Inborn Metabolic Diseases Diagnosis and Treatment - part 8 pdf

32.1 · Overview of Plasma Lipid and Lipoprotein Metabolism 32 393 hepatic tissues also have abundant LDL receptors. LDL cholesterol can also be removed via non-LDL receptor mechanisms. One class of cell surface receptors, termed scavenger receptors, takes up chemically modified LDL such as oxidized LDL ( . Fig. 32.1), which has been generated by release of oxygen radicals from endothelial cells. Scavenger receptors are not regulated by intracellular cholesterol levels. In peripheral tissues such as macrophages and smooth muscle cells of the arterial wall, excess cholesterol accumulates within the plasma membrane, and then is transported to the endoplasmic reticulum where it is esterified to cholesteryl esters by the enzyme, acyl-CoA cholesterol acyltransferase. It is at this stage that cytoplasmic droplets are formed and that the cells are converted into foam cells (an early stage of atherogenesis). Later on, cholesteryl esters accumulate as insoluble residues in athero- sclerotic plaques. The optimal level of plasma LDL to prevent atherosclerosis and to maintain normal cholesterol homeostasis in humans is not known. At birth, the average LDL cholesterol level is 30 mg/dL. After birth, if the LDL cholesterol level is <100 mg/dl, LDL is primarily removed through the high affinity LDL receptor pathway. In Western societies, the LDL cholesterol is usually >100 mg/dl; the higher the LDL-cholesterol the greater the amount that is removed by the scavenger pathway. While the exogenous and endogenous pathways are conceptually considered as separate pathways, an imbal- ance in one often produces an abnormal effect in the other. Thus, reduced LPL activity or decreased apo C-II, as well as elevated apo C-III or apo C-I, can promote hypertriglyceridemia and accumulation of remnant particles from both chylomicrons and VLDL. When the remnant particles are sufficiently small (Svedberg flotation units 20 to 60), they can enter the vascular wall and promote atherogenesis. The greater the cholesterol content of the remnants, the more atherogenic they are. This scenario can be further complicated by VLDL overproduction or by reduced LDL receptor activity. 32.1.3 Reverse Cholesterol Transport and High Density Lipoproteins Reverse cholesterol transport (. Fig. 32.2) refers to the process by which unesterified or free cholesterol is removed from extrahepatic tissues, probably by extraction from cell membranes via the ATP binding cassette transporter ABCA1, and transported on HDL [3]. HDL particles are heterogeneous and differ in their percentage of apolipoproteins (A-I, A-II, and A-IV) . HDL can be formed by remod- eling of apolipoproteins cleaved during the hydrolysis of tri glyceride-rich lipoproteins (chylomicrons, VLDL and IDL). They can also be synthesized by intestine, liver and macrophages as nascent or pre-E HDL particles that are relatively lipid-poor and disc-like in appearance . Pre-E-1 . Fig. 32.2. The pathway for HDL metabolism and reverse cholesterol transport. See text for abbreviations. Modified and reproduced with permission from Braunwald E (ed) Essential atlas of heart diseases, Appleton & Lange, Philadelphia, 1997, p 1.29 Chapter 32 · Dyslipidemias VII 394 HDL is a molecular species of plasma HDL of approximately 67 kDa that contains apoA-I, phospholipids and unesterified chol esterol, and plays a major role in the retrieval of cholesterol from peripheral tissues. HDL particles possess a number of enzymes on their cell surface [4]. One enzyme, lecithin-cholesterol acyltransferase (LCAT), plays a significant role by catalyzing the conversion of unesterified to esterified cholesterol ( . Fig. 32.2, Table 32.3). Esterified cholesterol is nonpolar and will localize in the center core of the HDL particle, allowing it to remove more unesterified cholesterol from cells. Esterified cholesterol can be transferred, via the action of cholesteryl ester transfer protein (CETP), to VLDL and IDL particles ( . Fig. 32.2). These TG-rich lipoproteins can be hydrolyzed to LDL, which can then be cleared by hepatic LDL receptor. Another enzyme that plays a critical role in the metabolic fate of HDL is hepatic lipase (HL), which hydrolyzes the triglycerides and phospholipids on larger HD L particles (HDL-2), producing smaller HDL particles (HDL-3). Nascent HDL particles are re- generated by the action of HL and phospholipid transfer protein (PTP) ( . Table 32.3). HDL may also deliver cholesteryl esters to the liver directly via the scavenger receptor SRB-1 ( . Fig. 32.2) [3, 5]. A number of epidemiological studies has shown an inverse relationship between coronary artery disease (CAD) and HDL cholesterol. HDL are thought to be cardioprotective due to their participation in reverse cholesterol transport, and perhaps also by their role as an antioxidant [3]. HDL impedes LDL oxidation by metal ions, an effect that may be due to the influence of several molecules on HDL, including apoA-I, platelet-activating factor acetylhydrolase, and paraoxonase [4]. Accumulation of HDL-2, thought to be the most cardioprotective of the HDL subclasses, is favored by estrogens, which negatively regulate hepatic lipase. In contrast, progesterone and androgens, which positively regulate this enzyme, lead to increased production of HDL-3. Clinical studies have begun to address the effect of HDL cholesterol on cardiovascular endpoints. Men in the Veterans Administration High-density Lipoprotein Inter- vention Trial, with known CAD and treated with gemfibrozil for approximately 5 years, had a 24% reduction in death from CAD, nonfatal myocardial infarction and stroke, compared to men treated with placebo. This risk reduction was associated with a 6% increase in HDL cholesterol, 31% decrease in triglyceride levels and no significant change in LDL cholesterol levels [6]. Further analysis using nuclear magnetic resonance spectroscopy indicated that the shift from small, dense LDL particles to larger LDL particles and an increase in HDL-3 with gemfibrozil explained a further amount of the percent reduction in CAD. In the Bezafibrate Infarction Prevention Study, bezafibrate significantly raised HDL cholesterol by 18% and reduced relative risk for nonfatal myocardial infarction and sudden death by 40% in a subpopulation of study participants with triglycerides >200 mg/dl [7]. 