Spotlight on Lipoproteins and Apolipoproteins: Apo B, Apo A-1, and Lp(a)

This Optimal DX Spotlight Article discusses how Functional Blood Chemistry Analysis uses apolipoprotein markers to read cardiovascular risk beyond a standard lipid panel, and why Lp(a) is the one marker you measure only once.

Introduction

Although a standard lipid profile provides information about how much cholesterol is in circulation, it does not indicate the number of particles that carry cholesterol. Because the number of atherogenic particles represents the greatest driving force behind atherosclerotic processes, a patient can have a reassuring lipid profile, yet possess a significant burden of small cholesterol-depleted particles that lodge in the walls of arteries. Apolipoprotein markers represent a method of quantifying the amount of atherogenic particles and weighing atherogenic burden against protective capacity.

This spotlight will review four apolipoproteins, Apo B, ApoA-I, the ratio of Apo B to ApoA-I, and Lipoprotein(a), as they relate to assessing cardiovascular risk beyond traditional cholesterol measures. The first three of these markers reflect risk that can be modified through dietary means, metabolic health, and lifestyle modification. They thus lend themselves to repeated measurements over time. Lipoprotein(a) is a unique marker, primarily influenced by genetic determinants, remains relatively constant throughout an individual's lifetime, and typically requires measurement only once. Understanding this difference in measurement approach affects the manner in which each marker should be tested and acted upon.

Physiological overview

Each and every atherogenic lipoprotein particle, including very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and lipoprotein(a), contains exactly one molecule of Apo B-100. Chylomicrons and their remnants contain Apo B-48. As a result, Apo B is a direct count of the number of atherogenic particles present in circulation, irrespective of how much cholesterol each particle contains. Apo A-1 is the primary structural protein of high-density lipoprotein (HDL) and serves as a co-factor in several of its anti-inflammatory functions, including activation of lecithin-cholesterol acyl transferase, stabilization of prostacyclin, and regulation of thrombosis. The ratio of Apo B to Apo A-1 demonstrates the relative contribution of particles involved in the deposition of cholesterol within arterial walls versus those that assist in clearance.

Lipoprotein(a) is composed of one molecule of Apo(a) bound to an Apo B-containing LDL-like particle. Apo(a) is coded by the LPA gene and exhibits considerable variation in molecular weight among individuals due to polymorphism in kringle IV repeats. This variation in molecular weight dictates the circulating concentration of Lp(a) and accounts for the differences observed in response to various forms of medical management compared to the remaining lipid markers.

Four markers relevant to functional assessment

Optimal DX defines standard reference ranges for these four markers and then defines functionally relevant ranges. Functionally relevant ranges are narrower than standard ranges to identify risk earlier in the disease process.

Apolipoprotein B (Apo B)

As previously described, Optimal DX defines the functional range for Apo B as 52 – 80 mg/dl. Elevated Apo B represents an increased burden of atherogenic particles. Each Apo B particle that enters the arterial wall can serve as a nidus for initiating atherosclerosis and contributes to the development of new plaque, destabilization of existing plaque, endothelial erosion and oxidative modifications further enhance its atherogenic properties. Studies examining relationships between Apo B levels and coronary disease severity indicate increasing levels of Apo B correlate with greater plaque instability in patients with stable coronary artery disease. Moreover, studies examining outcomes following statin therapy indicate residual risk after statin therapy correlates more closely with Apo B than with LDL-C. Furthermore, studies demonstrate that Apo B levels less than 73 mg/dl are associated with improved survival rates.

Studies also demonstrate associations between Apo B levels and obesity, insulin resistance and white adipose dysfunction that drive postprandial hypertriglyceridemia. Conversely, low levels of Apo B may be observed with conditions such as hyperthyroidism, malnutrition, chronic inflammation or use of certain pharmacotherapies.

Apolipoprotein A-1 (Apo A-1)

The Optimal DX functional range for Apo A-1 is 150 – 214 mg/dl.

