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Hypercholesterolemia: A Complex System

— Back to basics on cholesterol carriers and measurement

MedpageToday
Illustration of the letter i on a piece of paper over a hand over a blood droplet with an upward arrow over cholesterol
Key Points

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Hypercholesterolemia is a deceptively simple term for the derangement of a robustly complex system in which cholesterol plays a key role.

Cholesterol is a type of lipid from which many other steroid hormones, such as estrogen, testosterone, and cortisol, are synthesized. Cholesterol is also integral to cell membranes, where it helps regulate fluidity and physical properties of the bilayer structure.

The liver is the hub of cholesterol-related metabolic activity. This organ maintains cholesterol homeostasis through synthesis of cholesterol, uptake of that newly created cholesterol by lipoprotein carriers, release of cholesterol-rich lipoprotein into the blood for use throughout the body, storage by esterification, and degradation and conversion into bile acids.

High density lipoprotein (HDL) transfers cholesterol from the periphery or from dietary intake back to the liver to be broken down for use by the liver or excretion, earning it the "good cholesterol" moniker.

Low density lipoprotein (LDL) transports most of the cholesterol in the blood, while another carrier -- very low-density lipoprotein (VLDL) -- is the main carrier for triglycerides, another type of lipoprotein that stores energy, helps insulate cells, and aids in the absorption of fat-soluble vitamins. The main protein in both of these carriers is apolipoprotein B-100 (ApoB), which acts as a ligand binding LDL receptors to the carrier particles to help regulate uptake and recycling.

Among the lipoprotein carriers, LDL is the most well known as related to atherosclerotic cardiovascular disease (ASCVD), which results from degeneration of the walls of the arteries due to accumulated fatty deposits and scar tissue that restricts circulation and raises risk of thrombosis. LDL cholesterol carries a deserved reputation as the dominant atherogenic form, but VLDL also contributes to ASCVD. VLDL and LDL cholesterol together are dubbed non–HDL cholesterol, with a stronger link to atherosclerosis than either component alone.

Measuring Cholesterol

Hypercholesterolemia specifically refers to high non-HDL cholesterol. Defining what "high" is will be explored in further installments of this Medical Journey series, as will the process of atherosclerosis.

Direct measurement of LDL is costly and labor intensive, so calculated measures fulfill most clinical purposes.

The standard method to calculate LDL cholesterol is the Friedewald formula, which is total cholesterol minus HDL cholesterol and subtracting out triglycerides divided by five. "When triglyceride levels are not elevated, this equation is sufficiently accurate," according to the 2018 American Heart Association/American College of Cardiology (AHA/ACC) .

The standard calculation doesn't work so well when triglyceride levels are elevated above 400 mg/dL, though, because the equation relies on a fixed factor of five for the ratio of fasting triglycerides (TG) to VLD cholesterol. Guidelines recommend that an initial nonfasting lipid measurement that shows triglycerides of 500 mg/dL or higher in adults should be repeated in the fasting state.

In cases of hypertriglyceridemia, ultracentrifugal single spin analysis or immunoprecipitation is more reliable than an estimated value. "Several commercial direct assays have been developed for this purpose, but there remain substantial concerns regarding their standardization and accuracy, especially at high TGs and in those with known coronary disease," noted an expert analysis .

The has also been developed with an adjustable factor based on a patient's non-HDL cholesterol and triglyceride values to substitute for the factor of five; and a newer estimation formula dubbed has been proposed for use in high triglyceride patients.

In most cases, dietary cholesterol won't have much impact on lipid measurements. The AHA/ACC gives a class I recommendation for either fasting or nonfasting tests in the primary prevention setting for adults ages 20 and older who aren't on lipid-lowering therapy. Studies have shown fairly similar prognostic value and associations with cardiovascular disease outcomes, the guidelines note. "If more precision is necessary, fasting lipids can be measured, but a nonfasting sample is reasonable for most situations."

One exception may be if the patient has had an "extremely high-fat meal" in the prior 8 hours. Another is adults with a family history of premature ASCVD or genetic hyperlipidemia, in which case more precision may be needed from a fasting lipid profile to help identify familial lipid disorders.

The Friedewald estimation breaks down the most at lower levels of LDL cholesterol, particularly below 70 mg/dL. For those patients, direct measurement is suggested as reasonable by the guidelines, as is use of the Martin/Hopkins equation, which has been validated for LDL cholesterol levels under 70 mg/dL when triglycerides are over 150 mg/dL.

Other Lipoproteins

ApoB has a high correlation with non-HDL cholesterol levels and can help sort out if high triglycerides need to be treated to manage atherogenic risk. "Nevertheless, apoB measurement carries extra expense, and its measurement in some laboratories may not be reliable," the cholesterol guidelines note.

The guideline suggested triglyceride levels of 200 mg/dL or higher as a relative indication for apoB measurement. Levels persistently over 130 mg/dL, corresponding to an LDL cholesterol of 160 mg/dL or higher, "can be considered a risk-enhancing factor."

The same is true for lipoprotein (a), or Lp(a), which is a modified form of LDL that is possibly also atherogenic. Due to a link to ASCVD risk at higher levels, it carries "relative indications" for measurement in patients with family history of premature ASCVD or personal history of ASCVD not explained by major risk factors.

"Current evidence shows that it should be considered in women only in the presence of hypercholesterolemia and with the understanding that the improvement in risk prediction in adult women in a large clinical trial was minimal," the guidelines cautioned.

Up next: Pathophysiology of Hypercholesterolemia