Generally primary dyslipidemia are due to mutations of various genes. Thus these disorders of lipid are inheritable and have a obvious family history, which is important in dignosing the primary dyslipidemia. Primary disorders of lipid consist of disorders of elevated apoB-containing lipoproteins, disorders of low apoB-containing lipoproteins level, disorders of low HDL-C level, and disorders of high HDL-C level.


Primary Disorders of Elevated ApoB-Containing Lipoproteins

ApoB-containing lipoproteins include chylomicrons (apoB-48), VLDL (apoB-100), IDL (apoB-100), and LDL (apoB-100). To understand dyslipidemia, we here list the component of each lipoprotein.

Chylomicron consists of 3% of cholesterol, 90% of triglyceride, 6% of phospholipid, and 1% of protein.

VLDL consists of 22% of cholesterol, 55% of triglyceride, 15% of phospholipid, and 8% of protein.

IDL consists of roughly similar amounts of cholesterol and triglyceride.

LDL consists of 50% of cholesterol, 5% of triglyceride, 25% of phospholipid, and 20% of protein.

HDL consists of 20% of cholesterol, 5% of triglyceride, 25% of phospholipid, and 50% of protein.


Lipid disorders associated with elevated LDL-C and normal triglycerides

1. Familial Hypercholesterolemia (FH). FH is an autosomal codominant disorder characterized by elevated plasma levels of LDL-C and normal triglycerides, tendon xanthomas, and premature coronary atherosclerosis.

FH is caused by a large number (>1000) mutations in the LDL receptor gene, which can be divided into homozygous FH and heterozygous FH. The estimated incidence of homozygous FH is 1/1,000,000, and heterozygous FH of 1/500. The elevated levels of LDL-C in FH are due to an increase in the production of LDL from IDL (since a portion of IDL is normally cleared by LDLR endocytosis on the liver) and a delayed removal of LDL from the blood also by LDLR on the liver.

Fredrickson Classification of HyperlipoproteinemiasPS: 40%-60% of IDL is removed by the liver via LDLR with cofactor ApoE. Approximately 70% of circulating LDL is cleared by LDLR in the liver (also with cofactor ApoE). For more information about the metabolism of lipoproteins please refer http://forum.tomhsiung.com/physiology-and-pathophysiology/402-the-pathway-of-lipids.html

Individuals with two mutated LDL receptor alleles (homozygous) have much higher LDL-C levels than those with one mutant allele (heterozygous). Among homozygous FH individuals, patients can be classified into one of two groups based on the amount of LDL receptor activity measured in their skin fibroblasts: those patients with <2% of normal LDL receptor activity are called receptor negative and those patients with 2-25% normal LDL receptor activity are called receptor defective. In patients with homozygous FH total cholesterol levels are usually >500 mg/dL and can be higher than 1000 mg/dL.

Heterozygous FH is one of the most common single-gene disorders (occuring in approximately 1 in 500). The elevated level of LDL-C usually is 200-400 mg/dL and the triglyceride is normal.

2. Familial defective ApoB-100 (FDB)

FDB is a dominantly inherited disorder that clinically resembles heterozygous FH. This disease is rare in most populations except individuals of German descent, where the frequency can be as high as 1 in 1000. FDB is also characterized by elevated plasma LDL-C levels with normal triglycerides, tendon xanthomas, and an increased incidence of premature ASCVD (atherosclerotic cardiovascular disease).

FDB is caused by mutations in the LDL receptor-binding domain of apoB-100, most commonly due to a substitution of glutamine for arginine at position 3500 (Arg3500Glu). As a consequence of the mutation in apoB-100, LDL binds the LDL receptor with reduced affinity, and LDL is removed from the circulation at a reduced rate (both IDL and LDL, similar like FH).

Clinically, patients with FDB tend to have lower plasma levels of LDL-C than FH heterozygotes.

3. Autosomal dominant hypercholesterolemia due to mutations in PCSK9 (ADH-PCSK9 or ADH3)

ADH3 is a rare autosomal dominant disorder caused by gain-of-function mutations in proprotein converstase subtilisin/kexin type 9 (PCSK9). PCSK9 is a secreted protein that binds to the LDL receptor, resulting in its degradation. Normally, after LDL binds to the LDL receptor it is internalized along with the receptor. In the low pH of the endosome, LDL dissociates from the receptor and the receptor returns to the cell surface. The LDL is delivered to the lysosome. When PCSK9 binds the receptor, the complex is internalized and the receptor is redirected to the lysosome rather than to the cell surface.

The mutations causing enhanced activity of PCSK9 results in reduced number of hepatic LDL receptors and the hypercholesterolemia. Loss-of-function mutations in PCSK9 cause low LDL-C levels.

4. Autosomal recessive hypercholesterolemia (ARH)

ARH is a rare disorder due to mutations in a protein (LDLRAP) involved in LDL receptor-mediated endocytosis in the liver, which is characterized by hypercholesterolemia, tendon xanthomas, and premature coronary artery disease. In the absence of LDLRAP, LDL binds to the LDL receptor but the lipoprotein-receptor complex fails to be internalized.

