Introduction

Lipoprotein (a), also known as Lp (a), is a form of low-density lipoprotein (LDL) that is an established and genetically determined risk factor for atherosclerosis, coronary artery disease, stroke, thrombosis, and aortic stenosis.[1] Structurally, it is a variant of LDL, and it features apolipoprotein(a), which is bound to apolipoprotein B100. These two structures are bound via one disulfide bridge. They are also assembled in the hepatocyte cell membranes.

There is an inverse relationship between plasma concentrations of Lp (a) and the apolipoprotein (a) isoform. The isoform variation is induced by the different number of kringle IV repeats in the LPA gene. The variation in kringle units leads to the variable levels of Lp(a) seen in the general population. In general, those with fewer kringle repeats will have smaller Lp(a) particles but have higher serum levels. Also, the larger the isoforms of apolipoprotein (a), the greater the accumulation of its precursor intracellularly within the endoplasmic reticulum. 

Lp(a) levels above 50mg/dl are correlated to an increased risk of cardiovascular disease.[2] Screening patients for elevated Lp(a) could help identify those who require more aggressive lipid therapy and cardiovascular disease risk management. It has been suggested that Lp(a) could provide a possible explanation for younger patients who experience coronary artery disease with or without other risk factors. Internationally, there is a general disagreement on screening guidelines. To date, no specific therapy exists for the treatment of elevated Lp(a). Most generalized screening aims to identify it as an existing risk factor and subsequently seek to optimize overall cardiac health as the primary treatment. While certain medications such as PCSK9 inhibitors and niacin directly lower Lp(a) levels, there is no FDA-approved medication for the treatment of elevated lipoprotein (a). Further research will help improve both screening guidelines and treatment modalities. 

Etiology and Epidemiology

There is a correlation between elevated Lp(a) levels and cardiovascular disease along with stroke.[3] This has been generally attributed to the atherosclerotic and thrombotic properties of this lipoprotein. Lp(a) levels are also considered to be determined genetically. The LPA gene polymorphisms generally lead to highly variable levels of Lp(a) within the population.[4] These levels range from <1mg/dl to >1000mg/dl. Those of African descent can have higher Lp(a) levels on average than White race and Asian patient populations.[2] Patients with Lp(a) levels >50 mg/dL are considered to have an elevated risk of heart disease.[5] 

During the general screening, many patients will have very low Lp(a) levels or mild to moderate elevations. To date, there is no convincing evidence that mild to moderate elevations (below 50 mg/dL) leads to an elevated risk of heart disease or stroke. 

Pathophysiology

Lipoprotein(a) is a general promoter of atherosclerosis and thrombosis. Due to its structure, Lp(a) leads to reduced fibrinolysis. Specifically, apolipoprotein(a) carries a similar structure to tissue plasminogen activator (TPA) and plasminogen. This allows it to compete with plasminogen for its specific binding site and hence interfere with its function, which leads to reduced fibrinolysis. Thrombogenesis is also stimulated by Lp(a) as it leads to increased plasminogen activator inhibitor-1.[3][6]

Lp(a) induces atherosclerosis as it carries cholesterol and attaches to oxidized phospholipids. It also attaches to macrophages and leads to the formation of foam cells. This mechanism ultimately leads to the deposition of cholesterol within the atherosclerotic plaques.[7]

It is uncertain if Lp(a) has any benefits for the human body. One theory has been that Lp(a) has a role in wound healing. However, those with markedly lower Lp(a) levels do not appear to have any long-term health risks.

Diagnostic Tests

Lipoprotein(a) is screened via a serum blood test. The general purpose of screening for Lp(a) is to further identify those at higher risk for cardiovascular disease.

Today, there is variability in expert opinion on when to screen for elevated lipoprotein(a). The National Lipid Association recommends that Lp(a) be considered for testing when there is a significant family history of premature ASCVD in first-degree relatives, personal history of premature ASCVD, and severe primary hyperlipidemia. The National Lipid Association also recommends it to aid in the process of shared decision-making for statin therapy for those in the borderline ASCVD risk category.[8] The American College of Cardiology and American Heart Association do not have official screening guidelines on Lp(a).[9] Canadian guidelines recommend universal screening for Lp(a).

