Analyzing the Cholesterol Message

Every few years Australian pathologist Ken Sikaris presents at a conference the latest science on cholesterol and heart disease risk. The current dogma used by the typical physician is decades out of date and may lead to unnecessary or potentially damaging prescriptions.

Summary

The source is an excerpt from a video transcript featuring Prof. Ken Sikaris, a pathologist, discussing his views and research on cholesterol, lipid metabolism, and low-carbohydrate diets. He recounts how his personal health results and research into small dense LDL and triglycerides led him to reconsider traditional low-fat dietary advice, particularly after attending lectures by Robert Lustig. Sikaris emphasizes the harm of fructose and high-carbohydrate diets, linking them to the development of fatty liver and adverse lipid profiles, and highlights that the total cholesterol/HDL ratio is a superior predictor of cardiovascular risk and the presence of small dense LDL compared to total cholesterol or LDL levels alone. The text also includes a Q&A session where Sikaris addresses topics such as the reliability of lab tests, the impact of sex differences on lipid profiles, the significance of Lp(a), and the potential for new, more specific tests like Lp-PLA2.

The following is a summary of the audio presented by Prof. Ken Sikaris on analyzing the cholesterol message, drawing on his personal experience, pathology expertise, and current research into diet and lipid physiology.

🤔 The Pathologist’s Journey and Small Dense LDL

Prof. Sikaris’s interest in cholesterol began with his own “diabolical” lipid results in 1989, which featured very high triglycerides and low HDL (below 1.0). While in charge of the lipid lab at St Vincent’s Hospital, his research focused on predicting LDL types. They found that if triglycerides were above 1.5, patients developed small dense LDL (sdLDL), a much more harmful phenotype than the healthy buoyant LDL (phenotype A). He later concluded that wherever cardiovascular disease (CVD) existed, small dense LDL was also present.

His perspective dramatically shifted in 2008 after hearing Robert Lustig lecture in Australia, leading him to recognize the harms of sugar and fructose.

🍎 Diet, Fructose, and Fatty Liver

The speaker was involved in Damon Gameau’s movie, which highlighted the impact of diet. When Gameau consumed a low-fat, high-carb diet, he rapidly developed a fatty liver within two to three weeks, proving that fatty liver can be generated just as quickly as it can be reversed.

💡 Fructose is the Culprit:

  • Fructose, especially in processed foods, is the primary driver of rising triglycerides and worsening HDL.
  • Fructose is converted directly to fat in the liver.
  • High triglycerides (over 1.5) are the most predictive factor for a fatty liver. The speaker is “almost certain” a patient has a fatty liver if their triglycerides are above 1.5, regardless of other liver function tests.
  • A fatty liver indicates fat is accumulating in every tissue, including the muscle, heart, brain, and kidney, which severely affects metabolism and insulin sensitivity.

⚖️ Macronutrients and Physiology

Drawing on David Rheim’s geometry of nutrition, Sikaris discussed how macronutrient balance impacts weight and fatty liver risk:

  • Increasing protein promotes weight loss.
  • Increasing carbohydrates moves individuals toward weight gain and fatty liver. Low-carb diets are associated with weight loss and no fatty liver (“The Cool Zone”).
  • High fat content alone does not strongly cause weight gain or loss; it is mainly influenced by carbs and protein.

🎯 The Total Cholesterol/HDL Ratio: The Bottom Line

Sikaris stressed that the traditional focus on Total Cholesterol and LDL is outdated. He advises doctors and patients to look at “the bottom line” of the lipid report:

Diet Type Impact on Traditional Markers Impact on Predictive Ratio
High Carb (Carbohydrate-Dependent) Decreases LDL & Total Cholesterol (which people love). Worsens Total Cholesterol/HDL ratio (lowers HDL, increases trigs).
High Saturated Fat Increases LDL & Total Cholesterol. Improves Total Cholesterol/HDL ratio (increases HDL, net positive effect).

The Total Cholesterol/HDL Ratio is the most powerful predictor of small dense LDL and cardiovascular disease outcomes, better than individual measures like triglycerides, LDL, or HDL alone. This ratio is used in major cardiovascular risk calculators.

🚚 How Small Dense LDL is Created

Small dense LDL is intrinsically linked to carbohydrate metabolism:

  1. Fructose Overload: A liver overloaded with fructose exports fat via VLDL (Very Low-Density Lipoprotein), the body’s fat transport truck.
  2. Impaired Clearance: In high-carb adapted individuals, muscle tissue is “carb adapted” and uninterested in burning fat.
  3. Delayed Traffic: The VLDL clearance is delayed, causing triglycerides to remain high. VLDL also becomes the most glycated lipoprotein in the blood, especially in diabetics.
  4. Junk LDL: As VLDL hangs around, an enzyme called cholesterol ester transport protein (CETP) causes it to change, making the resultant LDL progressively smaller and denser.
  5. Atherogenesis: This small dense LDL is “junk LDL” and can only be cleared by macrophages. If these macrophages are in the blood vessel wall, they become engorged, leading to fatty streaks and atheromas.

SdLDL (and related oxidized/glycated LDL) is the modern understanding of the cause of atherosclerosis among cardiologists. Even in inherited hypercholesterolemia (FH), the LDL hangs around so long that it becomes small and dense, which is what makes it so atherogenic.

📈 The Lipid Energy Hypothesis and LMHRs

Sikaris supported the findings of the Lean Mass Hyper-responder (LMHR) KET trial, which studied low-carb individuals with very high LDL (above 5.0) but excellent lipid profiles (high HDL > 1.6 and low trigs < 0.9). Since their Total Cholesterol/HDL ratios were low (e.g., 4.1, well below 4.5), they were considered low risk, and the trial confirmed no rapid increase in cardiovascular risk compared to a matched low-risk group.

This supports the lipid energy hypothesis: lipids are about energy transport. In fat-adapted, low-carb individuals, high LDL is not indicative of disease but of high lipid energy traffic, where “empty trucks” (LDL) are rapidly being used and lining up to return to the liver for more fat.

🔬 Specialized Testing and Policy

When asked about testing not covered by Medicare, Sikaris advocated for:

  • Lipoprotein-Associated Phospholipase A2 (Lp-PLA2): This protein, made by macrophages in the plaque, is a pure measure of plaque activity and should be available as a cheap test.
  • Hemoglobin A1c (HbA1c): He is a “big fan” of this test and believes everyone should know their HbA1c, noting its high reliability when measured by precise laboratory assays.
  • LDL Profiling: While he finds the profile useful for patient motivation to show clear changes in response to diet, he acknowledged that the Total Cholesterol/HDL ratio often makes the expensive test redundant.

He also touched on specific considerations:

  • Women’s Lipids: Lipid profiles are theoretically more accurate if measured during the follicular phase of the menstrual cycle, as the luteal phase (and especially pregnancy) naturally raises cholesterol and triglycerides significantly to support the baby.
  • Familial Hypercholesterolemia (FH): Patients with persistently high LDL (above 5.5 or total cholesterol above 10) qualify for subsidized genetic testing, which should be requested from a specialist.
  • Thyroid Antibodies: Elevated anti-thyroid peroxidase antibodies are common (30–40%) in women who have had pregnancies (due to fetomaternal microchimerism) and are often meaningless unless the TSH level is also abnormal. Treating based only on antibodies is discouraged due to the risk of increased bone turnover from unnecessary thyroxin.