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Chapter 135

Xanthomatoses and
Lipoprotein Disorders
Ernst J. Schaefer & Raul D. Santos

LIPID AND LIPOPROTEIN


METABOLISM
Familial Lipprotein (a) Excess
Lipoprotein (a) levels [mainly LDL with apo(a)
attached] are in large part determined by the
number of apo(a) isoforms, which are inherited. A
decreased number of kringle 4-like repeats results
in less intrahepatic degradation of apo(a) and more
secretion. Most patients with familial Lp(a) excess
have decreased numbers of kringle 4 repeats.
Familial lipoprotein(a) excess is found in about
20% of familial premature coronary heart disease
(CHD).38 The metabolism of apo(a) requires further
elucidation. In our view, apo(a) attaches itself to
VLDL apoB-100, and then remains with VLDL as it
is converted to LDL, or if the VLDL is catabolized
directly, the apo(a) is detached and recombines
with a newly formed VLDL particle, or is catabolized. Lp(a) excess is associated with both increased
apo(a) and apoB-100 secretion into plasma Lp(a),
as well as delayed clearance of apo(a), especially in
patients with elevated LDL.39 Lp(a) is measured by
using immunoassays specific for apo(a). Elevated
levels of Lp(a) have been shown to be an independent predictor of CHD. Elevated Lp(a) levels can be
lowered by using niacin at a dose of 2 g/day.40 Clinical trials currently underway with niacin will test the
hypothesis whether lowering elevated Lp(a) will
reduce CHD risk. Patients with markedly elevated
Lp(a) levels may occasionally develop tendinous or
tubo-eruptive xanthomas.

Familial Combined Hyperlipidemia


The most common familial cause of elevated LDL
cholesterol is known as familial combined hyperlipidemia, found in about 15% of patients with
premature CHD.38 These patients have been shown
to have increased production of VLDL, LDL and
reduced levels of HDL. Patients almost always have
elevated levels of apoB-100. Affected family members have elevated triglyceride levels, elevated LDL
cholesterol levels, or both, and often have low HDL

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

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208 Chapter 135: Xanthomatoses and Lipoprotein Disorders

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

liver transaminitis and transaminases should be


checked prior to initiation of statin therapy, at 23
months, then annually.
FIBRATES.
Fibrates are the very useful and effective triglyceride lowering agents. Two fibrates are currently
in use: (1) gemfibrozil and (2) fenofibrate. These
agents are peroxisomal proliferation activation
receptor-(PPAR-) agonists and increase lipoprotein lipase, apoA-I and apoA-II gene expression, and
decrease apoC-III gene expression, resulting in up
to a 50% reduction in triglycerides, very slight LDL
cholesterol reductions, and modest increases in
HDL cholesterol.64 The use of these agents has been
shown to increase the synthesis of HDL proteins,
but also to significantly enhance the fractional
catabolism of HDL proteins.65
Fenofibrate is currently the most widely used
fibrate, and has the benefit of not having any interactions with statins in contrast to gemfibrozil. Studies have shown that fenofibrate use is associated
with very large and significant benefits in reducing
evidence of microvascular disease in patients with
diabetes mellitus.6469 Fibrates are well tolerated.
The most common side effect is dyspepsia. Myopathy and hepatitis is rare, though they may increase
the formation of gallstones as they promote cholesterol secretion into bile. Caution should be taken in
patients on warfarin and certain hypoglycemic as
fibrates may potentiate there effects.
NIACIN.
Niacin is the most effective agent currently available for increasing HDL. The most widely used form
of niacin has been reformulated as an extended
release product (Niaspan), which causes less flushing than immediate release niacin or other forms of
extended release niacin. Niaspan at a dose of 2 g/
day taken at bedtime decreases LDL cholesterol by
about 10%20%, triglycerides by about 30%, and
Lp(a) by about 25%, while increasing HDL cholesterol by approximately 25%30%.40 Side effects may
include flushing, gastric irritation, and elevations
of uric acid, glucose, and liver enzymes in some
patients. Niacin should not be used in patients
with liver disease or a history of an ulcer. The most
common side effect is cutaneous flushing and may
be minimized by daily aspirin taken prior to niacin
administration. Studies have shown that niacin
significantly reduces CHD risk and promotes regression of coronary atherosclerosis.7079

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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

Anion Exchange Resins


Anion exchange resins bind bile acids in the intestine, increase the conversion of liver cholesterol
to bile acids, and upregulate LDL receptors in liver,
decreasing plasma LDL by about 15%20%. They include cholestyramine, colestipol, and colesevelam.
Side effects can include bloating and constipation,
elevation of triglycerides, and interference with
the absorption of digoxin, tetracycline, d-thyroxine,
phenylbutazone, and coumadin A new resin, colesevelam is available in tablet form and is given at
a dose of six 625 mg tablets per day, and has been
shown to lower LDL cholesterol by 16%18%, and
also improves glycemic control in patients with
diabetes.80 Anion exchange resins are effective in
combination with statins and also ezetimibe, especially in statin intolerant patients to get them to
their LDL cholesterol goals.

Xanthomatoses and Lipoprotein Disorders 209

Fish Oil Capsules


High doses of fish oil as well as diets very high in
oily fish have long been known to significantly lower triglyceride levels based on studies carried out by
Connor and colleagues in Portland, Oregon.81 Highdose fish oil or high-fish diets suppress the immune
response by decreasing monocyte production of interleukins 1 and 6 and tumor necrosis factor alpha,
as well as by decreasing helper T cells and delayed
hypersensitivity response as determined by skin
testing.82 The two active molecules in fish oil are (1)
eicosapentanoic acid (EPA) and (2) decohexanoic
acid (DHA). Over-the-counter fish oil capsules are
available, as is a prescription form of concentrated
fish oil known as LOVAZA given as two 1 g capsules
twice daily (total dose is 1,860 mg of EPA and 1,500
mg of DHA). This formulation given at this dose will
substantially lower triglycerides levels especially
in patients with hypertriglyceridemia.83 The same
effect can be obtained with regular fish oil capsules
at a far lower cost, but three 1 g capsules twice
daily need to be taken. Fish oil at this dose not only
lowers triglyceride levels, but can raise the levels
of large HDL particles substantially, but only raises
HDL cholesterol modestly by 5%10%. Their major
effect is to decrease the secretion of VLDL triglyceride and apoB.84
Overall the data from studies suggest that EPA has
immunologic effects, while DHA is more likely to
have lipid modifying effects and effects on membrane fluidity. There is also data suggesting the fish
intake associated with increased plasma phospholipid DHA decreases the risk of dementia and
Alzheimer disease.92 It does appear the low-dose
fish oil (12 capsules per day) will decrease the risk
of death in the first year after myocardial infarction,
and that a supplement containing 1,800 mg of EPA
will reduce CHD risk especially in those with high
triglycerides and low HDL.8387 Moreover, it also
clear that high-dose fish oil (four capsules per day
of LOVAZA or six or more regular fish oil capsules
per day) will significantly lower triglyceride levels.
Fish oil can be safely given together with statin
therapy.83

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210 Chapter 135: Xanthomatoses and Lipoprotein Disorders

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