32.1.4 Lipid Lowering Drugs In recent years, pharmacologic manipulation of the metabolic and cellular processes of lipid and lipoprotein metabolism ( . Figs. 32.1 and 32.2) has greatly improved the treatment of dyslipidemias. Inhibitors of the rate-limiting enzyme of cholesterol synthesis, HMG-CoA reductase, called statins, effectively decrease the intrahepatic cholesterol pool ( . Fig. 32.1) This effect, in turn, leads to the pro- teolytic release of SREBPs from the cytoplasm into the nucleus where they stimulate the transcription of the LDL receptor gene, resulting in an increased uptake of plasma LDL by the liver. Resins, which sequester bile acids, prevent entero-hepatic recycling and reuptake of bile acids through the ileal bile acid transporter. More hepatic cholesterol is converted into bile acids, lowering the cholesterol pool, and thus also inducing LDL receptors ( . Fig. 32.1). A cholesterol absorption inhibitor interferes with the uptake of cholesterol from the diet and bile by a cholesterol transporter (CT) ( . Fig. 32.1). This decreases the amount of cholesterol delivered by the chylomicron remnants to the liver, producing a fall in the hepatic cholesterol pool and induction of LDL receptors. Niacin, or vitamin B 3 , when given at high doses, inhibits the release of FFA from adipose tissue, decreases the hepatic production of apoB-100, leading to decreased production of VLDL, and subsequently, IDL and LDL ( . Fig 32.1). Fibrates are agonists for peroxisome proliferator activator receptors (PPAR), which upregulate the LPL gene and repress the apo C-III gene; both of these effects enhance lipolysis of triglycerides in VLDL ( . Fig. 32.1). Fibrates also increase apo A-I production, while niacin decreases HDL catabolism, both leading to increased HDL levels. 32.2 Disorders of Exogenous Lipoprotein Metabolism Two disorders of exogenous lipoprotein metabolism are known. Both involve chylomicron removal. 32.2.1 Lipoprotein Lipase Deficiency Patients with classic lipoprotein lipase (LPL) deficiency present in the first several months of life with very marked hypertriglyceridemia, often ranging between 5,000 to 10,000 mg/dl ( . Table 32.4). The plasma cholesterol level is usually 1/10 of the triglyceride level. This disorder is often suspected because of colic, creamy plasma on the top of a hematocrit tube, hepatosplenomegaly, or eruptive xanthomas. Usually only the chylomicrons are elevated (type I phenotype) ( . Table 32.5), but occasionally the VLDL are also elevated (type V phenotype). The disorder can present later in childhood with abdominal pain and pancreatitis, a 32 395 life-threatening complication of the massive elevation in chylomicrons. Lipemia retinalis is usually present, premature atherosclerosis is uncommon. Familial LPL deficiency is a rare, autosomal recessive condition that affects about one in one million children. Parents are often consanguineous. The large amounts of chylomicrons result from a variety of mutations in the LPL gene. When chylomicrons are markedly increased, they can replace water (volume) in plasma, producing artifactual decreases in concentrations of plasma constituents; for ex- ample, for each 1,000 mg/dl increase of plasma triglyceride, serum sodium levels decrease between 2 and 4 meq/liter. The diagnosis is first made by a test for post-heparin lipolytic activity (PHLA). LPL is attached to the surface of endothelial cells through a heparin-binding site. After the intravenous injection of heparin (60 units/kg), LPL is released and the activity of the enzyme is assessed in plasma drawn 45 min after the injection. The mass of LPL released can also be assessed, using an ELISA assay. Parents of LPL deficient patients often have LPL activity halfway between normal controls and the LPL deficient child. The parents may or may not be hypertriglyceridemic. Treatment is a diet very low in fat (10–15% of calories) [8]. Lipid lowering medication is ineffective. Affected infants can be given Portagen, a soybean-based formula containing medium-chain triglycerides (MCT). MCT do not require the formation of chylomicrons for absorption, since they are directly transported from the intestine to the liver by the portal vein. A subset of LPL-deficient patients with unique, possibly posttranscriptional genetic defects, respond to therapy with MCT oil or omega-3 fatty acids by normalizing fasting plasma triglycerides; a therapeutic trial with MCT oil should, therefore, be considered in all patients presenting with the familial chylomicronemia syndrome [8]. Older children may also utilize MCT oil to improve the palatability and caloric content of their diet. Care must be taken that affected infants and children get at least 1% of their calories from the essential fatty acid, linoleic acid. 32.2.2 Apo C-II Deficiency Marked hypertriglyceridemia (TG >1,000 mg/dl) can also present in patients with a rare autosomal recessive disorder affecting apo C-II, the co-factor for LPL. Affected homozygotes have been reported to have triglycerides ranging from 500 to 10,000 mg/dl ( . Table 32.4). Apo C-II deficiency can be expressed in childhood but is often delayed into adulthood. The disorder is suspected by milky serum or plasma or by unexplained recurrent bouts of pancreatitis. A type V lipoprotein phenotype ( . Table 32.5) is often found, but a type I pattern may also be present. Eruptive xanthomas and lipemia retinalis may also be found. As with the LPL defect, those with apo C-II deficiency do not get premature atherosclerosis. The diagnosis can be confirmed by a PHLA test, and measuring apo C-II levels in plasma, using an ELISA assay. Apo C-II levels are very low to undetectable. The deficiency can be corrected by the addition of normal plasma to the in vitro assay for PHLA. Apo C-II deficiency is even rarer than LPL deficiency and caused by a variety of mutations. Obligate heterozygous carriers of apo C-II mutants usually have normal plasma lipid levels, despite a 50% reduction in apo C-II levels. The treatment of patients with apo C-II deficiency is the same as that discussed above for LPL deficiency. Infusion of normal plasma in vivo into an affected patient will decrease plasma triglycerides levels. 32.3 Disorders of Endogenous Lipoprotein Metabolism These diseases comprise disorders of VLDL overproduction and of LDL removal. . Table 32.4. Guidelines for plasma triglyceride levels in adults Triglyceride levels Category mg/dl mmol/l <150 <1.71 Desirable 150–199 1.71–2.67 Borderline 200–399 2.28–4.55 Elevated 400–999 4.56–11.39 High >1,000 >11.40 Very High . Table 32.5. Lipoprotein phenotypes of hyperlipidemia Lipoprotein phenotype Elevated lipoprotein Type I Chylomicrons Type IIa LDL Type IIb LDL, VLDL Type III Cholesterol-enriched IDL Type IV VLDL Type VChylomicrons, VLDL 32.3 · Disorders of Endogenous Lipoprotein Metabolism Chapter 32 · Dyslipidemias VII 396 32.3.1 Disorders of VLDL Overproduction Familial Hypertriglyceridemia Patients with familial hypertriglyceridemia (FHT) most often present with elevated triglyceride levels with normal LDL cholesterol levels (type IV lipoprotein phenotype) ( . Table 32.5). The diagnosis is confirmed by finding at least one (and preferably two or more) first degree relatives with a similar type IV lipoprotein phenotype. The VLDL levels may increase to a considerable degree, leading to hypercholesterolemia as well as marked hypertriglyceridemia (>1,000 mg/dl) and occasionally to hyperchylomicronemia (type V lipoprotein phenotype) ( . Table 32.5). This extreme presentation of FHT is usually due to the presence of obesity and type II diabetes. Throughout this spectrum of hypertriglyceridemia and hypercholesterolemia, the LDL cholesterol levels remain normal, or low normal. The LDL particles may be small and dense, secondary to the