Primary Hypercholesterolemia

•  Familial Hypercholesterolemia

  • Autosomal dominant trait

  • Serum cholesterol (heterozygous adults): 260-500 mg/dL

  • Triglycerides: within normal limits

  • Clinical Manifestations: (heterozygous)

    • tendinous xanthomatosis

    • xanthelasmas (eyelids -- soft yellowish spots or plaques; form of xanthomas)

    • premature coronary atherosclerosis

  • Clinical Manifestations: (homozygous)

    • coronary vascular disease childhood

    • serum cholesterol levels > 1000 mg/dL

    • early tuberous and tendinous xanthomatosis

    • plaque-like, elevated xanthomas of aortic valves, digital webs, buttocks, extremities

  • Mechanism:familial hypercholesterolemia

    • High-affinity LDL receptor defect

  •  Clinical Management:familial hypercholesterolemia

    • in heterozygotes: drug regimens can result in normal LDL levels

    • niacin may be beneficial in patients with no LDL receptor function

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• Familial Ligand-Defective Apolipoprotein B

  • Clinical consequence:familial ligand-defective apolipoprotein B

    • impaired LDL endocytosis leads to moderately severe hypercholesterolemia

    • Tendon xanthomas possible

  • Treatment:familial ligand-defective apolipoprotein B

    • probably effective: niacin

    • variably effective: HMG-CoA reductase inhibitors

• Familial Combined Hyperlipoproteinemia:

  • may present with LDL elevation only; or VLDL and LDL elevation

  • serum cholesterol levels usually less than 350 mg/dL

  •  Premature CHD: common

  • Treatment: niacin or reductase inhibitor; alternatively, resin plus niacin

• Lp(a) Hyperlipoproteinemia

  • associated with increased atherogenesis

  • niacin may be helpful

 HDL Deficiency

• Genetic factors leads to very low HDL serum levels

• Familial hypoalphalipoproteinemia: more common HDL disorder

  • HDL cholesterol < 35 mg/dL (semidominant genetic transmission)

  •  premature atherosclerosis (low HDL plasma levels: perhaps only identified risk factor)

  • Treatment:

    1. avoid or limit other CHD risk factors

    2.  niacin to promote higher LDL levels

• If hypertriglyceridemia is present, HDL cholesterol levels will be low due to cholesterol ester exchange from HDL leads to triglyceride-rich lipoproteins

  • Hypertriglyceridemia treatment may reduce HDL cholesterol to normal

 Secondary Hyperlipoproteinemia

*adapted from: Table 35-4:Malloy, M. J, and Kane, J. P., Agents Used in Hyperlipidemia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 567.

• Estrogen: small doses may induce a severe hypertriglyceridemia (combining very low estrogen dose with the progestational agent will diminish this effect); if estrogen treatment is required, trans-dermal administration is preferred because hepatic first pass effect is avoided

• Hyperlipidemia associated with chronic nephrotic syndrome: requires treatment (due to  CHD prevalence in this patient population)

  • Drugs of choice: bile acid-binding resin + niacin (vitamin B3)

• Hyperlipidemia associated with cholestasis:

  • Treatment indication: neuropathy associated with xanthomatous neuronal involvement

    • Plasmapheresis preferred