New Laboratory Tests

The key to understanding cholesterol homeostasis

By Thomas Dayspring MD, FACP, FNLA, NCMP, Director, North Jersey Institute of Menopausal Lipidology

It is well-known that lipoprotein abnormalities are a major risk factor for cardiovascular disease (CVD), which can be reduced by lowering atherogenic lipoprotein levels. Those levels depend on lipoprotein production, trafficking, and clearance. Production of cholesterol, a zoosterol essential for human life, depends on its cellular synthesis (all cells) and absorption (enterocytes). Noncholesterol sterols have slight structural differences: Many are phytosterols (e.g., sitosterol, campesterol) and others are cholesterol synthesis precursors (desmosterol) or metabolites (cholestanol). Phytosterols serve no human purpose and cannot be synthesized or absorbed to any major extent by animals. Small quantities are present in many fruits, vegetables, vegetable oils, nuts, seeds, cereals, and legumes. A stanol is a saturated sterol and is nonabsorbable. Since most absorbed cholesterol is biliary in origin, dietary cholesterol has little effect on absorption. Markers of both cholesterol absorption (e.g., beta-sitosterol, campesterol, cholestanol) and synthesis (e.g., desmosterol) can be measured and manipulated by statins, which in a dose dependent fashion block cholesterol synthesis, or by ezetimibe, fenofibrate, supplemental phytosterols or stanols, which reduce absorption.

People vary in their cholesterol homeostasis or balance —
the amount they synthesize, absorb, and excrete.

People vary in their cholesterol homeostasis or balance — the amount they synthesize, absorb, and excrete. After absorption into the enterocyte (via a membrane influx transporter, Niemann Pick C1 Like 1 protein or NPC1L1), virtually all noncholesterol sterols and some cholesterol are effluxed back into the gut lumen via membrane sterol efflux transporters (ATP binding cassette transporters G5 and G8, ABCG5/ABCG8; Fig. 1). Genetic polymorphisms in these transporters partly explain individual differences in cholesterol balance: Most humans absorb approximately 50% of the luminal sterols into the enterocyte, but hyperabsorbers absorb 60-80% and hypoabsorbers approximately 20-30%. After absorption, cholesterol, but not phytosterols, can be esterified and incorporated with triglycerides and phospholipids into chylomicrons. No cholesterol measurement distinguishes whether it has been absorbed or endogenously synthesized. Since phytosterols or stanols under normal physiologic circumstances do not enter the circulation, their plasma concentrations serve as clinical markers of cholesterol absorption. Hyperabsorbers, in whom phytosterols do gain systemic entry (owing to an imbalance between NPC1L1 and ABCG5/G8), are diagnosable by increased absorption markers. With rare loss-offunction mutations in ABCG5 or ABCG8, all phytosterols are absorbed and none are effluxed back out, leading to phytosterolemia, with up to 100-fold elevation in plasma phytosterol levels, associated with childhood xanthomas and premature atherosclerosis. Very high levels of cholestanol, a cholesterol metabolite yet also marker of absorption, occur in the rare recessive condition cerebrotendinous xanthomatosis (CTX), associated with several neurological deficits.

Baseline markers of absorption and synthesis can help to predict CV risk and optimize lipid-lowering lifestyle/drug therapy, including prediction of patient response to statins. Several large clinical studies have shown that elevated plasma noncholesterol sterols are powerful markers of CHD risk: In the DEBATE study low cholesterol absorption was associated with less CV events and better survival¹. However, other large population-based and prospective studies provide conflicting data. Until long-term placebocontrolled randomized clinical trials with CV end-points have clarified this issue, physicians should proceed cautiously with patients in whom LDL-C is being lowered at the expense of elevating phytosterols.

The HDL, Inc. Noncholesterol Sterols/Stanols Test measures beta-sitosterol, campesterol, and cholestanol as markers of cholesterol absorption, and desmosterol as a marker of cholesterol synthesis. Testing enables physicians to: 1) identify patients with phytosterolemia or CTX; 2) identify patients with cholesterol hypersynthesis who should respond well to statins; 3) identify patients with hyperabsorptive states (often associated with Type 2 diabetes, metabolic syndrome, menopause or family history of premature CHD) who are usually statin hyporesponders; 4) identify drug-induced hyperabsorbers (a complication of statin monotherapy) for whom lipid-lowering therapy should include ezetimibe, phytostanol or fibrate; 5) identify patients on ezetimibe monotherapy (which can induce cholesterol synthesis) who might benefit from addition of a statin, fibrate or phytostanol; 6) monitor patients with underlying hyperabsorptive states who may unknowingly be raising phytosterol levels by using supplemental phytosterols to lower cholesterol. Although commonly used for this purpose, currently no data exist to indicate that plant sterol ingestion results in prevention of CVD.

1. Strandberg TE et al. JACC 2006;48:708-714

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