What is the pathophysiology of type II hyperlipoproteinemia (HLP)?

Updated: Jun 27, 2019
  • Author: Henry J Rohrs, III, MD; Chief Editor: Stuart Berger, MD  more...
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Answer

In children, type IIA HLP is defined by LDL-C concentrations of 130 mg/dL or higher. The plasma is clear in type IIA HLP because LDL particles are not large enough to scatter light, as opposed to IDL, VLDL, or lipoprotein remnants that are large enough to cause turbidity.

In type IIB HLP, TG levels (VLDL levels) are elevated to 125 mg/dL or higher, and LDL-C levels are also elevated. If the TG level is typically 300-400 mg/dL or higher, the plasma appears visibly turbid (lipemic).

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated LDL-C levels with or without a concurrent elevation in TG levels. Thus, individuals with FH may display a type IIA or B phenotype. FH affects approximately one in 500 persons in the general population. Besides premature cardiovascular disease, clinical findings in adults include tendon xanthomas (especially involving the Achilles tendons and the extensor tendons of the hands) and arcus senilis (involving the cornea). FH results from an inherited defect in the LDL-R. Because the LDL-R also clears IDL, and because VLDL is the precursor of IDL and LDL, patients with FH may also display elevations in IDL and VLDL.

If an individual inherits two defective alleles of the LDL-R gene (homozygous FH), LDL production increases by approximately 200-300%. Adults who are heterozygous for FH have two- to three-fold higher total cholesterol (TC) levels of 300-600 mg/dL, and LDL-C levels are commonly 250 mg/dL or higher. Patients who are homozygous for FH have TC levels of 600-1500 mg/dL. Homozygous FH leads to extremely premature and hazardous atherosclerosis. In addition, aortic valvar disease can occur in children with homozygous FH.

Besides valve dysfunction, the ostia of the coronary arteries can become obstructed. Fortunately, homozygous FH is very rare, affecting only one in 1 million persons. Children with homozygous FH have suffered myocardial infarctions as early as age 3 years. Death during adolescence is common. Homozygous FH should thus be strongly suspected in deaths from myocardial infarction in individuals aged 20 years or younger.

In heterozygous FH, affected family members have elevated LDL-C concentrations beginning early in life. Cord blood TC and LDL-C levels are already elevated. Untreated males with FH often develop cardiovascular disease in the fourth or fifth decade of life, but the disease can manifest in teenagers. The mean age of death in males with untreated FH is 45 years. Untreated women with FH usually have onset of cardiovascular disease in the fifth or sixth decade of life. Of persons who have survived myocardial infarctions that occurred when they were younger than 60 years, 5% have FH.

A defect in apoprotein B-100 is phenotypically similar to FH and occurs with a similar frequency. Elevated LDL-C levels result when the apoprotein B molecule is defective, even if the LDL-R molecule is normal. In FH, IDL and VLDL concentrations can be elevated because IDL is cleared via the LDL-R; however, in familial defective apoprotein B-100, because the LDL-R molecule is normal, IDL, VLDL, and TG levels are usually normal. In contrast to FH, tendon xanthomas and arcus senilis may be absent in patients with defective apoprotein B-100. Modest hypercholesterolemia (250-300 mg/dL) is usually present, with a TC level lower than in adults with FH (mean TC concentration in defective apoprotein B-100 is 269 mg/dL, vs approximately 360 mg/dL in FH). LDL-C levels are raised by approximately 70 mg/dL. As in FH, patients with familial defective apoprotein B-100 may develop premature cardiovascular disease.

Familial defective apoprotein B-100 and FH can be very difficult to clinically differentiate when patients with FH display a type IIA phenotype; however, in the absence of secondary conditions that raise TG levels, the presence of a type IIB phenotype essentially excludes familial defective apoprotein B-100.

Familial combined hyperlipidemia (FCH) is inherited as an autosomal dominant trait. The etiology of FCH appears to be an overproduction of apoprotein B–containing particles (VLDL, LDL, or both). Affected individuals may exhibit type IIA, type IIB, or type IV phenotypes. In a single family with FCH, some individuals may display isolated elevations in TC/LDL (type IIA HLP) or TG (type IV HLP) levels, whereas other affected members may have a combined hyperlipidemia (increased LDL-C and TG levels [type IIB HLP]). The co-occurrence of FCH plus hypertension has been called familial dyslipidemic hypertension. Similar to FH, premature cardiovascular disease can occur in patients with FCH. Overall, FCH affects approximately 1 in 200-300 persons in the general population and occurs in approximately 15% of individuals younger than 60 years who survive a myocardial infarction.

Other causes of type IIA or IIB phenotypes include hypothyroidism, nephrosis, biliary tract disease, and diabetes mellitus. In hypothyroidism, hepatic LDL-R expression is reduced, leading to elevated LDL-C levels because of reduced LDL clearance. Lipoprotein production is typically increased in patients with nephrosis. This may be a compensation for hypoalbuminemia. With glycation of apoprotein B in patients with diabetes mellitus and increased VLDL synthesis, LDL-C levels commonly rise.


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