Since the standard reference range for Apo A-1 is as low as 115 – 125 mg/dl, many patients have technically "normal" levels of Apo A-1 but remain below the levels associated with protective effects. Therefore, the functionally relevant range for Apo A-1 is established at 150 mg/dl to define levels associated with credible protective effects.

Apo A-1 is a more direct measure of protective capacity than HDL-C alone. Low levels of Apo A-1 have been demonstrated to be an independent risk factor for CVD and have identified CVD better than HDL-C alone in multiple studies. Low Apo A-1 has also been predictive of cardiovascular and ischemic heart disease mortality in elderly populations and CVD in young patients. Additionally, low Apo A-1 has also been correlated with greater severity of ischemic stroke and diabetic retinopathy.

Apo B to Apo A-1 ratio

The Optimal DX functional range for the ratio of Apo B to Apo A-1 is 0.00 – 0.60.

Research indicates that this ratio provides superior identification of coronary artery disease than total cholesterol, LDL-C, HDL-C or the older lipid ratios. An increasing ratio has been correlated with increasing severity of CAD, MACEs and metabolic syndrome, NAFLD and diabetic complications. Specifically, a ratio > 0.865 has been correlated with a threefold increase in risk for MACEs. Furthermore, diabetic patients exhibiting ratios > 0.72 were found to have significantly greater incidence of newly diagnosed coronary disease. The AMORIS cohort study found elevated ratios were predictive up to 20 years prior to cardiovascular events.

To capture an imbalance during its progression toward an increasingly unfavorable balance, ODX limits the ceiling at .60, below the standard cutoffs for men (.77) and women (.63).

Lipoprotein(a)

The Optimal DX functional range for Lp(a) is 0 to 18 nmol/L.

Lp(a) has been shown to be more atherogenic than LDL-C. Studies have demonstrated an independent association of Lp(a) with MI, IS, CAS, PAD, and VP. Cardiovascular outcome trials establish that there exists an incremental increase in risk with concentrations above 18 nmol/L. Studies conducted on cohorts from Denmark have demonstrated that the risk of MACE increases linearly with Lp(a) > 18 nmol/L. The Copenhagen General Population Study demonstrated similar results for IS risk. Thus, according to current evidence, Lp(a) levels <18 nmol/L are associated with reduced risk for both MACE and IS.

It is important to recognize that Lp(a) is currently being measured in either nmol/L or mg/dL. While conversion from mass units (mg/dL) to moles (nmol/L) involves application of approximately 2.15 nmol/L/mg/dL, this is only an approximation given that Apo(a) isoforms vary greatly among individuals based on kringle IV repeat polymorphism, and published conversions have ranged from ~2 to ~2.8. Consequently, when converting Lp(a) results from mass units to moles (or vice versa), estimates should be viewed cautiously.

Therefore, Optimal DX recommends reporting Lp(a) in nmol/L and encourages laboratories to provide results in nmol/L rather than mg/dL. If results arrive in mg/dL from an outside laboratory or assay with questionable accuracy, Optimal DX recommends estimating the result using cautionary language.

Outside these few reasonable exceptions, it appears sufficient to obtain only one accurate measurement of Lp(a).

Functional patterns of dysfunction

Excessive atherogenic particles

• Apo B > 80 mg/DL
• Apo B/Apo A-1 ratio > .6
• Frequently accompanied by elevated triglyceride levels and decreased HDL-C
  Indicates an excessive number of circulating atherogenic particles and active atherogenic pressures even when LDL-C levels appear acceptable.

Suggests a high circulating particle burden and active atherogenic pressure, even when LDL-C reads acceptable.

Reduced protective capacity

• Apo A-1 < 150 mg/DL
• Ratio trend upwards even when apo B appears acceptable

Indicates decreasing protective capacity; often precedes an elevated ratio.