hypertriglyceridemia, but the number of these particles is not increased (see also below). Patients with FHT often manifest hyperuricemia, in addition to hyperglycemia. There is a greater propensity to peripheral vascular disease than CAD in FHT. A family his- tory of premature CAD is not usually present. The unusual rarer patient with FHT who has a type V lipoprotein phenotype may develop pancreatitis. The metabolic defect in FHT appears to be due to the increased hepatic production of triglycerides but the production of apo B-100 is not increased. This results in the enhanced secretion of very large VLDL particles that are not hydrolyzed at a normal rate by LPL and apoC-II. Thus, in FHT there is not an enhanced conversion of VLDL into IDL and subsequently, into LDL ( . Fig. 32.1). Diet, particularly reduction to ideal body weight, is the cornerstone of therapy in FHT. For patients with persistent hypertriglyceridemia above 400 mg/dl, treatment with fibric acid derivatives, niacin or the statins may reduce the elevated triglycerides by up to 50%. Management of type II diabetes, if present, is also an important part of the management of patients with FHT ( 7 Sect. 32.7). Familial Combined Hyperlipidemia and the Small Dense LDL Syndromes Clinical Presentation Patients with familial combined hyperlipidemia (FCHL) may present with elevated cholesterol alone (type IIa lipoprotein phenotype), elevated triglycerides alone (type IV lipoprotein phenotype), or both the cholesterol and triglycerides are elevated (type IIb lipoprotein phenotype) ( . Table 32.5). The diagnosis of FCHL is confirmed by the finding of a first degree family member, who has a different lipoprotein phenotype from the proband. Other charac- teristics of FCHL include the presence of an increased number of small, dense LDL particles, which link FCHL to other disorders, including hyperapobetalipoproteinemia (hyperapoB), LDL subclass pattern B, and familial dyslipid- emic hypertension [9]. In addition to hypertension, patients with the small-dense LDL syndromes can also manifest hyperinsulinism, glucose intolerance, low HDL cholesterol levels, and increased visceral obesity (syndrome X). From a clinical prospective, FCHL and other small, dense LDL syndromes clearly aggregate in families with premature CAD, and as a group, these disorders are the most commonly recognized dyslipidemias associated with premature CAD, and may account for one-third, or more, of the families with early CAD. Metabolic Derangement There are three metabolic defects that have been described both in FCHL patients and in those with hyperapoB: (1) overproduction of VLDL and apo B-100 in liver; (2) slower removal of chylomicrons and chylomicron remnants; and, (3) abnormally increased free-fatty acids (FFA) levels [9, 10]. The abnormal FFA metabolism in FCHL and hyper- apo B subjects may reflect the primary defect in these patients. The elevated FFA levels indicate an impaired metabolism of intestinally derived triglyceride-rich lipoproteins in the post-prandial state and, as well, impaired insulin- mediated suppression of serum FFA levels. Fatty acids and glucose compete as oxidative fuel sources in muscle, such that increased concentrations of FFA inhibit glucose uptake in muscle and result in insulin resistance. Finally, elevated FFA may drive hepatic overproduction of triglycerides and apo B. It has been hypothesized that a cellular d efect in the adipocytes of hyperapoB patients prevents the normal stimulation of FFA incorporation into TG by a small molecular weight basic protein, called the acylation stimulatory protein (ASP) [11]. The active component in chylomicrons responsible for enhancement of ASP in human adipocytes does not appear to be an apolipoprotein, but may be transthyretin, a protein that binds retinol-binding protein and complexes thyroxin and retinol [11]. ASP also appears to be generated in vivo by human adipocytes, a process that is accentuated postprandially, supporting the hypothesis that ASP plays an important role in clearance of triglycerides from plasma and fatty acid storage in adipose tissue [11]. Recently, Cianflone and co-workers [12] reported that an orphan G protein coupled receptor (GPCR), called C5L2, bound ASP with high affinity and promoted triglyceride synthesis and glucose uptake. The functionality of C5L2 is not known, nor is it known if there might be a defect in C5L2 in some patients with hyperapoB. A defect in the adipocytes of hyperapoB patients might explain both metabolic abnormalities of TG-rich particles in hyperapoB. Following ingestion of dietary fat, chylomicron TG is hydrolyzed by LPL, producing FFA. The defect in the normal stimulation of the incorporation of FFA into TG by ASP in adipocytes from hyperapoB patients leads to 32 397 increased levels of FFA that: (1) flux back to the liver in- creasing VLDL apo B production; and, (2) feedback inhibit further hydrolysis of chylomicron triglyceride by LPL [9]. Alternatively, there could be a defect in stimulation of release of ASP by adipocytes, perhaps due to an abnormal transthyretin/retinol binding system [11]. In that regard, plasma retinol levels have been found to be significantly lower in FCHL patients. This may possibly also affect the peroxisome proliferator activator receptors which are retinoic acid dependent. Kwiterovich and colleagues isolated and characterized three basic proteins (BP) from normal human serum [13]. BP I stimulates the mass of cellular triacylglycerols in cultured fibroblasts from normals about two fold, while there is a 50% deficiency in such activity in cultured fibroblasts from hyperapoB patients. In contrast, BP II abnormally stimulates the formation of unesterified and esterified cholesterol in hyperapoB cells [13]. Such an effect might further accentuate the overproduction of apolipoprotein B and VLDL in hyperapoB patients [9]. Pilot data in hyperapoB fibroblasts indicate a deficiency in the high-affinity binding of BP I, but an enhanced high-affinity binding of BP II [13]. HyperapoB fibroblasts have a baseline deficiency in protein tyrosine phosphorylation that is not reversed with BP I, but is with BP II. These observations together suggest the existence of a receptor-mediated process for BP I and BP II that involves signal transduction [13]. We postulate that a defect in a BP receptor might exist in a significant number of patients with hyperapoB and premature CAD. Genetics The basic genetic defect(s) in FCHL and the other small, dense LDL syndromes are not known. FCHL and these other syndromes are clearly genetically heterogeneous, and a number of genes (oligogenic effect) may influence the expression of FCHL and the small dense LDL syndromes [9, 14, 15]. In a Finnish study, Pajukanta and coworkers mapped the first major locus of FCHL to chromosome1q21–23, and recently provided strong evidence that the gene underlying the linkage is the upstream transcription factor-1 (USF-1) gene [16]. USF-1 regulates many importantgenes in plasma lipid metabolism, including certain apolipoproteins and HL. Linkage of type 2 diabetes mellitus