Hyperlipoproteinemia, Type Iii

A number sign (#) is used with this entry because hyperlipoproteinemia type III is caused by homozygous, compound heterozygous, or heterozygous mutation in the APOE gene (107741) on chromosome 19q13.

Description

Hyperlipoproteinemia type III, also called dysbetalipoproteinemia, is characterized by hyperlipidemia due to accumulation of remnants of the triglyceride (TG)-rich lipoproteins (TGRL), very low density lipoproteins (VLDL), and chylomicrons (CM), in response to dysfunctional genetic variants of apolipoprotein E or absence of apoE (summary by Blum, 2016).

Clinical Features

In normal individuals, chylomicron remnants and very low density lipoprotein remnants are rapidly removed from the circulation by receptor-mediated endocytosis in the liver. In familial dysbetalipoproteinemia, or type III hyperlipoproteinemia, increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants because of a defect in apolipoprotein E. Accumulation of the remnants can result in xanthomatosis and premature coronary and/or peripheral vascular disease. Hyperlipoproteinemia III can either be due to primary heritable defects in apolipoprotein metabolism or secondary to other conditions such as hypothyroidism, systemic lupus erythematosus, or diabetic ketoacidosis. Most patients with familial dysbetalipoproteinemia are homozygous for the E2 isoform (Breslow et al., 1982). Only rarely does the disorder occur with the heterozygous phenotypes E3E2 or E4E2. The E2 isoform shows defective binding of remnants to hepatic lipoprotein receptors (Schneider et al., 1981; Rall et al., 1982) and delayed clearance from plasma (Gregg et al., 1981). Additional genetic and/or environmental factors must be required for development of the disorder, however, because only 1-4% of E2E2 homozygotes develop familial dysbetalipoproteinemia. Since the defect in this disorder involves the exogenous cholesterol transport system, the degree of hypercholesterolemia is sensitive to the level of cholesterol in the diet (Brown et al., 1981). Even on a normal diet, the patient may show increased plasma cholesterol and the presence of an abnormal lipoprotein called beta-VLDL. VLDL in general is markedly increased while LDL is reduced. Carbohydrate induces or exacerbates the hyperlipidemia, resulting in marked variability in plasma levels and ready therapy through dietary means. Often tuberous and planar and sometimes tendon xanthomas occur as well as precocious atherosclerosis and abnormal glucose tolerance. Tuberous and tuberoeruptive xanthomas are particularly characteristic. Development of the phenotype is age dependent, being rarely evident before the third decade. Subsequent description of specific biochemical alterations in apolipoprotein structure and metabolism has proven this phenotype to be genetically heterogeneous. In the first application of apoprotein immunoassay to this group of disorders, Kushwaha et al. (1977) found that apolipoprotein E (arginine-rich lipoprotein) is high in the VLD lipoproteins of type III. They also found that exogenous estrogen, which stimulates triglyceride production in normal women and those with endogenous hypertriglyceridemia, exerted a paradoxical hypotriglyceridemic effect in this disorder (Kushwaha et al., 1977). The abnormal pattern of apoE by isoelectric focusing (IEF), specifically, the absence of apoE3, is the most characteristic biochemical feature of HLP III. Gregg et al. (1981) showed that apoE isolated from subjects with type III HLP had a decreased fractional catabolic rate in vivo in both type III HLP patients and normal persons.

Ghiselli et al. (1981) studied a black kindred with type III HLP due to deficiency of apolipoprotein E. No plasma apolipoprotein E could be detected. Other families with type III HLP have had increased amounts of an abnormal apoE. In addition, the patients of Ghiselli et al. (1981) had only mild hypertriglyceridemia, increased LDL cholesterol, and a much higher ratio of VLDL cholesterol to plasma triglyceride than reported in other type III HLP families. The proband was a 60-year-old woman with a 10-year history of tuberoeruptive xanthomas of the elbows and knees, a 3-year history of angina pectoris, and 80% narrowing of the first diagonal coronary artery by arteriography. Her father had xanthomas and died at age 62 of myocardial infarction. Her mother was alive and well at age 86. Three of 7 sibs also had xanthomas; her 2 offspring had no xanthomas. The evidence suggests that apoE is important for the catabolism of chylomicron fragments. The affected persons in the family studied by Ghiselli et al. (1981) had plasma levels of apoE less than 0.05 mg/dl by radioimmunoassay, and no structural variants of apoE were detected by immunoblot of plasma or VLDL separated by 2-dimensional gel electrophoresis. Anchors et al. (1986) reported that the apoE gene was present in the apoE-deficient patient and that there were no major insertions or deletions in the gene by Southern blot analysis. Blood monocyte-macrophages isolated from a patient contained levels of apoE mRNA 1 to 3% of that present in monocyte-macrophages isolated from normal subjects. The mRNA from the patient appeared to be of normal size. Anchors et al. (1986) suggested that the decreased apoE mRNA might be due to a defect in transcription or processing of the primary transcript or to instability of the apoE mRNA. The decreased plasma level of apoE resulted in delayed clearance of remnants of triglyceride-rich lipoproteins, hyperlipidemia, and the phenotype of type III HLP.

