The key to understanding cholesterol “balance”
Cholesterol is essential for life, but too much may be harmful
Cholesterol, the most well-known sterol, is needed by the body to make cell membranes and molecules such as hormones and vitamins. It can be synthesized by most cells in the body and is absorbed from the digestive tract. However, high blood levels of cholesterol, when carried by LDL particles, are a risk factor for cardiovascular disease (CVD).
The Noncholesterol Sterols/Stanol test reveals the unique balance between cholesterol synthesis and absorption in any individual. This “cholesterol balance” is mediated by cellular cholesterol transporters (ABCG5/8 and NPC1L1) in the intestine and the liver, which also facilitate entry and exit of “phytosterols” obtained from dietary plants such as nuts, seeds, fruits, and vegetables.
Why measure Noncholesterol Sterols/Stanol?
Plasma cholesterol measurements alone do not indicate whether cholesterol has been absorbed or made within the human body. Due to genetic differences, some people synthesize more cholesterol than they absorb and vice versa.
Noncholesterol Sterols/Stanols 101
“Noncholesterol sterols” like phytosterols (e.g., sitosterol and campesterol) are not made by the body and have a dietary origin. Stanols (e.g. cholestanol) are byproducts of sterol metabolism – simply saturated sterols (meaning they have lost the double bond within the sterol molecule), which radically changes their structure and ability to be absorbed. These 3 molecules are absorbed much less efficiently than cholesterol, and thus serve as biomarkers of cholesterol absorption. Desmosterol is a cholesterol precursor and serves as a biomarker of cholesterol synthesis. Together, these 4 biomarkers reveal the absorption/synthesis status of plasma cholesterol in a given individual.
Noncholesterol sterols/stanols are structurally similar to cholesterol. The slight differences make sitosterol, campesterol, and cholestanol nonabsorbable in the body, and less easy to absorb from the diet.
Knowing whether abnormal cholesterol balance is due to hyperabsorption, hypersynthesis, both, or neither, can help a clinician more effectively evaluate cardiovascular risk and prescribe the most appropriate lipid-lowering therapies
Sitosterol, Campesterol, and Cholestanol- Cholesterol absorption markers
Since they are present in the plasma purely from the diet and intestinal absorption, phytosterols (sitosterol and campesterol), are reliable markers of cholesterol absorption. They compete with cholesterol for intestinal absorption and are sometimes used therapeutically to reduce cholesterol absorption.
As stanols are normally very poorly absorbed, cholestanol, an intestinally produced metabolite of cholesterol, is also measured to assess cholesterol absorption.
To Statin or not to Statin? targeting therapies
Personalizing lipid-lowering therapies by consideration of cholesterol balance
Statins, the first line drugs for reducing elevated plasma LDL-C, LDL-P, or apoB, work by blocking cholesterol synthesis. Noncholesterol Sterols/Stanol testing will help a clinician to reduce CV events in the primary as well as secondary prevention of CVD by revealing the patient’s balance between cholesterol synthesis and absorption.
People who tend to overproduce cholesterol (hypersynthesizers) will have elevated plasma desmosterol levels and increased risk for CVD. Metabolic syndrome is often characterized by increased cholesterol synthesis and decreased absorption.1 Patients with elevated desmosterol levels will benefit most from statin therapy.
If an elevated LDL-C or LDL-P is due to increased cholesterol absorption (identified by elevated sitosterol, campesterol, and/or cholestanol), a statin will be less effective.* Such patients (hyperabsorbers), will likely respond better to regimens that include cholesterol absorption inhibitors (e.g., ezetimibe). Clinical studies have shown that elevated levels of these sterol/stanol absorption markers increase risk for CVD.2,3,4 Patients who are found to be hyperabsorbers should NOT take high-dose phytosterols supplements
The higher the cholesterol absorption, the less efficacious ! is the statin.
Optimizing lipid-lowering therapies by monitoring shifts in cholesterol balance
Noncholesterol Sterols/Stanol testing can detect when statin monotherapy is suppressing cholesterol synthesis or undesirably (and reflexively) promoting sterol absorption. Testing in patients on cholesterol absorption inhibitors (e.g., ezetimibe) can testify to their action and identify those who develop compensatory cholesterol synthesis. In these cases, statin/ezetimibe combination therapy, with a fibrate or phytostanol, may have the greatest lipidlowering effects.
Two rare hyperabsorption disorders: phytosterolemia and CTX
Phytosterolemia patients have rare genetic mutations in the ABCG5/8 transporter and may display markedly elevated phytosterol levels (up to 200x normal values), have premature CVD, and suffer cardiovascular events despite normal lipid profiles. Patients with xanthomas (skin nodules) should be investigated for high cholestanol levels, indicative of another rare disorder, cerebrotendinous xanthomatosis (CTX), where levels are 3-15x higher than the general population and may lead to neurological problems. Plasma cholestanol is slightly elevated in familial hypercholesterolemia.