as well as FCHL to the region harboring the USF-1 gene has been observed in several different populations worldwide [17], raising the possibility that USF-1 may also contribute to the metabolic syndrome and type 2 diabetes. Treatment and Prognosis The treatment of FCHL and hyperapoB starts with a diet reduced in total fat, saturated fat and cholesterol. This will reduce the burden of post-prandial chylomicrons and chylomicron remnants (which may also be atherogenic). Reduction to ideal body weight may improve insulin sensi- tivity and decrease VLDL overproduction. Regular aerobic exercise also appears important. Two classes of drugs, fibric acids and nicotinic acid, lower triglycerides and increase HDL and may also convert small, dense LDL to normal sized LDL. The HMG-CoA reductase inhibitors do not appear as effective as the fibrates or nicotinic acid in con- verting small, dense LDL into large, buoyant LDL. However, the statins are very effective in lowering LDL cholesterol and the total number of atherogenic, small, dense LDL particles. In many patients with FCHL, combination therapy of a statin with either a fibrate or nicotinic acid will be required to obtain the most optimal lipoprotein profile [9] ( 7 also Sect. 32.7). Patients with the small, dense LDL syndromes appear to have a greater improvement in coronary stenosis severity on combined treatment. This appears to be associated with drug-induced improvement in LDL buoyancy. Lysosomal Acid Lipase Deficiency: Wolman Disease and Cholesteryl Ester Storage Disease Wolman disease is a fatal disease that occurs in infancy [18]. Clinical manifestations include hepatosplenomegaly, steatorrhea, and failure to thrive. Patients have a lifespan that is generally under one year, while those with cholesteryl ester storage disease (CESD) can survive for longer periods of time [19]. In some cases, patients with CESD have devel- oped premature atherosclerosis. Lysosomal acid lipase (LAL) is an important lysosomal enzyme that hydrolyzes LDL-derived cholesteryl esters into unesterified cholesterol. Intracellular levels of unesterified cholesterol are important in regulating cholesterol synthesis and LDL receptor activity. In LAL deficiency, cholesteryl esters are not hydrolyzed in lysosomes and do not generate unesterified cholesterol. In response to low levels of intracellular unesterified cholesterol, cells continue to synthesize cholesterol and apo B-containing lipoproteins. In CESD, the inability to release free cholesterol from lysosomal cholesteryl esters results in elevated synthesis of endogenous cholesterol and increased production of apo B-containing lipoproteins. Wolman disease and CESD are autosomal recessive disorders due to mutations in the LAL gene on chromosome 10. Lovastatin reduced both the rate of cholesterol synthesis and the secretion of apo B-containing lipoproteins, leading to significant reductions in total –197 mg/dl) and LDL (–102 mg/dl) cholesterol and triglycerides (–101 mg/dl) [20]. 32.3.2 Disorders of LDL Removal These disorders, characterized by marked elevations of plasma total and LDL cholesterol, provided the initial insights into the role of LDL in human atherosclerosis. The elucidation of the molecular defects in such patients, with monogenic forms of marked hypercholesterolemia, has 32.3 · Disorders of Endogenous Lipoprotein Metabolism Chapter 32 · Dyslipidemias VII 398 provided unique and paramount insights into the mechanisms underlying cholesterol and LDL metabolism and the biochemical rationale for their treatment. Here we will discuss six monogenic diseases that cause marked hypercholesterolemia: familial hypercholesterolemia (FH); familial ligand defective apo B-100 (FDB); heterozygous FH3; autosomal recessive hypercholesterolemia (ARH); sitosterolemia, and cholesterol 7-α-hydroxylase deficiency. Familial Hypercholesterolemia (LDL Receptor Defect) Clinical Presentation Familial hypercholesterolemia (FH) is an autosomal dominant disorder that presents in the heterozygous state with a two- to three-fold elevation in the plasma levels of total and LDL cholesterol [1]. Since FH is completely expressed at birth and early in childhood, it is often associated with premature CAD; by age 50, about half the heterozygous FH males and 25 percent of affected females will develop CAD. Heterozygotes develop tendon xanthomas in adulthood, often in the Achilles tendons and the extensor tendons of the hands. Homozygotes usually develop CAD in the second decade; atherosclerosis often affects the aortic valve, leading to life-threatening supravalvular aortic stenosis. FH homozygotes virtually all have planar xanthomas by the age of 5 years, notably in the webbing of fingers and toes and over the buttocks. Metabolic Derangement and Genetics FH is one of the most common inborn errors of metabolism and affects 1 in 500 worldwide ( . Table 32.6). FH has a higher incidence in certain populations, such as Afrikaners, Christian Lebanese, Finns and French-Canadians, due to founder effects [21]. FH is due to one of more than 900 different mutations in the LDL receptor gene [21]. About one in a million children inherit two mutant alleles for the LDL receptor, presenting with a four- to eight-fold increase in LDL cholesterol levels (FH homozygous phenotype). Based on their LDL receptor activity in cultured fibroblasts, FH homozygotes are classified into LDL receptor-negative (<2% of normal activity) or LDL receptor-defective (2–25% of normal activity) homozygotes [1]. Most FH homozygotes inherit two different mutant alleles (genetic compounds) but some have two identical LDL receptor mutations (true homozygotes). Mutant alleles may fail to produce LDL receptor proteins (null alleles), encode re ceptors blocked in intracellular transport between endoplasmic reticulum and Golgi (transport-defective alleles), produce proteins that cannot bind LDL normally (binding defective), those that bind LDL normally, but do not internalize LDL (internalization defects), and those that disrupt the normal recycling of the LDL receptor back to the cell surface (recycling d efects) [1]. Prenatal diagnosis of FH homozygotes can be per- formed by assays of LDL receptor activity in cultured amni- otic fluid cells, direct DNA analysis of the molecular defect(s), or by linkage analysis using tetranucleotide DNA polymorphisms. Treatment Treatment of FH includes a diet low in cholesterol and saturated fat that can be supplemented with plant sterols or stanols to decrease cholesterol absorption. FH heterozygotes usually respond to higher doses of HMG-CoA reductase inhibitors. However, the addition of bile acid binding sequestrants or a cholesterol absorption inhibitor (see also below) is often necessary to also achieve LDL goals. Espe- cially in those FH heterozygotes that may be producing increased amounts of VLDL, leading to borderline hypertriglyceridemia and low HDL cholesterol levels, niacin (nicotinic acid) may be a very useful adjunct to treatement. Nicotinic acid can also be used to lower an elevated Lp (a) lipoprotein. FH homozygotes may respond somewhat