome is currently underway. The statin/ezetimibe combination is ideal for getting patients to
their LDL cholesterol goal. 1,2,34,35