The levels of plasma LDL-C tend to be intermediate between the levels present in FH homozygotes and FH heterozygotes. LDL receptor function in cultured fibroblasts is normal or only modestly reduced in ARH, whereas LDL receptor function in lymphocytes and the liver is negligible.

5. Sitosterolemia

Sitosterolemia is another rare autosomal recesive disease that can result in severe hypercholesterolemia, tendon xanthomas, and premature ASCVD. Misshapen red blood cells and megathrombocytes are visible on blood smear. Episodes of hemolysis are a distinctive clinical feature of this disease compared to other genetic forms of hypercholesterolemia.

Sitosterolemia is caused by mutations in either of two members of the ATP-binding cassette (ABC) half transporter family, ABCG5 and ABCG8. These genes are expressed in enterocytes and hepatocytes. The proteins heterodimerize to form a functional complex that pumps plant sterols such as sitosterol and campesterol, and animal sterols, predominantly cholesterol, into the gut lumen and into the bile. In normal individuals, <5% of dietary plant sterols are absorbed by the proximal small intestine and delivered to the liver. Absorbed plant sterols are preferentially secreted into the bile and are maintained at very low levels.

In sitosterolemia, the intestinal absorption of sterols is increased and biliary excretion of the sterols is reduced, resulting in increased plasma and tissue levels of both plant sterols and cholesterol. Incorporation of plant sterols into cell membranes results in misshapen red blood cells and megathrombocytes that are visible on blood semear.

6. Polygenic hypercholesterolemia

This condition is characterized by hypercholesterolemia due to elevated LDL-C with a normal plasma level of triglyceride in the absence of secondary causes of hypercholesterolemia.

Plasma LDL-C levels are generally not as elevated as they are in FH and FDB.

7. Elevated plasma levels of lipoprotein(a)

Unlike the other major classes of lipoproteins, that have a normal distribution in the population, plasma levels of Lp(a) have a highly skewed distribution with levels varying over 1000-fold range. Levels are strongly influenced by genetic factors, with individuals of African and South Asian descent having higher levels than those of European descent.


Lipid Disorders Associated with Elevated Triglycerides

1. Familial chylomicronemia syndrome

Genetic deficiency or inactivity of either LPL or ApoC-II (cofactor of LPL) results in impaired lipolysis and profound elevations in plasma chylomicrons. These patients can also have elevated plasma levels of VLDL, but chylomicronemia predominates. The fasting plasma is turbid, and if left at 4℃ for a few hours, the chylomicrons float to the top and form a creamy supernatant. In these disorders, fasting triglyceride levels are almost invariably>1000 mg/dL. Fasting cholesterol levels are also elevated but to a lesser degree.

LPL deficiency has autosomal recessive inheritance and has a frequency of approximately 1 in 1 million in the population. ApoC-II deficiency is also recessive in inheritance pattern and is even less common than LPL deficiency. Multiple different mutations in the LPL and apo-C-II genes cause these diseases. Obligate LPL heterozygotes have normal or mild-to-moderate elevations in plasma triglyceride levels, whereas individuals heterozygous for mutation in apoC-II do not have hypertriglyceridemia.

For unknown reasons, some patients with persistent and pronounced chylomicronemia never develop pancreatitis, eruptive xanthomas, or hepatosplenomegaly.

2. ApoA-V deficiency

ApoA-V circulates at much lower concentrations than the other major apolipoproteins. Individuals harboring mutations in both ApoA-V alleles can present as adults with chylomicronemia. The exact mechanism of action of ApoA-V is not known, but it appears to be required for the association of VLDL and chylomicrons with LPL.

3. GPIHBP1 deficiency

After LPL is synthesized in adipocytes, myocytes or other cells, it is transported across the vascular endothelium and is attached to a protein on the endothelial surface of capillaries called GPIHBP1. Homozygosity for mutations that interfere with GPIHBP1 synthesis or folding  cause severe hypertriglyceridemia

The frequency of chylomicronemia due to mutations in GPIHBP1 has not been established but appears to be very rare.

4. Hepatic lipase deficiency

HL is a member of the same gene family as LPL and hydrolyzes triglycerides and phospholipids in remnant lipoproteins and HDLs. HL deficiency is a very rare autosomal recessive disorder characterized by elevated plasma levels of cholesterol and triglycerides (mixed hyperlipidemia) due to the accumulation of circulating lipoprotein remnants (both IDL & chylomicrons remnants;supporting reference: Removal of chylomicron remnants in transgenic mice overexpressing normal and membrane-anchored hepatic lipase at http://www.ncbi.nlm.nih.gov/pubmed/15520453) and either a normal or elevated plasma level of HDL-C (HL hydrolyze TG and phopholipids of large HDL).

PS: HL hydrolyzes both TG and PL principally on remnant lipoproteins and HDL, and may facilitate the uptake of apoB-containing lipoproteins through interaction with HSPG (heparan sulfate proteoglycan).