to high doses of HMG-CoA reductase inhibitors and nicotinic acid, both of which decrease production of hepatic VLDL, leading to decreased production of LDL. Choles- terol absorption inhibitors also lower LDL in FH homozygotes. In the end, however, FH homozygotes will require LDL apheresis every two weeks to effect a further lowering of LDL into a range that is less atherogenic. If LDL apheresis is not sufficient, then heroic hepatic trans- plantation may be considered. In the future, ex vivo gene therapy for FH homozygotes may become the treatment of choice [22]. Familial Ligand-Defective Apo B Heterozygotes with familial ligand-defective apo B (FDB) may present with normal, moderately elevated, or markedly increased LDL cholesterol levels [21] ( . Table 32.6). Hypercholesterolemia is usually not as markedly elevated in FDB as in patients with heterozygous FH, a difference at- tributed to effective removal of VLDL and IDL particles through the interaction of apo E with the normal LDL receptor in FDB. About 1/20 affected patients present with tendon xanthomas and more extreme hypercholesterolemia. This disorder represents a small fraction of patients with premature CAD, i.e. no more than 1%. In FDB patients, there is delayed removal of LDL from blood despite normal LDL receptor activity. A mutant allele produces a defective ligand binding region in apo B-100, leading to decreased binding of LDL to the LDL receptor. The most commonly recognized mutation in FDB is a missense mutation (R3500Q) in the LDL receptor-binding do- main of apo B-100 [21]. The frequency of FDB heterozygotes is about 1 in 1,000 in Central Europe but appears less common in other populations ( . Table 32.6). Since the clearance of VLDL remnants and IDL occurs through the binding of apo E, and not apo B, to the LDL (B, E) receptor, the clearance of these triglyceride enriched particles in this disorder is not affected. 32 399 Dietary and drug treatment of FDB is similar to that used for FH heterozygotes. Induction of LDL receptors will enhance the removal of the LDL particles that contain the normal apo B-100 molecules, as well as increase the removal of VLDL remnant and IDL that utilize apo E and not apo B-100 as a ligand for the LDL receptor. Heterozygous FH3 Another form of autosomal dominant hypercholesterolemia, termed heterozygous FH3 has been described [21]. While the clinical phenotype is indistinguishable from FH heterozygotes, the disorder does not segregate with LDLR. The disorder results from a mutation in PCS K9, a gene that codes for neural apoptosis-regulated convertase 1, a member of the proteinase K family of subtilases. Further research about the function of PCSK9, and its relation to LDL metabolism, promises to provide new insights into the genetic and molecular control of marked hypercholesteromia and very high LDL levels. Autosomal Recessive Hypercholesterolemia Autosomal recessive hypercholesterolemia (ARH) is a rare autosomal recessive disorder characterized clinically by LDL cholesterol levels intermediate between FH heterozygotes and FH homozygotes. ARH patients often have large tuberous xanthomas but their onset of CAD is on average later than that in FH homozygotes. To date, most of the families reported have been Lebanese or Sardinian. The cholesterol levels in the parents are often normal, but can be elevated. The ARH protein functions as an adapter linking the LDL receptor to the endocytic machinery [21]. A defect in ARH prevents internalization of the LDL receptor. Strik- ingly, in ARH there is normal LDL receptor activity in fibroblasts but it is defective in lymphocytes. To date at least ten mutations have been described in ARH, all involving the interruption of the reading frame, producing truncated ARH [21]. Fortunately, patients with ARH respond quite drama- tically to treatment with statins, but some will also require LDL apheresis. A bile acid sequestrants or a cholesterol absorption inhibitor may be added to the statin to effect a further reduction in LDL cholesterol. Sitosterolemia This is a rare, autosomal, recessive trait in which patients present with normal to moderately to markedly elevated total and LDL cholesterol levels, tendon and tuberous xanthomas, and premature CAD [21]. Homozygotes manifest abnormal intestinal hyperabsorption of plant or shell fish sterols (sitosterol, campesterol, and stigmasterol) and of cholesterol. In normal individuals, plant sterols are not absorbed and plasma sitosterol levels are low (0.3 to 1.7 mg/dl) and are less than 1% of the total plasma sterol, while in homozygotes with sitosterolemia, levels of total plant sterols are elevated (13 to 37 mg/dl) and represent 7–16% of the total plasma sterols. Patients often present in childhood with striking tuberous and tendon xanthomas despite normal or FH heterozygote-like LDL cholesterol levels. The clinical diagnosis is made by documenting the elevated plant sterol levels. The parents are normocholes- terolmic and have normal plant sterol levels. Two ABC half transporters, ABCG5 and ABCG 8 [21], together normally limit the intestinal absorption of plant sterols and cholesterol and promote the elimination of these dietary sterols in the liver. Sitosterolemia is caused by two mutations in either of the two adjacent genes that encode these half-transporters ( . Table 32.6), thereby enhancing absorption of dietary sterols, and decreasing elimination of these sterols from liver into bile. This leads to suppression of the LDL receptor gene, inhibition of LDL receptor synthesis and elevated LDL levels. Dietary treatment is very important in sitosterolemia and primarily consists of diet very low in cholesterol and in plant sterols. Thus, in contrast to a standard low cholesterol, low saturated fat diet, plant foods with high fat, high plant sterol content such as oils and margarines, must be avoided. Bile acid binding resins, such as cholestyramine, are particularly effective in lowering plant sterol and LDL sterol concentrations. The cholesterol absorption inhibitor, ezetimibe, is also quite effective [23]. These patients respond poorly to statins. Cholesterol 7α - Hydroxylase Deficiency Only a few patients have been described with a deficiency in the rate limiting enzyme of bile acid synthesis, cholesterol 7α-hydroxylase that converts cholesterol into 7α-hydroxy- cholesterol ( 7 Chap. 34 and . Fig. 34.1). Both hypercholesterolemia and hypertriglyceridemia were reported [21]. It is postulated that this defect increases the hepatic cholesterol pool, and decreases LDL receptors. As with the sitosterolemics, these subjects were relatively resistent to statin therapy. 