section
2 0 .3
Lipoprotein-Associated Disorders
441
due to deficiency of apo C-II, an essential cofactor for LPL,
or to the presence of an inhibitor of LPL in the plasma.
Hyperchylomicronemia may be accompanied by an in-
crease in VLDL (type V hyperlipoproteinemia) in which
LPL is not absent but may be defective. Occasionally, this
disorder is linked to low levels of apo C-II.
The severe hypertriacylglycerolemia of types I and V
may result in “eruptive xanthomas,” elevated papules in
the skin containing lipid-laden phagocytic cells. Phagocy-
tosis of lipoproteins by macrophages in liver and spleen
may produce hepatosplenomegaly, abdominal pain, and
occasionally acute pancreatitis. Since insulin may be re-
quired for LPL production, LPL deficiency may be sec-
ondary to diabetes mellitus. Hyperchylomicronemia that
occurs with LPL deficiency does not usually predispose to
atherosclerosis. However, in some patients with hyperchy-
lomicronemia due to mutations in the LPL gene, premature
atherosclerosis does occur. In most patients morbidity and
mortality is caused by pancreatitis. Dietary fat restriction
reduces the hyperchylomicronemia and patients lead fairly
normal lives.
Reduced hepatic uptake of chylomicron remnants and
reduction in conversion of plasma VLDL to LDL lead
to accumulation of two populations of remnant particles
in plasma, a condition known as
dysbetalipoprotein em ia
(type III hyperlipoproteinemia). On paper electrophoresis,
the abnormal VLDL produces a band in the
ft
to the pre-/3
region (“broad
fF"
pattern). Relative to their concentration
of apo B, both populations of remnants are depleted in
apo C and enriched in mutant apo E. Since hepatic uptake
of remnant particles depends on apo E, the increased res-
idence in plasma of these remnants suggests a structural
abnormality in apo E. The six phenotypes comprise three
homozygous (E-4:E-4, E-3:E-3, and E-2:E-2) and three
heterozygous forms (E-4:E-3, E-3:E-2, and E-4:E-2). The
apo-E isoforms differ by single amino acid substitutions
at two sites. Apo E-2 has cysteine at residues 112 and
158, apo E-3 has cysteine at 112 and arginine at 158, and
apo E-4 has arginine at 112 and 158. Patients with
d y s-
betalipoprotein em ia
exhibit phenotype E-2:E-2; apo E-2,
which is different from the predominant wild-type apo E-3,
is known as mutant E-2. Apo E-2 has a much lower affinity
(
1
%) for the hepatic receptors compared with other phe-
notypes.
Type 111 h yperlipoprotein em ia
is a multifactorial
disorder. The expression of the disorder not only involves
the inheritance of two alleles for apo E-2:apo E-2, but also
requires other genetic, hormonal, and environmental fac-
tors. For example, diabetes mellitus and hypothyroidism
are frequently associated with type III hyperlipoproteine-
mia. Age, sex, nutritional status, and alcohol consumption
are all factors that affect this disorder. There are other
rare variants of apo E (e.g., Arg-142 —>• Cys, Arg-145 —»■
Cys, Lys-146 -» Glu) which can give rise to type III hy-
perlipoproteinemia, independent of other factors. The as-
sociation of apo E-4 and Alzheimer’s disease has been
confirmed in many populations, but its significance in the
pathology of the disorder awaits explanation (Chapter 4).
Patients with type III hyperlipoproteinemia exhibit in-
creased plasma cholesterol and triacylglycerol and the
presence of /1-VLDL. Dysbetalipoproteinemics are prone
to premature vascular disease, eruptive xanthomas on el-
bows and knees, and planar xanthomas in the palmar and
digital creases. These patients respond well to therapy.
Dietary therapy is preferred, but drug therapy (see below)
may also be necessary.
Primary elevation of VLDL, or
h yperprebetalipopro-
teinem ia
(type IV hyperlipoproteinemia), occurs in famil-
ial hypertriacylglycerolemia or familial combined hyper-
lipidemia. The former is characterized by overproduction
of VLDL triacylglycerols but normal synthesis of apo B-
100. A familial form is characterized by overproduction
of triacylglycerols and apo B-100. These disorders differ
from familial combined hyperlipidemia in not showing
increased levels of LDL. A third form of primary hyper-
triacylglycerolemia has been identified in which there is
decreased catabolism of VLDL rather than overproduc-
tion. Mild hyperchylomicronemia may appear to compli-
cate these disorders based on defective VLDL metabolism;
however, it is usually due to obesity or excess dietary
fat intake and should not be confused with the severe
hyperchylomicronemias mentioned earlier. Patients with
either familial combined hyperlipidemia or familial hy-
pertriglyceridemia are at risk for mortality from cardio-
vascular disease. Expression of the apolipoprotein (APO)
gene (
A P O A V
) that is located proximal to
A PO A I/C III/A IV
gene cluster, decreases plasma triacylglycerol levels. Sin-
gle nucleotide polymorphisms in the
A PO A V
gene locus
are associated with high levels of plasma triacylglycerol.
Prospective studies have shown that plasma triacylgly-
cerol levels greater than 150mg/dl are an independent risk
factor for cardiovascular disease and mortality.
Hypercholesterolemias
F am ilial h yperch olesterolem ia (FH)
is an inborn error of
metabolism due to a defective LDL-receptor protein. Five
classes of mutations have been identified consisting of
more than 150 different alleles. The defects in the receptor
function can be grouped into five types:
1. The receptor may not be synthesized at all;
2. The receptor may not be transported to the surface;
3. The receptor may fail to bind LDL;
4. The receptor may fail to cluster in coated pits; or
5. The receptor may fail to release LDL in the endosome.
