Hypercholesterolemia is a lipid disorder characterized by excess non-HDL cholesterol in the blood. According to the CDC, nearly 94 million American adults over age 20 have high total cholesterol (TC), and 73.5 million have elevated LDL cholesterol (LDL-C). Elevated cholesterol increases the risk of atherosclerotic cardiovascular disease (ASCVD), a buildup of plaque in the arteries that can lead to heart attack, stroke, and other adverse cardiovascular events. (1, 2)

Conventionally, hypercholesterolemia is diagnosed with a basic lipid panel and managed with lifestyle modifications and statin medications. However, recent advances in research have demonstrated that calculating cardiovascular risk as it pertains to cholesterol is more complex than what can be measured on a basic lipid panel. Functional medicine doctors utilize specialty testing to more accurately stratify lipid particle composition, cholesterol levels, and cardiovascular risk. A functional medicine doctor considers these biomarkers when recommending protocols that lower high cholesterol.

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What is Cholesterol?

Cholesterol is a waxy lipid called a sterol used by the body to maintain cell membranes and synthesize vitamins, steroid hormones, and bile acids. Cholesterol comes from two sources: endogenously derived cholesterol from the liver and exogenously derived cholesterol from dietary animal products (i.e., meat, eggs, and dairy products). (3, 4)

Cholesterol is carried and transported through the body in lipoproteins. Low-density lipoprotein (LDL) transports cholesterol to body tissues. It can become oxidized, forming fatty buildups and plaques in the arteries, which causes atherosclerosis. High-density lipoprotein (HDL) picks up cholesterol from cells and transports it back to the liver to be recycled or eliminated from the body. A healthy level of HDL is protective against heart attack and stroke. (5)

High Cholesterol Signs & Symptoms

High cholesterol by itself does not cause symptoms. However, you may become symptomatic if high cholesterol causes atherosclerosis and cardiovascular disease (CVD). This is why screening for high cholesterol and other cardiovascular risk factors is important before CVD develops.

Atherosclerosis causes a narrowing of the blood vessels, resulting in ischemia - the inadequate perfusion of blood to critical tissues and organs. Ischemia causes symptoms like chest pain, fatigue, and shortness of breath. (6)

Other common manifestations of CVD include swelling in the limbs and irregular heartbeat. (7)

What Causes High Cholesterol?

There are both genetic and acquired causes of high cholesterol.

The most common genetic disorder that causes high cholesterol is called familial hypercholesterolemia, which results from mutations in the LDL-receptor, apolipoprotein B (ApoB), or proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. These gene mutations negatively impact LDL clearance from circulation, resulting in LDL-C levels greater than 190 mg/dL. (2)

The majority of high cholesterol is caused by unhealthy lifestyle behaviors. An unhealthy diet with excess intake of saturated and trans fats, lack of physical activity, smoking, and obesity can cause the liver to produce more LDL-C than the body needs. (2, 8)

Certain medications can also affect a person's lipid profile. These include, but are not limited to, birth control pills, corticosteroids, antivirals, diuretics, and immunosuppressants.

Medical conditions associated with causing high cholesterol include hypothyroidism, kidney disease, diabetes, liver disease, and pregnancy. (2, 9, 10)

Functional Medicine Labs to Test for Root Cause of High Cholesterol

Advanced Lipid Panel

A basic lipid panel measuring TC, LDL-C, HDL-C, and triglycerides can diagnose high cholesterol. However, measuring cholesterol levels with an advanced lipid panel is more beneficial to assess the cardiovascular risk associated with high cholesterol. An advanced panel includes the basic lipid markers and a lipoprotein fractionation, which calculates the number and size of lipoprotein particles carrying cholesterol in circulation. Additional biomarkers to consider adding to this advanced panel to determine an individual's risk for developing CVD include the following:

ApoB

This test measures the concentration of lipoproteins with a protein called ApoB on their surface. ApoB-containing lipoprotein particles are drivers of atherosclerosis, making this marker a stronger predictor of heart attack than LDL-C.

Lp(a)

Lp(a) is an LDL subtype that has apolipoprotein(a) attached to its surface and is a risk factor for CVD. Because genetics primarily drive elevations in Lp(a), this biomarker explains the reason behind an individual's elevated cholesterol and helps in treatment decision-making. (11)

Oxidized LDL (OxLDL)

OxLDL measures oxidative protein damage of the ApoB subunit. Elevated levels promote vascular inflammation and cardiometabolic disease.

Inflammation Markers

hs-CRP is a well-documented clinical marker of cardiac-related inflammation. Less well-known are Lp-PLA2, which measures arterial disease activity and immune activation, and myeloperoxidase, a marker of arterial-specific inflammation. Elevations in any of these are associated with ASCVD and cardiovascular events.

Lifestyle Panel

The Lifestyle Panel from Boston Heart includes a basic lipid panel, hs-CRP, the HDL Map, and the Cholesterol Balance tests. This unique panel provides additional information regarding HDL lipoprotein populations, endogenous production of cholesterol, and gastrointestinal absorption of cholesterol. Understanding these elements clarifies basic lipid panel results and directs treatment recommendations.