32.4 Disorders of Endogenous and Exogenous Lipoprotein Transport 32.4.1 Dysbetalipoproteinemia (Type III Hyperlipo proteinemia) This disorder is often associated with premature atherosclerosis of the coronary, cerebral and peripheral arteries. Xanthomas are often present and usually are tuberoeruptive or planar, especially in the creases of the palms. Occasionally, tuberous and tendon xanthomas are found. Patients with dysbetalipoproteinemia present with elevations in both plasma cholesterol and triglycerides, usually but not always, above 300 mg/dl. The hallmark of the disorder is the presence of VLDL that migrate as beta lipoproteins (E-VLDL), 32.4 · Disorders of Endogenous and Exogenous Lipoprotein Transport Chapter 32 · Dyslipidemias VII 400 rather than prebeta lipoproteins (type III lipoprotein phenotype) ( . Table 32.5). E-VLDL reflect the accumulation of cholesterol-enriched remnants of both hepatic VLDL and intestinal chylomicrons ( . Fig. 32.1) [24]. These remnants accumulate because of the presence of a dysfunction- al apoE, the ligand for the receptor-mediated removal of both chylomicron and VLDL remnants by the liver. There are two genetic forms of dysbetalipoproteinemia [24]. The most common form is inherited as a recessive trait. Such patients have an E 2 E 2 genotype. The E 2 E 2 genotype is necessary but not sufficient for dysbetalipoproteinemia. Other genetic and metabolic factors, such as overproduction of VLDL in the liver seen in FCHL, or hormonal and environmental conditions, such as hypothyroidism, low estrogen state, obesity, or diabetes are necessary for the full blown expression of dysbetalipoproteinemia. The recessive form has a delayed penetrance until adulthood and a prevalence of about 1:2000. In the rarer form of the disorder, inherited as a dominant and expressed as hyperlipidemia even in childhood, there is a single copy of another defective apo E allele [24]. The diagnosis of dysbetalipoproteinemia includes: (1) demonstration of E 2 E 2 genotype; (2) performing pre- parative ultracentrifugation and finding the presence of E-VLDL on agarose gel electrophoresis (floating E lipoproteins); and, (3) a cholesterol enriched VLDL (VLDL cholesterol/triglyceride ratio > 0.30; normal ratio 0.30). LDL and HDL cholesterol levels are low or normal. Patients with this disorder are very responsive to therapy. A low-fat diet is important to reduce the accumulation of chylomicron remnants, and reduction to ideal body weight may decrease the hepatic overproduction of VLDL particles. The drug of choice is a fibric acid deriva- tive, but nicotinic acid and HMG-CoA reductase inhibitors may also be effective. Treatment of the combined hyperlipidemia in dysbetalipoproteinemia with a fibrate will correct both the hypercholesterolemia and hypertriglyceridemia; this effect is in contrast to treatment of FCHL with fibrates alone, which usually reduces the triglyceride level, but increases the LDL cholesterol level. 32.4.2 Hepatic Lipase Deficiency Patients with hepatic lipase (HL) deficiency can present with features similar to dyslipoproteinemia (type III hyper- lipoproteinemia) (see above), including hypercholesterolemia, hypertriglyceridemia, accumulation of triglyceride- rich remnants, planar xanthomas and premature cardiovascular disease [25]. Recurrent bouts of pancreatitis have been described. The LDL cholesterol is usually low or normal in both disorders. HL hydrolyzes both triglycerides and phospholipids in plasma lipoproteins. As a result, HL converts IDL to LDL and HDL-2 to HDL-3, thus playing an important role in the metabolism of both remnant lipoproteins and HDL ( . Figs. 32.1 and 32.2). HL shares a high degree of homology to LPL and pancreatic lipase. HL deficiency is a rare genetic disorder, which is inherited as an autosomal recessive trait. The frequency of this disorder is not known, and it has been identified in only a small number of kindreds. Obligate heterozygotes are normal. The molecular defects described in HL deficiency include a single A o G substitution in intron I of the HL gene [26]. HL deficiency can be distinguished from dysbetalipoproteinemia in two ways: first, the elevated triglyceride- rich lipoproteins have a normal VLDL cholesterol/triglyceride ratio <0.3, because the triglyceride is not being hydrolyzed by HL; and second, the HDL cholesterol often exceeds the 95th percentile in HL deficiency but is low in dysbetalipoproteinemia. The diagnosis is made by a PHLA test (see above). Absent HL activity is documented by measuring total PHLA activity, and HL and LPL activity separately. Treatment includes a low total fat diet. In one report, the dyslipidemia in HL deficiency improved on treatment with lovastatin but not gemfibrozil. 32.5 Disorders of Reduced LDL Cholesterol Levels 32.5.1 Abetalipoproteinemia Abetalipoproteinemia is a rare, autosomal recessive disorder in patients with undetectable plasma apo B levels [27]. Patients present with symptoms of fat malabsorption and neurological problems. Fat malabsorption occurs in infancy with symptoms of failure to thrive (poor weight gain and steatorrhea). Fat malabsorption is secondary to the inability to assemble and secrete chylomicrons from enterocytes. Neurological problems begin during adolescence and include dysmetria, cerebellar ataxia, and spastic gait. Other manifestations include atypical retinitis pigmentosa, anemia (acanthocytosis) and arrhythmias. Tota l cholesterol levels are exceedingly low (20 to 50 mg/dl) and no detectable levels of chylomicrons, VLDL, or LDL are present. HDL levels are measurable but low. Parents have normal lipid levels. It was initially thought that the lack of plasma apo B levels were due to defects in the APOB gene. Subsequent studies have demonstrated no defects in the APOB gene. Immunoreactive apo B-100 is present in liver and intestinal cells. Wetterau and colleagues [28] found that the defect in synthesis and secretion of apo B is secondary to the absence of microsomal triglyceride transfer protein (MTP), a mole- cule that permits the transfer of lipid to apo B. MTP is a heterodimer composed of the ubiquitous multifunctional protein, protein disulfide isomerase, and a unique 97-kDa 32 401 subunit. Mutations that lead to the absence of a functional 97-kDa subunit cause abetalipoproteinemia. Over a dozen mutant 97-kDa subunit alleles have been described. Treatment of patients with abetalipoproteinemia is dif- ficult. Steatorrhea can be controlled by reducing the intake of fat to 5 to 20 g/day. This measure alone can result in marked clinical improvement and growth acceleration. In addition, the diet should be supplemented with linoleic acid (e.g., 5 g corn oil or safflower oil/day). MCT as a caloric sub stitute for long-chain fatty acids may produce hepatic fibrosis, and thus MCT should be used with caution, if at all. Fat-soluble vitamins should be added to the diet. Rickets can be prevented by normal quantities of vitamin D, but 200–400 IU/kg/day of vitamin A may be required to raise the level of vitamin A in plasma to normal. Enough vitamin K (5–10 mg/day) should be given to maintain a normal prothrombin time. Neurologic and retinal complications may be prevented, or ameliorated, through oral supplemen- tation with vitamin E (150-200 mg/kg/day). Adipose tissue rather than plasma may be used to assess the delivery of vitamin E. 32.5.2 Hypobetalipoproteinemia Patients with hypobetalipoproteinemia often have a reduced risk for premature atherosclerosis and an increased life span. These patients do not