Extreme atherogenic balance

• Ratios > .72 in higher-risk patients; ratios > .865 strongly associated with increased MACEs
• High apo B levels accompanied by low apo A-1 levels

Studies associate this pattern with increased risk of developing newly diagnosed coronary disease and significantly increased risks (> 300%) for MACEs. Warrants aggressive therapeutic efforts and close monitoring.

Increased genetic risk

• Elevated Lp(a) > 18 nmol/L added to any of the preceding patterns

Genetic influences dictate fixed amounts of additional risk added onto modifiable markers. The larger the value for Lp(a), the greater need to pursue aggressive modification of changeable factors.

Statin considerations

• Decreasing apo B levels and ratio while simultaneously having persistent or increasing elevation in Lp(a)

Statins reduce apo B levels and improve ratio but may elevate Lp(a); therefore, Lp(a) can remain elevated even when LDL-C levels are optimally managed. These opposing trends may lead a clinician to believe a patient is improving on conventional markers while Lp(a) moves in the opposite direction. The results from one accurate measurement settle this question.

Why Lp(a) usually requires only one test

Unlike virtually all other markers in a functional blood chemistry panel that tend to respond to dietary alterations, exercise programs, sleep quality improvement/decline, stress exposure/reduction, and medication efficacy/intolerance; Lp(a) is generally resistant to alteration by these variables. As a result, measuring Lp(a) tends to yield similar values over long periods unless there are specific interventions directed at reducing circulating levels (e.g., nicotinic acid). Based on this property, Lp(a) represents an ideal marker for determining an individual's lifetime cardiovascular risk; thereby allowing clinicians to determine how aggressively they should pursue reduction in other cardiovascular risk factors.

One documented example illustrating potential responsiveness includes a plant-based diet that lowered mean Lp(a) values by approximately 16% over four weeks accompanied by equivalent reductions in LDL-C and Apo B and inflammatory markers; however, mean values remained well above the clinically desirable range.

The relative constancy exhibited by Lp(a) values has implications concerning frequency of testing. Given that an accurate measurement of Lp(a) yields an individual's lifetime cardiovascular risk; re-testing Lp(a) on every subsequent panel would add unnecessary expense without contributing additional meaningful information. Reasonable exceptions include confirming an initial result obtained from unreliable assays or converters from mass units to moles or confirming results that appear inconsistent with expected values (e.g., intermediate values like 35 nmol/L that fail to align with both outcome literature and appropriate conversion). Otherwise one valid measurement is likely sufficient.

In summary; Apo B, apoA-I and Apo B/apoA-I ratio represent markers whose values should be monitored longitudinally. Lp(a) represents a marker whose value should be assessed only once during a patient's lifetime; although this value will inform how aggressively the clinician pursues reduction in other measurable cardiovascular risk factors.

Common causes for modifiable apolipoproteins

Multiple factors contribute to modifiable apolipoproteins, including:

• Insulin resistance and metabolic syndrome
• Obesity and white adipose tissue dysfunction
• Hypothyroidism
• Diets consisting predominantly of refined carbohydrates and processed fats
• Chronic inflammation
• Smoking and excessive ethanol consumption

Low apoA-I is uniquely affected by:

• Smoking
• Consuming high amounts of carbohydrate or polyunsaturated fatty acids
• Certain pharmacotherapeutic agents including androgens, diuretics, beta blockers and progestins

Lp(a) stands out. Lp(a) is genetically-determined. The factors listed above do produce Lp(a). However, there is some evidence that uncontrolled diabetes, hypothyroidism, estrogen deficiency and renal disease may contribute to increased levels.

