Lipoprotein(a)) is a lipoprotein subclass. Genetic studies and numerous epidemiologic
studies have identified Lp(a) as a risk factor for atherosclerotic diseases such as coronary
heart disease and stroke. Lipoprotein(a) was discovered in 1963 by Kåre
Berg and the human gene encoding apolipoprotein(a) was cloned in 1987.
Structure Lipoprotein(a) [Lp(a)] consists of an LDL-like
particle and the specific apolipoprotein(a) [apo(a)], which is covalently bound to the
apoB of the LDL like particle. Lp(a) plasma concentrations are highly heritable and mainly
controlled by the apolipoprotein(a) gene [LPA] located on chromosome 6q26-27. Apo(a) proteins
vary in size due to a size polymorphism [KIV-2 VNTR], which is caused by a variable number
of so-called kringle IV repeats in the LPA gene. This size variation at the gene level
is expressed on the protein level as well, resulting in apo(a) proteins with 10 to > 50
kringle IV repeats. These variable apo(a) sizes are known as "apo(a) isoforms". There
is a general inverse correlation between the size of the apo(a) isoform and the Lp(a) plasma
concentration One theory for the size/plasma level correlation involves difference rates
of protein synthesis. There appears to be a relationship between the number of kringle
repeats and the processing time of the precursor apo protein. That is, the larger the isoform,
the more apo(a) precursor protein accumulates intracellularly in the endoplasmic reticulum.
Lipoprotein is not fully synthesized until the precursor protein is released from the
cell, so the slower rate of production for the larger isoforms limits the plasma concentration.
Apo(a) is expressed by liver cells, and the assembly of apo(a) and LDL particles seems
to take place at the outer hepatocyte surface. The half-life of Lp(a) in the circulation
is about 3 to 4 days. Catabolism and clearance
The mechanism and sites of Lp(a) catabolism are largely unknown. Uptake via the LDL receptor
is not a major pathway of Lp(a) metabolism. The kidney has been identified as playing
a role in Lp(a) clearance from plasma. Populations
Lp(a) concentrations vary over one thousandfold between individuals, from < 0.2 to > 200 mg/dL.
This range of concentrations is observed in all populations studied so far. The mean and
median concentrations between different world populations show distinct particularities,
the main being the two- to threefold higher Lp(a) plasma concentration of populations
of African descent compared to Asian, Oceanic, or European populations. The general inverse
correlation between apo(a) isoform size and Lp(a) plasma concentration is observed in
all populations. However, mean Lp(a) associated with certain apo(a) isoforms varies between
populations. Function
The physiological function of Lp(a)/apo(a) is still unknown. A function within the coagulation
system seems plausible, given the aspect of the high homology between apo(a) and plasminogen.
In fact, the LPA gene derives from a duplication of the plasminogen gene.
Other functions have been related to recruitment of inflammatory cells through interaction
with Mac-1 integrin, angiogenesis, and wound healing.
However, individuals without Lp(a) or with very low Lp(a) levels seem to be healthy.
Thus, plasma Lp(a) is not vital, at least under normal environmental conditions. Since
apo(a)/Lp(a) derived rather recently in mammalian evolution - only old world monkeys and humans
have been shown to harbour Lp(a) - its function might not be vital but just evolutionarily
advantageous under certain environmental conditions, e.g. in case of exposure to certain infectious
diseases. Another possibility, suggested by Linus Pauling,
is that Lp(a) is a primate adaptation to L-gulonolactone oxidase deficiency, found only in certain
lines of mammals. GULO is required for converting glucose to ascorbic acid, which is needed
to repair arteries; following the loss of GULO, those primates that adopted diets less
abundant in vitamin C may have used Lp(a) as an ascorbic-acid surrogate to repair arterial
walls. Pathology
The structure of lipoprotein is similar to plasminogen and tPA and it competes with plasminogen
for its binding site, leading to reduced fibrinolysis. Also, because Lp(a) stimulates secretion of
PAI-1, it leads to thrombogenesis. Lp(a) also carries cholesterol and thus contributes to
atherosclerosis. In addition, Lp(a) transports the more atherogenic proinflammatory oxidized
phospholipids, which attract inflammatory cells to vessel walls, and leads to smooth
muscle cell proliferation. Lipoprotein(a) and disease
High Lp(a) in blood is a risk factor for coronary heart disease, cerebrovascular disease, atherosclerosis,
thrombosis, and stroke. The association between Lp(a) levels and stroke is not as strong as
that between Lp(a) and cardiovascular disease. Lp-a concentrations may be affected by disease
states,, but are only slightly affected by diet, exercise, and other environmental factors.
Most commonly prescribed lipid-reducing drugs have little or no effect on Lp(a) concentration.
Results using statin medications have been mixed in most trials, although a meta-analysis
published in 2012 suggests that atorvastatin may be of benefit. Niacin and aspirin are
two relatively safe, easily available and inexpensive drugs known to significantly reduce
the levels of Lp(a) in some individuals with high Lp(a); they should be used under the
supervision of a qualified physician. High Lp(a) predicts risk of early atherosclerosis
independently of other cardiac risk factors, including LDL. In patients with advanced cardiovascular
disease, Lp(a)indicates a coagulant risk of plaque thrombosis. Apo(a) contains domains
that are very similar to plasminogen. Lp(a) accumulates in the vessel wall and inhibits
binding of PLG to the cell surface, reducing plasmin generation, which increases clotting.
This inhibition of PLG by Lp(a) also promotes proliferation of smooth muscle cells. These
unique features of Lp(a) suggest Lp(a) causes generation of clots and atherosclerosis.