Although nearly every type III hyperlipoproteinemic person has the E2/E2 phenotype, 95 to 99% of persons with this phenotype do not have type III HLP nor do they have elevated plasma cholesterol levels. Rall et al. (1983) showed that apoE2 of hypo-, normo-, and hypercholesterolemic subjects showed the same severe functional abnormalities. Thus, factors in addition to the defective receptor binding activity of the apoE2 are necessary for manifestation of type III HLP. A variety of factors exacerbate or modulate type III. In women, it most often occurs after menopause and in such patients is particularly sensitive to estrogen therapy. Hypothyroidism exacerbates type III and thyroid hormone is known to enhance receptor-mediated lipoprotein metabolism. Obesity, diabetes, and age are associated with increased hepatic synthesis of VLDL and/or cholesterol; occurrence of type III in E2/E2 persons with these factors may be explained thereby. Furthermore, the defect in familial combined HLP (144250), which is, it seems, combined with E2/E2 in the production of type III (Utermann et al., 1979; Hazzard et al., 1981), may be hepatic overproduction of cholesterol and VLDL. As pointed out by Brown and Goldstein (1983), familial hypercholesterolemia (FH; 143890) is a genetic defect of the LDL receptor (LDLR; 606945), whereas familial dysbetalipoproteinemia is a genetic defect in a ligand. The puzzle that all apoE2/2 homozygotes do not have extremely high plasma levels of IDL and chylomicron remnants (apoE-containing lipoproteins) may be solved by the observation that the lipoprotein levels in these patients are exquisitely sensitive to factors that reduce hepatic LDL receptors, e.g., age, decreased levels of thyroid hormone and estrogen, and the genetic defect of FH. Presumably, high levels of hepatic LDL receptors can compensate for the genetic binding defect of E2 homozygotes.

Bersot et al. (1983) studied atypical dysbetalipoproteinemia characterized by severe hypercholesterolemia and hypertriglyceridemia, xanthomatosis, premature vascular disease, the apoE3/3 phenotype (rather than the classic E2/2 phenotype), and a preponderance of beta-VLDL. They showed that the beta-VLDL from these subjects stimulated cholesteryl ester accumulation in mouse peritoneal macrophages. They suggested that the accelerated vascular disease results from this uptake by macrophages which are converted into the foam cells of atherosclerotic lesions.

Schaefer et al. (1986) described a unique American black kindred with premature cardiovascular disease, tuberoeruptive xanthomas, and type III HLP associated with familial apolipoprotein E deficiency. Four homozygotes had marked increases in cholesterol-rich, very low density lipoproteins and intermediate density lipoproteins (IDL). Homozygotes had only trace amounts of plasma apoE, and accumulations of apoB-48 (107730) and apoA-4 (107690) in VLDL, IDL, and low density lipoproteins. Obligate heterozygotes generally had normal plasma lipids and mean plasma apoE concentrations that were 42% of normal. The findings indicated that apoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. It had been shown that cultured peripheral blood monocytes synthesized low amounts of 2 aberrant forms of apoE mRNA but produced no immunoprecipitable forms of apoE. The expression studies were done comparing the normal and abnormal APOE genes transfected into mouse cells in combination with the mouse metallothionein I promoter.

Boerwinkle and Utermann (1988) studied the simultaneous effect of apolipoprotein E polymorphism on apolipoprotein E, apolipoprotein B, and cholesterol metabolism. Since both apoB and apoE bind to the LDL receptor and since the different isoforms show different binding affinity, these effects are not unexpected.