Metabolic Screening

Rule out medical conditions that can cause high cholesterol and increase ASCVD risk by ordering a comprehensive metabolic panel (CMP), hemoglobin A1c (HbA1c), fasting insulin, and thyroid panel.

Other Labs to Check

The ASCVD Calculator is a tool used in the primary prevention of ASCVD (for patients without ASCVD) to estimate a patient's baseline 10-year ASCVD risk, recommend management strategies, and monitor patient progress.

A coronary artery calcium (CAC) scan is specialized imaging that creates multiple images of the heart that can show plaque deposits in the blood vessels. The test result is a score that reflects the total area and density of calcium deposits. A CAC helps to quantify the risk of heart disease for people with high cholesterol and dictate the level of intervention required for treatment.

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Conventional Treatment for High Cholesterol

The 2019 ACC/AHA Guidelines for managing high cholesterol and primary prevention of CVD emphasize a healthy diet that includes vegetables, fruits, nuts, whole grains, lean vegetable or animal protein, and fish. The diet should have minimal trans fats, red and processed meats, refined carbohydrates, and sweetened beverages. The guidelines also state that adults should engage in at least 150 minutes of moderate-intensity or 75 minutes of vigorous-intensity physical activity weekly. (15)

Statin therapy is the first-line treatment in patients with LDL-C greater than 190 mg/dL, diabetes mellitus, 40-75 years of age, and at sufficient ASCVD risk. Concurrently, cardiovascular comorbidities, including hypertension and type 2 diabetes, should be managed appropriately. Other pharmacologic alternatives to statins for lowering cholesterol include ezetimibe and PCSK9 inhibitors. (15)

Functional Medicine Treatment Protocol for High Cholesterol

For those who want to pursue alternatives to pharmacotherapy, don't tolerate pharmacologic medications, or aren't reaching outcomes with medication alone, adding natural supplements to dietary modifications and physical activity can provide additional benefits.

Therapeutic Diet and Nutrition Considerations for High Cholesterol

The Mediterranean diet is an evidence-based heart-healthy diet that is shown to reduce CVD risk and mortality, improve lipid profiles, and reduce inflammation. Meals are centered around fresh fruits and vegetables, nuts, seeds, legumes, and olive oil. This nutritional plan effectively lowers cholesterol by limiting unhealthy fats, sodium, and refined carbohydrates and increasing dietary fiber intake. (12-14)

The DASH diet is another whole foods nutrition plan focused on incorporating fresh fruits and vegetables, whole grains, beans, nuts, low-fat dairy, fish, and poultry. It is considered to be a heart-healthy diet and is usually prescribed alongside physical activity providing the most significant benefit in lowering cholesterol and blood pressure.

Supplements Protocol for High Cholesterol

Red Yeast Rice

Red Yeast Rice (RYR) is the natural alternative to low-intensity statins, working by the same mechanism as its pharmacologic counterpart - inhibiting the enzyme responsible for the cellular production of cholesterol. Research shows RYR effectively lowers LDL-C levels between 15-25% within 6-8 weeks, in addition to total cholesterol and triglycerides (16). Additionally, RYR is less likely to cause muscle pain, a common symptom of statins related to statin-induced depletion of Coenzyme Q10 (CoQ10) and vitamin D.

Dose: 1,200 mg twice daily; consider dosing with CoQ10 50-100 mg daily and Vitamin D 2,000 IU daily to prevent side effects.

Duration: at least 6-8 weeks

Berberine

Compared to placebo and lifestyle interventions, meta-analyses show that berberine alone can reduce TC by 21-32 mg/dL and LDL-C by 23-26 mg/dL and increase HDL-C by 2-3 mg/dL (17, 18). Berberine can also make lipid-lowering drugs more effective when they are dosed together.

Dose: 500 mg twice daily

Duration: at least three months

Plant Sterols

Phytosterols, which include plant sterols and stanols, are natural compounds found in plants that can lower cholesterol levels by competing with gastrointestinal cholesterol absorption and assisting cholesterol's elimination from the body. This 2013 systematic review and meta-analysis of eight studies found that supplementation of plant sterols/stanols in tablet and capsule form significantly reduced LDL-C concentrations by 12 mg/dL.

Dose: 1 gram 2-3 times daily

Duration: at least 4-6 weeks

Garlic

Taking garlic for at least two months can modestly decrease TC and LDL-C by 10%. Consider garlic in patients with hypertension or those prone to infection, as garlic can also reduce systolic and diastolic blood pressure and increase immune cell function. (19)

Dose: 1,200 mg 1-2 times daily

Duration: at least two months

When to Retest Labs

After initiating or modifying the treatment plan, retest lipid markers 6-8 weeks later to monitor patient response.

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Summary

Hypercholesterolemia, or high cholesterol, is a cardiovascular condition characterized by elevated cholesterol in the blood. High cholesterol can increase the risk of atherosclerosis and heart disease, so optimizing blood lipids is important. Specialty testing can better define cardiovascular risk, helping to refine and personalize treatment recommendations to meet desired treatment goals.