have any physical stigmata of dyslipidemia. The concentrations of fat-soluble vitamins in plasma are low to normal. Most patients have low levels of LDL cholesterol below the 5th percentile (approximately 40 to 60 mg/dl), owing to the inheritance of one normal allele and one autosomal dominant mutant allele for a truncated apolipoprotein B. Hypobetalipoproteinemia occurs in about 1 in 2,000 people. Over several dozen gene mutations (nonsense and frame shift mutations) have been shown to affect the full transcription of apolipoprotein B and cause familial hypobetalipoproteinemia. The various gene mutations lead to the production of truncated apolipoprotein B. Occasionally, hypobetalipoproteinemia is secondary to anemia, dysproteinemias, hyperthyroidism, intestinal lymphangiectasia with malabsorption, myocardial infarction, severe infections, and trauma. Plasma levels of truncated apo B are generally low and are thought to be secondary to low synthesis and secretion rates of the truncated forms of apo B from hepatocytes and enterocytes. The catabolism of LDL in hypobetalipoproteinemia also appears to be increased. The diagnosis is confirmed by demonstrating the presence of a truncated apoB in plasma. No treatment is required. Neurologic signs and symptoms of a spinocerebellar degeneration similar to those of Friedreich ataxia and peripheral neuropathy have been found in several affected members. 32.5.3 Homozygous Hypobetalipo- proteinemia The clinical presentation of children with this disorder depends upon whether they are homozygous for null alleles in the APOB gene (i.e., make no detectable apo B) or homozygous (or compound heterozygotes) for other alleles who produce lipoproteins containing small amounts of apo B or a truncated apo B [29]. Null-allele homozygotes are similar phenotypically to those with abetalipoproteinemia (see above) and may have fat malabsorption, neurologic disease, and hematologic abnormalities as their prominent clinical presentation and will require similar treatment ( 7 above). However, the parents of these children are heterozygous for hypobetalipoproteinemia. Patients with homozygous hypobetalipoproteinemia may develop less marked ocular and neuromuscular manifestations, and at a later age, than those with abetalipoproteinemia. The concentrations of fat-soluble vitamins are low. 32.6 Disorders of Reverse Cholesterol Transport 32.6.1 Familial Hypoalphalipoproteinemia Hypoalphalipoproteinemia is defined as a low level of HDL cholesterol (<5th percentile, age and sex specific) in the presence of normal lipid levels [30]. Patients with this syndrome have a significantly increased prevalence of CAD, but do not manifest the clinical findings typical of other forms of HDL deficiency (see below). Low HDL cholesterol levels of this degree are most often secondary to disorders of triglyceride metabolism ( 7 above). Consequently, primary hypoalphalipoproteinemia, although more prevalent than the rare recessive disorders including deficiencies in HDL, is relatively uncommon. In some families, hypoalphalipoproteinemia behaves as an autosomal dominant trait but the basic defect is unknown. Since it is likely that the etiology of low HDL cholesterol levels is oligogenic (significant effect of several genes), Cohen, Hobbs and colleagues [31] tested whether rare DNA sequence variants in three candidate genes, ABCA1, APOA1 and LCAT, contributed to the hypoalpha phenotype. Nonsynonymous sequence variants were significantly more common (16% versus 2%) in individuals with hypoalpha (HDL cholesterol <5th %) than in those with hyperalpha (HDL cholesterol >95th %). The variants were most prevalent in the ABCA1 gene. 32.6.2 Apolipoprotein A-I Mutations The HDL cholesterol levels are very low (0–4 mg/dl), and the apolipoprotein A-I levels are usually <5 mg/dl. Corneal 32.6 · Disorders of Reverse Cholesterol Transport Chapter 32 · Dyslipidemias VII 402 clouding is usually present in these patients. Planar xanthomas are not infrequently described; the majority, but not all, of these patients develop premature CAD [30, 32, 33]. The APOA1 gene exists on chromosome 11 as part of a gene cluster with the APOC3 and APOA4 genes. A variety of molecular defects have been described in APOA1, including gene inversions, gene deletions, and nonsense and missense mutations. In contrast, APOA1 structural variants, usually due to a single amino acid substitution, do not have, in most instances, any clinical consequences [33]. Despite lower HDL cholesterol levels (decreased by about one half), premature CAD is not ordinarily present. In fact, in one Italian variant, APOA-I Milano , the opposite has been observed (i.e., increased longevity in affected subjects). In a recent study by Nissen et al. [34], these investigators tested proof of concept of apoA-I Milano by infusing recombinant apoA-I Milano /phospholipid complexes (ETC-216) in a small group of adults between the ages of 30–75 years with acute coronary syndrome. The study participants underwent five weekly infusions of placebo, low (15 mg/kg) or high (45 mg/kg) dose of ETC-216. The primary outpoint, change of percent atheroma volume as quantified by intravascular ultrasonography, decreased 3.2% (p<0.02) in subjects treated with ETC-216, while the percent atheroma volume increased in the placebo group. 32.6.3 Tangier Disease Its name is derived from the island of Tangier in the Chesapeake Bay in Virginia, USA, where Dr Donald Fredrickson described the first kindred. HDL cholesterol levels are extremely low and of an abnormal composition (HDL Tangier or T). HDL T are chylomicron-like particles on a high fat diet, which disappear when a patient consumes a low-fat diet [30]. The characteristic clinical findings in Tangier patients include the presence of enlarged orange yellow tonsils, splenomegaly and a relapsing peripheral neuropathy. The finding of orange tonsils is due to the deposition of beta carotene-rich cholesteryl esters (foam cells) in the lymph- atic tissue. Other sites of foam cell deposition include the skin, peripheral nerves, bone marrow, and the rectum. Mild hepatomegaly, lymphadenopathy and corneal infiltration (in adulthood) may also occur. The APOA1 gene in Tangier patients is normal. The underlying defect has now been determined to be a deficiency in ABCA1, an ATP binding cassette transporter [35]. Under normal circumstances, this plasma membrane protein has been shown to mediate cholesterol efflux to nascent, apo A-I rich HDL particles ( . Figs. 32.1 and 32.2). The presence of low HDL cholesterol in subjects with Tangier disease is due to the lack of cholesterol efflux by the deficient ABCA1 to nascent HDL and then increased catabolism of this lipid-poor HDL particle. The clinical diagnosis of Tangier disease can be confirmed by determining the reduced efflux of cholesterol from Tangier fibroblasts onto an acceptor in the culture medium [36]. In general, patients with Tangier disease have an increased incidence of atherosclerosis in adulthood [30]. Treatment with a low fat diet diminishes the abnormal lipoprotein species that are believed to be remnants of abnormal chylomicron metabolism. 