In a case-control study of 338 centenarians compared with adults aged 20 to 70 years of age, Schachter et al. (1994) found that the E4 allele of apoE, which promotes premature atherosclerosis, was significantly less frequent in centenarians than in controls (p = less than 0.001), while the frequency of the E2 allele, associated previously with types III and IV hyperlipidemia, was significantly increased (p = less than 0.01).

Feussner et al. (1996) reported a 20-year-old man with a combination of type III hyperlipoproteinemia and heterozygous familial hypercholesterolemia (FH; 143890). Multiple xanthomas were evident on the elbows, interphalangeal joints and interdigital webs of the hands. Lipid-lowering therapy caused significant decrease of cholesterol and triglycerides as well as regression of the xanthomas. Flat xanthomas of the interdigital webs were also described in 3 out of 4 previously reported patients with combination of these disorders of lipoprotein metabolism. Feussner et al. (1996) stated that these xanthomas may indicate compound heterozygosity (actually double heterozygosity) for type III hyperlipoproteinemia and FH.

Clinical Management

Among 1,383 Scottish adult patients with diabetes taking statin medication to reduce serum LDL cholesterol levels, Donnelly et al. (2008) found an association of APOE genotype with both baseline and treatment responses. E2 homozygotes achieved significantly lower LDL levels compared to E4 homozygotes (mean 0.6 versus 1.7 mmol/L; p = 2.96 x 10(-12)). All E2 homozygotes reached the target serum LDL level, compared to 32% of E4 homozygotes who did not (p = 5.3 x 10(-5)). The findings indicated that APOE genotype may be an important marker for clinical responses to statin drugs.

Molecular Genetics

Most patients with familial dysbetalipoproteinemia type III are homozygous for the E2 isoform arg258-to-cys mutation (R258C; 107741.0001) (Breslow et al., 1982).

In the kindred with apolipoprotein E deficiency studied by Ghiselli et al. (1981), the defect was shown by Cladaras et al. (1987) to involve an acceptor splice site mutation in intron 3 of the APOE gene (107741.0005).

Smit et al. (1987) described 3 out of 41 Dutch dysbetalipoproteinemic patients who were apparent E3/E2 heterozygotes rather than the usual E2/E2 homozygotes. All 3 genetically unrelated patients showed an uncommon E2 allele that contained only 1 cysteine residue. The uncommon allele cosegregated with familial dysbetalipoproteinemia which in these families seemed to behave as a dominant. Smit et al. (1990) showed that these 3 unrelated patients were heterozygous for E2(K146Q; 107741.0011).

Susceptibility to Coronary Artery Disease

Eto et al. (1989) presented data from Japan indicating that both the E2 allele and the E4 allele are associated with an increased risk of ischemic heart disease as compared with the E3 allele.

In 5 of 19 Australian men, aged 30 to 50, who were referred for coronary angioplasty (26%), van Bockxmeer and Mamotte (1992) observed homozygosity for E4. This represented a 16-fold increase compared with controls. Payne et al. (1992), O'Malley and Illingworth (1992), and de Knijff et al. (1992) expressed doubts concerning a relationship between E4 and atherosclerosis.

Frikke-Schmidt et al. (2007) presented evidence that combinations of SNPs in APOE and LPL (609708) identify subgroups of individuals at substantially increased risk of ischemic heart disease beyond that associated with smoking, diabetes, and hypertension.

Kathiresan et al. (2008) studied SNPs in 9 genes in 5,414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. All 9 SNPs, including rs4420638 of APOE, had previously been associated with elevated LDL or lower HDL. Kathiresan et al. (2008) replicated the associations with each SNP and created a genotype score on the basis of the number of unfavorable alleles. With increasing genotype scores, the level of LDL cholesterol increased, whereas the level of HDL cholesterol decreased. At 10-year follow-up, the genotype score was found to be an independent risk factor for incident cardiovascular disease (myocardial infarction, ischemic stroke, or death from coronary heart disease); the score did not improve risk discrimination but modestly improved clinical risk reclassification for individual subjects beyond standard clinical factors.

History

The nosography of the type III hyperlipoproteinemia phenotype up to 1977 was reviewed by Levy and Morganroth (1977).