The European Atherosclerosis Society has set criteria for when Lp(a) screening is generally recommended. Patients with a personal history of premature cardiovascular disease, recurrent cardiovascular disease while on statin therapy, and a ≥10% ten-year risk of cardiovascular disease. A family history of premature cardiovascular disease, elevated lipoprotein(a), and familial hypercholesterolemia are also indications for Lp(a) screening. The European Society of Cardiology has a general recommendation to screen Lp(a) at least once in a person’s lifetime.[10]

There is currently no recommendation or guideline regarding testing pediatric patient populations for Lp(a). This is primarily due to the lack of data on Lp(a) in the pediatric patient population. More research is required in this patient population to help develop better screening guidelines. 

Testing Procedures

A small venous blood sample is sufficient for testing Lp(a) levels.

Interfering Factors

Ethanol consumption, niacin supplements, aspirin, and oral estrogen supplementation can potentially interfere with the accuracy of the results.

Results, Reporting, and Critical Findings

The desirable and optimal test result range of Lp(a) is <14mg/dL. The highest risk range is >50 mg/dl. Patients with an Lp(a) of 14-30mg/dl are considered to be at borderline risk, and those within the range of 31-50md/dl are at high risk.

Lp(a) levels directly contribute to serum LDL levels. This is due to Lp(a) particles containing an LDL particle. 

Laboratory testing for Lp(a) often also includes lipoprotein-X (LpX) levels reported as a separate result. These are compounds consisting of cholesterol and phospholipids, and high levels are associated with cholestasis and hyperviscosity syndromes.

Clinical Significance

The primary reason for screening patients for Lp(a) is to help further identify those at high risk for heart disease, especially in the absence of other major risk factors. It also helps identify those patients who may require more intensive lipid therapy.

Patients with significantly elevated Lp(a) should generally be treated to a target of <50mg/dl. One treatment option is daily niacin, which may lower Lp(a) by 20% to 30%. However, niacin has not been associated with improved cardiac outcomes despite its known beneficial effect on all lipid markers as well as Lp(a).[11] Statins have shown mixed results and, in some cases, have actually been shown to increase Lp(a).[12] Nonetheless, statins are a primary treatment option for patients with hyperlipidemia. High Lp(a) levels may generally indicate the need for more intensive statin therapy to further optimize a patient's LDL level in the context of lowering their risk for coronary artery disease. PCSK9 inhibitors are also an option for lowering Lp(a). A meta-analysis showed PCSK9 inhibitors lowered Lp(a) by 26%, in addition to improved cardiac outcomes.[13] Cumulatively, it is not yet evident if elevated Lp(a) continues to be an independent significant risk factor even after successful treatment. 

Less commonly used options include lipid apheresis and the investigational therapy called antisense therapy. Generally, lipid apheresis may be reserved for the most severe refractory cases and have a very limited role in treating elevated Lp(a). Apheresis will also cause transient declines in the levels of Lp(a), and serum levels can generally begin to climb back up.[3]

Hormonal drugs may improve Lp(a) levels but are not necessarily associated with improved cardiovascular outcomes. Estrogen can improve Lp(a) levels and has been discussed in the context of improving potentially cardiac risk profiles but is not currently used as a therapy to improve lipid markers. Estrogen also does carry other potential risks for certain patient populations and hence is unlikely to become established as a treatment modality.[14] Testosterone replacement therapy (TRT) has been shown to lower Lp(a) levels. More research is needed on TRT to reach conclusions on its role in the context of preventative cardiology, as the cumulative evidence is currently unclear. Of note, testosterone replacement therapy can lead to lower HDL, which does elevate the risk of atherosclerosis. [15] L-carnitine may also lower Lp(a) levels but has been linked to elevated trimethylamine N-oxide (TMAO), potentially leading to atherosclerosis.[16] More therapies continue to arise, and a key factor will be whether or not cardiac outcomes are improved.[17] Further research is needed to help identify medications that lower Lp(a) levels directly. 

Quality Control and Lab Safety

For ideal results, patients should have fasted for at least 8 hours prior to the lab draw. 

Enhancing Healthcare Team Outcomes

Lipid therapy often requires an interprofessional healthcare team approach to achieve maximum success for the patient. The clinician oversees the prescription of lipid therapy medications while installing appropriate lifestyle modifications and referrals. Treatment of more advanced lipid disorders benefits from having a pharmacist and dietitian involved to ensure appropriate medication protocols are in place and optimized dietary interventions are instituted. This team-based effort is vital in the role of preventative cardiology for the patient population. [Level 5]

Lipoprotein(a) is a genetically determined independent risk factor for the development of atherosclerosis. Today, it is unclear if direct interventions and treatments of Lp(a) itself help change patient outcomes from a cardiac standpoint. But given that it is a known risk factor for heart disease, a team-based effort is required to minimize the patient's other cardiac risks to improve cardiac outcomes.