32.6.4 Lecithin-Cholesterol Acyltransferase Deficiency Lecithin-cholesterol acyltransferase (LCAT) is an enzyme located on the surface of HDL particles and is important in transferring fatty acids from the sn-2 position of phospha- tidylcholine (lecithin) to the 3-E-OH group on cholesterol ( . Table 32.3). In this process, lysolecithin and esterified cholesterol are generated (D-LCAT). Esterification can also occur on VLDL/LDL particles (E-LCAT). In patients with classic LCAT deficiency, both D- and E-LCAT activity are missing [37]. LCAT deficiency is a rare, autosomal, recessively inherited disorder . More than several dozen mutations in this gene, located on chromosome 16, have been described. The diagnosis should be suspected in patients presenting with low HDL cholesterol levels, corneal opacifications and renal disease (proteinuria, hematuria). Laboratory tests include the measurement of plasma free cholesterol to total cholesterol ratio. Levels above 0.7 are diagnostic for LCAT deficiency. In Fish Eye disease, only D-LCAT activity is absent. Pa- tients present with corneal opacifications, but do not have renal disease [37]. It has been hypothesized that the va- riability in clinical manifestations from patients with Fish Eye disease, compared to LCAT deficiency, may reside in the amount of total plasma LCAT activity. To date, no therapies exist to treat the underlying defects. Patients succumb primarily from renal disease, and atherosclerosis may be accelerated by the underlying nephrosis. Thus, patients with LCAT deficiency, and other lipid metabolic disorders associated with renal disease, should be aggressively treated including a low fat diet. This includes the secondary dyslipidemia associated with the nephrotic syndrome which responds to statin therapy. 32.6.5 Cholesteryl Ester Transfer Protein Deficiency The role of the cholesteryl ester transfer protein (CETP) in atherosclerosis has not been well defined. The CETP gene is upregulated in peripheral tissues and liver in response to dietary or endogenous hypercholesterolemia. HDL particles isolated from patients with CETP deficiency may be less effective in promoting cholesterol efflux from cultured cells. [...]... of urine by FAB-MS or ESI-MS/MS shows the presence of major ions attributable to the glycine conjugates of 7 -hydroxy-3-oxo-4-cholenoic acid and 7 ,12 -dihydroxy-4-cholenoic acid (m/z = 444 and 460; parents of m/z 74), and their taurine conjugates (m/z = 494 and 510; parents of m/z 80 ) and sometimes the taurine conjugate of 7 ,12 -dihydroxy-3-oxo-4-cholestenoic acid (m/z 552; parents of 80 ) The normal... concentration 0.2–12.7 µM) and cholic acid (normal concentration 0.4–6.7 µM) In contrast, the plasma concentrations of 3-oxo- 4 bile acids are markedly elevated, i.e 7 -hydroxy-3-oxo-4-cholenoic acid > 1.5µ M and 7 -dihydroxy-3-oxo-4-cholenoic acid > 2.0 µM Analysis of plasma bile acids by ESI-MS/MS shows taurine-conjugated (parents of m/z 80 ) and glycine conjugated (parents of m/z 74) 3-oxo- 4 bile acids present... 33.3.2 Metabolic Derangement CDPX2 is caused by a deficiency of the enzyme sterol 8- 7 isomerase (enzyme 17 in Fig 33.1), which catalyses the conversion of cholesta -8 ( 9)-en-3 -ol to lathosterol by shifting the double bond from the C8–C9 to the C7–C8 position [32–34] As a consequence of the deficiency, elevated levels of cholesta -8 ( 9)-en-3 -ol and 8- dehydrocholesterol can be detected in plasma and cells... cholesterol 1, cholesterol -hydroxylase; 2, -hydroxy5-C -steroid dehydrogenase/isomerase; 3, -3 -oxosteroid-5 27 reductase; 4, sterol 27-hydroxylase; 5, -methylacyl-CoA race- mase; 6, enzymes of peroxisomal biogenesis and -oxidation; 7, the bile acid amidating enzyme; 8, oxysterol 7 -hydroxylase Enzyme defects are depicted by solid bars across the arrows VII 423 34.2 · 3β-Hydroxy-Δ5-C27-Steroid Dehydrogenase... -hydroxy- 5-C27-steroid dehydrogenase deficiency: effects of chenodeoxycholic acid treatment J Lipid Res 32 :82 9 -8 41 7 Schwarz M, Wright, AC, Davis DL et al (2000) The bile acid synthetic gene 3-beta-hydroxy-delta-5-C27-steroid oxidoreductase is mutated in progressive intrahepatic cholestasis J Clin Invest 106:11751 184 8 Cheng JB, Jacquemin E, Gerhardt M et al (2003) Molecular genetics of 3β-Hydroxy-∆5-C27-steroid... such as 7 -hydroxycholest-4-en-3-one and 7 ,12 -dihydroxy-cholest-4-en3-one These intermediates can then undergo side-chain oxidation to produce the corresponding C24 bile acids The mechanism of hepatocyte damage and cholestasis in 5 reductase deficiency is unknown; as with 3 -dehydrogenase deficiency, toxicity of unsaturated intermediates and unsaturated bile acids and loss of bile-acid-dependent... Smith-Lemli-Opitz syndrome J Med Genet 41:57 7-5 84 23 Fitzky BU, Witsch-Baumgartner M, Erdel M et al (19 98) Mutations in the delta7-sterol reductase gene in patients with the Smith-LemliOpitz syndrome Proc Natl Acad Sci USA 95 :81 8 1 -8 186 24 Wassif CA, Maslen C, Kachilele-Linjewile S et al (19 98) Mutations in the human sterol delta7-reductase gene at 11q1 2-1 3 cause SmithLemli-Opitz syndrome Am J Hum Genet 63:5 5-6 2... cholestanol-to-cholesterol ratio may be a better discriminant than the absolute cholestanol concentration The following bile-acid precursors have been detected at increased concentrations in plasma: 7 -hydroxycholesterol, 7 -hydroxy-cholest-4-en-3-one, 7 ,12 -dihydroxycholest-4-en-3-one Plasma concentrations of bile acids are low; plasma concentrations of bile-alcohol glucuronides are elevated 427 34.5 · α-Methylacyl-CoA... (cholesta-5,7-dien-3 -ol) to produce cholesterol (cholest-5-en-3 -ol), generally regarded as the predominant final step in cholesterol biosynthesis As a consequence of the DHCR7 deficiency, low cholesterol and elevated levels of 7-dehydrocholesterol can be detected in plasma, cells and tissues of the vast majority of SLOS patients [19, 20] In addition, elevated 8- dehydrocholesterol (cholesta-5 ,8( 9)-dien-3 -ol)... -hydroxycholesterol to 7 -hydroxycholest-4-en-3-one When the enzyme is deficient, the accumulating 7 -hydroxycholesterol can undergo side-chain oxidation with or without 12 -hydroxylation to produce 3 ,7 -dihydroxy5-cholenoic acid and 3 ,7 ,12 -trihydroxy-5-cholenoic acid, respectively These unsaturated C24 bile acids are sulphated in the C3 position; a proportion is conjugated to glycine, and they can be found . transporter ABCA1, and transported on HDL [3]. HDL particles are heterogeneous and differ in their percentage of apolipoproteins (A-I, A-II, and A-IV) . HDL can be formed by remod- eling of apolipoproteins. high risk of CAD and usually reflects an elevation in the apo B- containing particles and a depression of the apo A-I-containing particles. Other tests may be ordered when clinically indicated,. metabolic and genetic factors that influence low density lipoprotein heterogeneity. Am J Cardiol 90:30i-48i(Suppl 8A) 10. Millar JS, Packard CJ (19 98) Heterogeneity of apolipoprotein B-10 0- containing

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