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The science behind Boston Heart Cholesterol Balance™

All individuals differ when it comes to the balance between cholesterol production and absorption. Some people synthesize cholesterol more than they absorb, while others absorb more than they synthesize.

Knowing how an individual produces and absorbs cholesterol can help determine the most effective LDL-C lowering therapy. Understanding in advance which therapy will have the greatest efficacy allows for a more successful and cost-effective CVD treatment strategy.

Lathosterol, the direct precursor of cholesterol, can be measured in plasma or serum. Eighty percent of synthesized cholesterol goes through lathosterol, while only 20% goes through desmosterol. Therefore lathosterol is the only valid marker of cholesterol production. People who overproduce cholesterol have elevated levels of lathosterol normalized to total blood cholesterol levels. Markedly elevated levels of lathosterol identify patients with increased risk of premature coronary heart disease.

Plant sterols found in the plasma, beta-sitosterol and campesterol, are direct measures of cholesterol absorption. Individuals who over-absorb cholesterol in the intestine have elevated levels of these markers. Decreased values, which reflect low cholesterol absorption, are optimal. Elevated levels are associated with:

    • Increased cholesterol absorption and elevated LDL-C levels;
    • Increased risk of CVD independent of LDL-C, as shown in both PROCAM (Assmann et al. 2006) and the Framingham Heart Study (Matthan et al. 2009);
    • Lack of clinical benefit from simvastatin, as shown in the 4S Study (Miettinen et al. 1998); and,
    • Mutation in genes encoding ABCG5 and ABCG8, in patients with marked elevations of plant sterols and premature heart disease.

Patients with coronary heart disease and/or carotid artery stenosis had significantly higher levels of beta-sitosterol and campesterol than age and gender matched controls despite similar HDL-C and LDL-C levels.
Framingham Offspring Study (2009)

Regression of coronary artery narrowing was positively correlated with significant decreases in the plasma lathosterol/cholesterol ratio and negatively correlated with significant increases in plasma beta-sitosterol/cholesterol ratio.
HDL Atherosclerosis Treatment Study (2003)

Cholesterol Balance Predicts Response to Therapy

Cholesterol balance affects patient response to LDL-C lowering therapies. Patients with high levels of lathosterol (over-producers) respond best to statins, which lower cholesterol production. Those with high levels of beta-sitosterol and campesterol (over-absorbers) respond best to ezetimibe, which lowers cholesterol absorption.

Statins inhibit HMG-CoA reductase, the rate-limiting step in cholesterol production.

    • In patients with reduced cholesterol production, seen as decreased lathosterol levels, using a statin will have minimal impact on LDL-C lowering.
    • Patients with high cholesterol synthesis receive the greatest benefit from statin therapy.

Ezetimibe is a cholesterol absorption inhibitor.

    • In patients with decreased cholesterol absorption, seen as lower levels of beta-sitosterol and campesterol, using ezetimibe will have minimal effect on LDL-C lowering.
    • Patients with high cholesterol absorption receive the greatest benefit from ezetimibe therapy and diet.

Sterol Analysis Using Boston Heart Cholesterol Balance™

Boston Heart Diagnostics is the only commercial laboratory that analyzes both the markers of cholesterol synthesis (lathosterol) and cholesterol absorption (beta-sitosterol and campesterol).

The Cholesterol Balance™ test utilizes an advanced chromatography technique to measure these key production and absorption markers. This analysis determines the contribution to total blood cholesterol from the amount produced by the body versus the amount absorbed in the intestines.

Test Results Guide Treatment Selection

The results of the Cholesterol Balance test allow healthcare providers to match the mechanism behind elevated LDL-C with the drug and/or diet therapy that will be most effective in helping patients to achieve their LDL-C goal.

The benefits of the Cholesterol Balance Test are:

    • Accurate measurement of lathosterol (the best and most precise marker of cholesterol synthesis) and beta-sitosterol and campesterol (the most precise markers of cholesterol absorption);
    • Diagnosis of over-production of cholesterol, observed in the most common genetic cause of elevated LDL-C, known as familial combined hyperlipidemia (seen in 15% of families with premature heart disease);
    • Diagnosis of over-absorption of cholesterol, seen in about 25% of the general population and associated with increased risk of CVD, as well as phytosterolemia, a rare disorder associated with marked cholesterol over-absorption and premature CVD;
    • Formulation of optimal therapy with lifestyle modification, statin therapy (inhibits cholesterol synthesis) ezetimibe therapy (inhibits cholesterol absorption), colesevelam therapy (binds bile acids therefore enhancing LDL clearance);
    • Allows healthcare providers to develop optimal strategies for getting their patients to target LDL-C goals as defined by the National Cholesterol Education Program.

Shortcomings in Other Methods of Sterol Analysis

Other sterol analysis methods measure desmosterol, an indirect cholesterol precursor associated with a minor synthetic pathway. Based on scientific evidence, desmosterol levels do not correlate nearly as well as lathosterol with direct measurements of cholesterol synthesis or the efficacy of statin therapy.

The Boston Heart Cholesterol Balance test is the only test to measure lathosterol, the direct precursor of cholesterol and therefore the best marker of cholesterol production. Over 40,000 patient studies have validated the efficacy of the Cholesterol Balance test in guiding optimal statin therapy. This is tens of thousands more study samples than any other commercial laboratory.

Scientific Milestones in Plasma Sterol Measurement

1998

In a subset of 868 patients with CHD participating in the Scandinavian Simvastatin Survival Study (4S) plasma sterols were measured. Subjects with elevated baseline markers of cholesterol absorption ATP binding cassette transporters G5 and G8 (ABCG5, ABCG8) are identified.1

2000

In patients with phytosterolemia who have marked elevation in plasma beta-sitosterol and campesterol (due to increased absorption) and premature CHD, mutations in the ATP binding cassette transporters G5 and G8 (ABCG5, ABCG8) are identified.2

2006,  2009

In both the Prospective Cardiovascular Muenster (PROCAM) Study and the Framingham Offspring Study elevated plasma levels of beta-sitosterol and campesterol are linked to an increased risk of CHD.3

2009

Dr. Ernst Schaefer and colleagues at Tufts University documented that familial combined hyperlipidemia, the most common cause of elevated triglycerides and LDL-C in families is linked to elevated plasma lathosterol and overproduction of cholesterol.4

2009

Dr. Ernst Schaefer and colleagues documented that statins decrease absolute and relative levels of lathosterol, a marker of cholesterol synthesis, while increasing absolute and relative markers of cholesterol absorption, namely beta-sitosterol and campesterol. Moreover the researchers confirmed findings by other groups that changes in these parameters predicted statin induced LDL-C lowering response.4


1. Miettinen, TA., Gylling, H, Strandberg, T, Sarna, S. for the Finnish 4S Investigators. Baseline serum cholestanol as predictor of recurrent coronary events in subgroups of Scandinavian simvastatin survival study. 1998;316:1127–1130.
2. Berge KE, von Bergmann K, Lutjohann D, et al. Heritability of plasma non cholesterol sterols and relationship to DNA sequence polymorphism in ABCG5 and ABCG8. J Lipid Res. 2002;43:486–494.
3. Matthan NR, Pencina M, LaRocque JM, et al. Alterations in cholesterol absorption /synthesis markers characterize Framingham Offspring Study participants with CHD. J Lipid Res. 2009;50:1927–1935.
4. Van Himbergen TM, Otokozawa S, Matthan NR, et al. Familial combined hyperlipidemia is associated with alterations in the cholesterol synthesis pathway. Arterioscler Thromb Vasc Biol. 2010;30:113–120.

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