Defects in the domain of apo B-100 that binds to the LDL receptor impair the endocytosis of LDL, leading to hypercholesterolemia of moderate severity. Tendon xanthomas may occur. Response to reductase inhibitors is variable. Upregulation of LDL receptors in liver increases endocytosis of LDL precursors but does not increase uptake of ligand-defective LDL particles. Fibrates or niacin may have beneficial effects by reducing VLDL production.
B-100 B-100 VLDL LDL BloodR HepatocyteAcetyl-CoA HMG-CoA reductase inhibitors Cholesterol Bile acids Niacin GutResins Ezetimibe HMG-CoA FIGURE 35–2 Sites of action of HMG-CoA reductase inhibitors, niacin, ezetimibe, and resins used in treating hyperlipidemias. Low-density lipoprotein (LDL) receptors are increased by treatment with resins and HMG-CoA reductase inhibitors. VLDL, very-low-density lipoproteins; R, LDL receptor.
Some persons with familial combined hyperlipoproteinemia have only an elevation in LDL. Serum cholesterol is often less than 350 mg/dL. Dietary and drug treatment, usually with a reductase inhibitor, is indicated. It may be necessary to add niacin or ezetimibe to normalize LDL.
This familial disorder, which is associated with increased atherogenesis and arterial thrombus formation, is determined chiefly by alleles that dictate increased production of the (a) protein moiety. Lp(a) can be secondarily elevated in patients with severe nephrosis and certain other inflammatory states. Niacin reduces levels of Lp(a) in many patients. Reduction of levels of LDL-C below 100 mg/dL decreases the risk attributable to Lp(a), as does the administration of low-dose aspirin. PCSK9 monoclonal antibodies also reduce levels of Lp(a) by about 25%.
Individuals lacking activity of lysosomal acid lipase (LAL) accumulate cholesteryl esters in liver and certain other cell types leading to hepatomegaly with subsequent fibrosis, elevated levels of
LDL-C, low levels of HDL-C, and often modest hypertriglyceridemia. Rarely, a totally ablative form, Wolman disease, occurs in infancy. A recombinant replacement enzyme therapy, sebelipase alfa, effectively restores the hydrolysis of cholesteryl esters in liver, normalizing plasma lipoprotein levels.
Deficiency of cholesterol 7α-hydroxylase can increase LDL in the heterozygous state. Homozygotes also can have elevated triglycerides, resistance to reductase inhibitors as a single agent, and increased risk of gallstones and coronary disease. A combination of niacin with a reductase inhibitor appears to be effective. Autosomal recessive hypercholesterolemia (ARH) is due to mutations in a protein that normally assists in endocytosis of LDL. High-dose reductase inhibitor plus ezetimibe is effective. The receptor chaperone PCSK9 normally conducts the receptor to the lysosome for degradation. Gain-of-function mutations in PCSK9 are associated with elevated levels of LDL-C and could be managed with a PCSK9 antibody. The ABCG5 and ABCG8 half-transporters act together in enterocytes and hepatocytes to export phytosterols into the intestinal lumen and bile, respectively. Homozygous or combined heterozygous ablative mutations in either transporter result in elevated levels of LDL enriched in phytosterols, tendon and tuberous xanthomas, and accelerated atherosclerosis. Ezetimibe is a specific therapeutic for this disorder.