Lipoprotein (a), Serum
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Lipoprotein (a) (Lp[a]), first reported in 1963 by the Norwegian physician-investigator, Kare Berg, consists of an ordinary LDL particle combined with an additional protein. As with LDL, the Lp(a) particle contains Apolipoprotein B100 (molecular weight=approximately 512,000 D), but additionally contains Apolipoprotein a (apo[a]) (molecular weight=275,000-800,000 D), which is covalently linked through a disulfide bond to apolipoprotein B100.
Apo(a) contains a series of amino acid repeats known as "kringles" containing 3 intrastrand disulfide bonds that are highly homologous to similar repeats found in plasminogen. There are a total of 11 apo(a) kringle sequences; 10 of them are present as single copies, but the remaining 1(K4 type 2) varies in copy number from 3 to 40. The copy number of the K4 type 2 kringle is genetically determined and results in a high degree of interindividual polymorphism in the molecular mass of apo(a), which can vary from 187 kDa to 662 kDa. The size of the Lp(a) particle varies accordingly. To date, 34 different isoforms of apo(a) have been identified.
Because of its shared homologies with LDL and plasminogen, factors thought to participate directly or indirectly in atherogenesis, Lp(a) has been the focus of numerous clinical and epidemiologic studies attempting to establish increased serum Lp(a) concentration as a risk factor for coronary heart disease (CHD) and stroke. Although results of studies to date are mixed, the preponderance of evidence strongly suggests that Lp(a) is an independent risk factor for CHD and possibly stroke, and the Lp(a) particle has been referred to as "the most atherogenic lipoprotein."
Serum concentrations of Lp(a) appear to be largely related to genetic factors, and unfortunately, diet and lipid-lowering pharmaceuticals do not have a major impact on Lp(a) levels. Nevertheless, measurement of serum Lp(a) may contribute to a more comprehensive risk assessment in high-risk patients.
Concentrations of Lp(a) particles in the blood can be expressed readily either as concentrations of Lp(a)-specific protein or as Lp(a) cholesterol. Cardiovascular Laboratory Medicine measures and reports Lp(a) cholesterol individually (LPAWS / Lipoprotein [a] Cholesterol, Serum) and as a part of the lipoprotein profile (LMPP / Lipoprotein Metabolism Profile). The cholesterol content of Lp(a) particles varies little, and Lp(a) cholesterol can be quantified readily. In many cases, we have observed Lp(a) cholesterol to be at levels of 25 mg/dL to 50 mg/dL, and in some cases to be >100 mg/dL. Thus, Lp(a) can contain significant proportions of the serum cholesterol. In such cases, knowledge of the concentration of Lp(a) and of the contribution of Lp(a) cholesterol to the serum total cholesterol should be helpful to physicians in their evaluation of cardiovascular risk levels.
Unlike Lp(a) cholesterol, accurate immunochemical measurement of Lp(a)-specific protein, is complicated by a number of factors. A significant problem is the issue of how to express the result of a quantitative test for Lp(a)-specific protein in meaningful terms. Because the molecular size of Lp(a)-specific protein varies over a broad range in the population (240,000-800,000 D), a test result primarily related to the number of molecules of Lp(a)-specific protein in a specimen cannot be expressed accurately or meaningfully in terms of mg protein/dL unless the molecular weight of the Lp(a)-specific protein in that specimen has been determined. An additional related concern is that the degree of atherogenicity of the Lp(a) particle in any specific case may depend on the molecular size of the Lp(a)-specific protein.
Alteration in serum Lp(a) concentration secondary to diet modification, exercise, or drug therapy is minimal. Therefore, it is inappropriate to use Lp(a) as a general screening test in the healthy population. However, in a patient with additional modifiable CHD risk factors, more aggressive therapy to normalize these factors may be indicated if the Lp(a) value is also increased.
Providing additional information on coronary heart disease (CHD) risk in patients known or suspected to be at increased risk based on other factors, including family history of premature CHD or stroke, hypertension, cigarette smoking, obesity, diabetes mellitus, increased concentration of LDL cholesterol, and depressed concentration of HDL cholesterol.
The frequency distribution of serum lipoprotein (a) (Lp[a]) concentrations is markedly skewed toward the low end, with approximately 85% of the population having concentrations <30 mg/dL.
Concentrations >30 mg/dL have been associated with increased risk of coronary heart disease in numerous studies. Observations over the last 3 decades have indicated that Lp(a) increases cardiovascular risk 2 to 3-fold when its level in the blood plasma is >30 mg/dL (correspondingly, Lp[a] cholesterol would be >5 mg/dL). Lp(a) concentrations of < =15 mg per dL (Lp[a] cholesterol < or =5 mg per dL) appear not to confer an increased risk. Multivariate analysis suggests that Lp(a) functions independently of the more conventional risk factors (eg, increased LDL cholesterol, cigarette smoking, diabetes). Although some recent observations have indicated that Lp(a)-associated cardiovascular risk is significant only when the concentration of the companion risk factor, LDL, also is increased.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
The epidemiologic database is most extensive for the Caucasian population. Studies on Asians (specifically Chinese, Japanese, and Koreans) indicate that lipoprotein (a) (Lp[a]) is a comparable risk factor for atherosclerosis in these groups as well. In African Americans, the median Lp(a) serum concentration is 2 to 3 times higher than in Caucasians. However, insufficient epidemiologic data are available on the African American population to equate the role of Lp(a) as a risk factor in African Americans.
Because Lp(a) behaves like an acute-phase protein, it should not be measured during periods of active inflammation. Serum Lp(a) levels should not be measured for a least 1 month after a myocardial infarction or stroke.
In most cases, the preferred test for quantifying Lp(a) is LPAWS / Lipoprotein (a) Cholesterol, Serum.
Not recommended as a screening test in the healthy population.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
< or =30 mg/dL
Values >30 mg/dL may suggest increased risk of coronary heart disease.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Utermann G: The mysteries of lipoprotein(a). Science 1989;246:904-910
2. Lackner C, Cohen JC, Hobbs HH: Molecular definition of the extreme size polymorphism in apolipoprotein(a). Hum Mol Genet 1993;2:933-940
3. Schaefer EJ, Lamon-Fava S, Jenner JL, et al: Lipoprotein(a) levels and risk of coronary heart disease in men. The Lipid Research Clinics Coronary Primary Prevention Trial. JAMA 1994;271:999-1003
4. Ridker PM, Hennekens CH, Stampfer MJ: A prospective study of lipoprotein(a) and the risk of myocardial infarction. JAMA 1993;270:2195-2199