When to consider assessing apolipoproteins/Lp(a)

There are no clinical manifestations of the burden of apolipoproteins/Lp(a). Therefore, the only means to identify individuals carrying excessive apolipoproteins/Lp(a) burden is through testing. Thus, a single measurement of Lp(a) in conjunction with a baseline measurement of apolipoproteins would be recommended if any of the following exist:

• Personal or family histories of premature cardiovascular disease (particularly events occurring prior to age 55 in males or 65 years of age in females)
• A discrepancy between a patient’s calculated LDL-C and their actual clinical risk, or a low-risk lipid profile in a patient with a high-risk clinical picture
• Presence of metabolic syndrome, insulin resistance, type ii diabetes, or non-alcoholic fatty liver disease
• Established coronary artery disease to further define residual risk
• Use of statin therapy with well-controlled LDL-C but uncertainty about the remaining risk
• Presence of calcification of the aortic valve or unexplained vascular abnormalities

Strategies for reducing cardiovascular risk due to elevated Lp(a)

Most interventions described below will impact the measurable markers and total atherogenic burden. Since the level of Lp(a) is generally fixed, the main focus when addressing elevated levels is to reduce the remainder of the patient's cardiovascular risk.

Diet

• Follow a diet rich in whole foods that has an anti-inflammatory effect. Include a high amount of fiber-rich foods, legumes, leafy green vegetables, and omega-3 fatty acids.
• Limit your intake of refined carbohydrates and processed fats, which increase particle number and negatively affect the atherogenic balance.
• Plant-based diets tend to lower Apo B and improve the ratio; they also tend to slightly decrease Lp(a).

Supplements

• Insulin resistance: berberine, alpha-lipoic acid, chromium, magnesium, and inositol support for insulin-resistant states because metabolic dysfunction drives Apo B and ratio.
• Omega-3 fatty acids: supports less atherogenic profile and lower inflammation.
• Niacin has been shown to decrease Lp(a); however, niacin's use for decreasing Lp(a) is currently limited and should be individualized.

Lifestyle/ stress management

• Aerobic exercise and resistance training improve insulin sensitivity and Apolipoprotein balance.
• Smoking cessation directly impacts apo-a1 and reduces overall vascular risk.
• sleep/stress management: part of total metabolic and inflammatory control.

Elevated Lp(a) is best addressed by aggressive reduction of every other modifiable factor (i.e., Apo B, blood pressure, glucose, inflammation, lifestyle). Lp(a) typically does not vary much from its baseline; therefore, the focus is on reducing the risk around it.

Monitoring/follow-up

• Apo B, ApoA1, and their ratio: reassess approximately every 8 to 12 weeks while actively intervening to monitor response; then at maintenance interval once stable.
• Lp(a): measure only once to establish lifetime risk. Repeat only to confirm an uncertain/mass unit result after initiating therapy known to alter it or when considering treatment targeting this marker.
• Monitor Apolipoprotein markers along with metabolic and inflammatory markers such as fasting insulin/glucose/hs-CRP/triglyceride.
• Observe the statin pattern of improving Apo B while increasing Lp(a).

Conclusion

Functional Medicine practitioners have a more complete picture of cardiovascular risk than cholesterol levels alone. Apo B counts the particles that drive atherosclerosis. Apo A-1 measures protective capacity. The ratio captures the balance between them. All can be respondent to interventions. They also reward for Monitoring. Lipoprotein (a) answers a different question. Lipoprotein (a) is genetically determined. For most patients lipoprotein (a) should only need to be measured once. Together these two types of markers tell you both how your patient is doing now and how aggressively to manage the risk that cannot change.

Bring these markers together with Optimal DX

Optimal DX brings these markers together in one place:

• Calculate and interpret the Apo B to Apo A-1 ratio automatically in the Functional Health Report
• Apply outcome-anchored functional ranges that flag risk earlier than standard cutoffs
• Read the full research reviews for each marker in the Resource Center

Become a member today and add apolipoprotein interpretation to every panel you review.

As a member, you will have access to:

• Advanced Functional Health Reports that go beyond basic lab interpretation
• A growing Resource Center with in-depth articles, guides, and clinical education
• Tools to help you build treatment plans based on your patient’s unique biomarker patterns

Explore membership options and see how Optimal DX can support your practice: https://www.optimaldx.com/pricing

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