5. Familial dysbetalipoproteinemia (FDBL)

Familial dysbetalipoproteinemia is characterized by a mixed hyperlipidemia due to the accumulation of remnant lipoprotein particles. ApoE is present in multiple copies on chylomicron and VLDL remnants and mediates their removal via hepatic lipoprotein receptors. The APOE gene ispolymorphic in sequence, resulting in the expression of the three common isoforms: apoE3, which is the most common; and apoE2 and apoE4, which both differ from apoE3 by a single amino acid.

ApoE4 is not associated with FDBL. ApoE2 has a lower affinity for the LDL receptor; therefore, chylomicron and VLDL remnants containing apoE2 are removed from plasma at a slower rate. Individuals who are homozygous for the E2 allele comprise the most common subset of patients with FDBL. Approximately 0.5% of the general population are apoE2/E2 homozygotes, but only a small minority of these individuals develop FDBL. In most cases, an additional, identifiable factor precipitates the development of hyperlipoproteinemia. The most common precipitating factors are high-fat diet, diabetes mellitus, obesity, hypothyroidism, renal disease, HIV infection, estrogen deficiency, alcohol use, or certain drugs.

Other mutations in apoE can cause a dominant form of FDBL where the hyperlipidemia is fully manifest in the heterozygous state, but these mutations are rare.

6. Familial hypertriglyceridemia (FHTG)

FHTG is a relatively common autosomal dominant diorder of unknown etiology (~1 in 500). FHTG is characterized by moderately elevated plasma triglycerides accompanied by more modest elevations in cholesterol. Some patients with FHTG have a more severe form of hyperlipidemia in which both VLDLs and chylomicrons are elevated (Type V hyperlipidemia), since VLDL and chylomicron compete for the same lipolytic pathway.

The major class of lipoproteins elevated in this disorders is VLDL, thus, patients with this disorder are often referred to as as having Type IV hyperlipoproteinemia. The elevated plasma levles of VLDL are due to increased production of VLDL, impaired catabolism of VLDL, or a combination of these mechanisms.

Increased intake of simple carbohydrates, obesity, insulin resistance, alcohol use, and estrogen treatment, all of which increase VLDL synthesis, can exacerbate this syndrome.

For unknown reasons, some patients with persistent and pronounced chylomicronemia never develop pancreatitis, eruptive xanthomas, or hepatosplenomegaly

FHTG appears not to be associated with increased risk of ASCVD in many families.

7. Familial combined hyperlipidemia (FCHL)

FCHL is generally characterized by moderate elevations in plasma levels of triglycerides (VLDL) and cholesterol (LDL) and reduced plasma levels of HDL-C. However, the disease typically has one of three possible phenotypes: (1). elevated plasma levels of LDL-C; (2). elevated plasma levels of triglycerides due to elevation in VLDL; or (3). elevated plasma levels of both LDL-C and triglyceride. And the lipoprotein profile can switch among these three phenotypes in the same individual over time and may depend on factors such as diet, exercise, and weight, etc.

Til today, the molecular etiology of FCHL remains poorly understood, and it is likely that defects in several different genes can cause the phenotype of FCHL.


Inherited Causes of Low Levels of HDL-C

1. Gene deletion in the ApoAV-AI-CIII-AIV locus and coding mutations in ApoA-I

Complete genetic deficiency of apoA-I due to deletion of the apoA-I gene result in the virtual absence of HDL from the plasma.

The genes encoding apoA-I, apoC-III, apoA-IV, and apoA-V are clustered together on chromsome 11, and some patients with no apoA-I have genomic deletions that include other genes in the cluster.

Missense and nonsense mutations in the apoA-I gene have been identified in some patients with low plasma level of HDL-C. ApoA-I is required for LCAT activity. With low levels and/or activity of mutant ApoA-I, LCAT activation is impaired, which precludes the normal esterifying of free cholesterol in the HDL and as a result the HDL is rapidly catabolismed from circulation.

2. Tangier disease (ABCA1 deficiency)

Tangier disease is a very rare autosomal codominant form of extremely low plasma HDL-C caused by mutations in the gene encoding ABCA1, a cellular transporter that facilitates efflux of unesterified cholesterol and phospholipids from cells to apoA-I, which form nascent HDL. Without ABCA1, the apoA-I secreted from the liver and intestine are poorly lipidated and as a result these apoA-I is immediately cleared from the circulation.

3. LCAT deficiency

LCAT deficiency is a very rare autosomal recessive disorder which is caused by mutations in LCAT, an enzyme synthesized in the liver and secreted into the plasma. In LCAT deficiency, the proportion of free cholesterol in circulating lipoproteins is greatly increased. Lack of normal cholesterol esterification impairs formation of mature HDL particles, resulting in the rapid catabolism of circulating apoA-I. Two genetic forms of LCAT deficiency have been described in humans: 1. complete deficiency or so-called classic LCAT deficiency, and 2. partial deficiency or fish-eye disease.

4. Primary hypoalphalipoproteinemia

Primary hypoalphalipoproteinemia is defined as a plasma HDL-C level below the tenth percentile in the setting of relatively normal cholesterol and triglyceride levels, with no apparent secondary causes of low plasma HDL-C and no clinical signs of LCAT deficiency or Tangier disease.

The metabolic etiology of this disease appears to be primarily accelerated catabolism of HDL and its apolipoproteins.