Vegetarians have higher levels of Lp-a than fish eaters in one homogeneous tribal population
of Tanzania raising the possibility that pharmacologic amounts of fish oil supplements may be helpful
to lower the levels of Lp-a. Some studies have shown that regular consumption
of moderate amounts of alcohol leads to significant decline in plasma levels of Lp-a while other
studies have not. Diagnostic testing
Numerous studies confirming a strong correlation between elevated Lp(a) and heart disease have
led to the consensus that Lp(a) is an important, independent predictor of cardiovascular disease.
Animal studies have shown that Lp(a) may directly contribute to atherosclerotic damage by increasing
plaque size, inflammation, instability, and smooth muscle cell growth. Genetic data also
support the theory that Lp(a) causes cardiovascular disease.
The European Atherosclerosis Society currently recommends that patients with a moderate or
high risk of cardiovascular disease have their lipoprotein levels checked. Any patient with
one of the following risk factors should be screened;
premature cardiovascular disease familial hypercholesterolaemia
family history of premature cardiovascular disease
family history of elevated lipoprotein recurrent cardiovascular disease despite statin
treatment ≥3% 10-year risk of fatal cardiovascular
disease according to the European guidelines ≥10% 10-year risk of fatal and/or non-fatal
cardiovascular disease according to the US guidelines
If the level is elevated, treatment should be initiated with a goal of bringing the level
below 50 mg/dL. In addition, the patient's other cardiovascular risk factors should be
optimally managed. Apart from the total Lp(a) plasma concentration, the apo(a) isoform might
be an important risk parameter as well. Prior studies of the relationship between
LP(a) and ethnicity have shown inconsistent results. Lipoprotein levels seem to differ
in different populations. For example, in some African populatation, Lp(a) levels are,
on average higher, than other groups, so that using a risk threshold of 30 mg/dl would
classify up to > 50% of the individuals as higher risk. Some part of this complexity
may be related to the different genetic factors involved in determining Lp(a) levels. One
recent study showed that in different ethic groups, different genetic alterations were
associated with increased Lp(a) levels. More recent data suggest that prior studies
were under-powered. The Atherosclerosis Risk in Communities followed 3467 African Americans
and 9851 whites for 20 years. The researchers found that an elevated Lp(a) conferred the
same risk in each group. However, African Americans had roughly three times the level
of Lp(a), and Lp(a) also predicted an increased risk of stroke.
Approximate levels of risk are indicated by the results below, although at present there
are a variety of different methods by which to measure Lp(a). A standardized international
reference material has been developed and is accepted by the WHO Expert Committee on
Biological Standardization and the International Federation of Clinical Chemistry and Laboratory
Medicine. Although further standardization is still needed, development of a reference
material is an importance step towards standardizing results.
Lipoprotein(a) - Lp(a) Desirable: < 14 mg/dL
Borderline risk: 14 - 30 mg/dL High risk: 31 - 50 mg/dL
Very high risk: > 50 mg/dL LP(a) appears with different isoforms of apolipoprotein
- 40% of the variation in Lp(a) levels when measured in mg/dl can be attributed to different
isoforms. Lighter Lp(a) are also associated with disease. Thus a test with simple quantitative
results may not provide a complete assessment of risk.
Treatment At the current time, the recommended treatment
for an elevated lipoprotein(a) is niacin, 1-3 grams daily, in general in an extended-release
form. Niacin therapy can reduce lipoprotein(a) levels by 20-30%. Aspirin may be beneficial,
as well. A recent meta-analysis suggests that atorvastatin may also lower Lp(a) levels.
In severe cases, such as familial hypercholesterolemia, or treatment resistant hypercholesterolemia,
lipid apheresis may result in dramatic reductions of lipoprotein(a). The goal of treatment is
to reduce levels to below 50 mg/dL. Other medications that are in various stages
of development include thyromimetics, cholesterol-ester-transfer protein, anti-sense oligonucleopeptides, and
proprotein convertase subtilisin/kexin type 9 inhibitors. L-carnitine may also reduce
lipoprotein a levels. Gingko biloba may be beneficial, but has not
been clinically verified. Coenzyme Q-10 and pine bark extract have been suggested as beneficial,
but neither has been proven in clinical trials. The effect of estrogen on lipoprotein(a) levels
is controversial. Estrogen replacement therapy in post-menopausal women appears to be associated
with lower lipoprotein(a) levels. However one large study suggested that there was a
decreased association between lipoprotein(a) levels and risk. In other words, it is unclear
what a high lipoprotein(a) level means in a woman on estrogen therapy. Estrogen as a
prevention strategy for heart disease is current topic of much research and debate. Risks and
benefits may need to be considered for each individual. At present, estrogen is not indicated
for treatment of elevated lipoprotein(a). Tamoxifen and raloxifen have not been shown
to reduce levels. The American Association of Pediatrics now
recommends that all children be screened for cholesterol between the ages of 9 and 11.
lipoprotein(a) levels should be considered in particular in children with a family history
of early heart disease or hypercholesterolemia. Unfortunately, there have not been enough
studies to determine which therapies might be beneficial.
Interactions Lipoprotein(a) has been shown to interact
with Calnexin, Fibronectin and Fibrinogen beta chain.
See also Lipoprotein
Apolipoprotein Very-low-density lipoprotein
Low-density lipoprotein Combined hyperlipidemia
References
Further reading
External links Lipoprotein(a) at the US National Library
of Medicine Medical Subject Headings