Page 644 - Basic _ Clinical Pharmacology ( PDFDrive )

630 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout

or ANGPTL4 and Apo A-V, are usually associated with severe cholesteryl esters, the level of total cholesterol may be as high as that of
lipemia (2000 mg/dL of triglycerides or higher when the patient triglycerides. Diagnosis is confirmed by the absence of the ε3 and ε4
is consuming a typical American diet). These disorders might not alleles of apo E, the ε2/ε2 genotype. Other apo E isoforms that lack
be diagnosed until an attack of acute pancreatitis occurs. Patients receptor ligand properties can also be associated with this disorder.
may have eruptive xanthomas, hepatosplenomegaly, hypersplen- Patients often develop tuberous or tuberoeruptive xanthomas, or
ism, and lipid-laden foam cells in bone marrow, liver, and spleen. characteristic planar xanthomas of the palmar creases. They tend to
The lipemia is aggravated by estrogens because they stimulate be obese, and some have impaired glucose tolerance. These factors,
VLDL production, and pregnancy may cause marked increases as well as hypothyroidism, can aggravate the lipemia. Coronary and
in triglycerides despite strict dietary control. Although these peripheral atherosclerosis occurs with increased frequency. Weight
patients have a predominant chylomicronemia, they may also loss, together with decreased fat, cholesterol, and alcohol consump-
have moderately elevated VLDL, presenting with a pattern called tion, may be sufficient, but a fibrate or niacin is usually needed to
mixed lipemia (fasting chylomicronemia and elevated VLDL). control the condition. These agents can be given together in more
Deficiency of lipolytic activity can be diagnosed after intravenous resistant cases. Reductase inhibitors are also effective because they
injection of heparin. A presumptive diagnosis is made by dem- increase hepatic LDL receptors that participate in remnant removal.
onstrating a pronounced decrease in triglycerides 72 hours after
elimination of daily dietary fat. Marked restriction of total dietary THE PRIMARY
fat and abstention from alcohol are the basis of effective long-term
treatment. Niacin, a fibrate, or marine omega-3 fatty acids may be HYPERCHOLESTEROLEMIAS
of some benefit if VLDL levels are increased. Apo C-III antisense LDL Receptor Deficient Familial
is a potential adjunct to therapy.
Hypercholesterolemia (FH)
Familial Hypertriglyceridemia This is an autosomal dominant trait. Although levels of LDL tend
to increase throughout childhood, the diagnosis can often be made
The primary hypertriglyceridemias probably reflect a variety of
genetic determinants. Many patients have centripetal obesity with on the basis of elevated umbilical cord blood cholesterol. In most
insulin resistance. Other factors, including alcohol and estrogens, that heterozygotes, cholesterol levels range from 260 to 500 mg/dL.
increase secretion of VLDL aggravate the lipemia. Impaired removal Triglycerides are usually normal. Tendon xanthomas are often
of triglyceride-rich lipoproteins with overproduction of VLDL present. Arcus corneae and xanthelasma may appear in the
can result in mixed lipemia. Eruptive xanthomas, lipemia retinalis, third decade. Coronary disease tends to occur prematurely. In
epigastric pain, and pancreatitis are variably present depending on the homozygous familial hypercholesterolemia, which can lead to
severity of the lipemia. Treatment is primarily dietary, with restriction coronary disease in childhood, levels of cholesterol often exceed
of total fat, avoidance of alcohol and exogenous estrogens, weight 1000 mg/dL and early tuberous and tendinous xanthomas occur.
reduction, exercise, and supplementation with marine omega-3 fatty These patients may also develop elevated plaque-like xanthomas
acids. Most patients also require treatment with a fibrate. If insulin of the aortic valve, digital webs, buttocks, and extremities.
resistance is not present, niacin may be useful. Some individuals have combined heterozygosity for alleles
producing nonfunctional and kinetically impaired receptors. In
Familial Combined Hyperlipoproteinemia heterozygous patients, LDL can be normalized with reductase
inhibitors or combined drug regimens (Figure 35–2). Homozy-
(FCH) gotes and those with combined heterozygosity whose receptors

In this common disorder, which is associated with an increased retain even minimal function may partially respond to niacin,
incidence of coronary disease, individuals may have elevated levels ezetimibe, and reductase inhibitors. Emerging therapies for these
of VLDL, LDL, or both, and the pattern may change with time. patients include mipomersen, employing an antisense strategy
Familial combined hyperlipoproteinemia involves an approximate targeted at apo B-100, and lomitapide, a small molecule inhibitor
doubling in VLDL secretion and appears to be transmitted as a of microsomal triglyceride transfer protein (MTP), and monoclo-
dominant trait. Triglycerides can be increased by the factors noted nal antibodies directed at PCSK9. LDL apheresis is effective in
above. Elevations of cholesterol and triglycerides are generally mod- medication-refractory patients.
erate, and xanthomas are absent. Diet alone does not normalize
lipid levels. A reductase inhibitor alone, or in combination with nia- Familial Ligand-Defective Apolipoprotein
cin or fenofibrate, is usually required to treat these patients. When B-100
fenofibrate is combined with a reductase inhibitor, either pravas-
tatin or rosuvastatin is recommended because neither is metabolized Defects in the domain of apo B-100 that binds to the LDL
via CYP3A4. Marine omega-3 fatty acids may be useful. receptor impair the endocytosis of LDL, leading to hypercho-
lesterolemia of moderate severity. Tendon xanthomas may occur.
Familial Dysbetalipoproteinemia Response to reductase inhibitors is variable. Upregulation of LDL
receptors in liver increases endocytosis of LDL precursors but does
In this disorder, remnants of chylomicrons and VLDL accumu- not increase uptake of ligand-defective LDL particles. Fibrates or
late and levels of LDL are decreased. Because remnants are rich in niacin may have beneficial effects by reducing VLDL production.