Cholesterol – Updated

This is a full rewrite of the original articles that I published in Chemistry in Australia in 2014, updated to include all the new information that is available.

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When I was younger, my cholesterol readings were fine. Then one day, around my fortieth birthday, the numbers suddenly crept upward. Nothing dramatic changed in my diet. I wasn’t living off fried chicken or ice cream, yet my general practitioner shook his head and began the standard conversation about statins. I was meant to take them for life, apparently, to keep a number inside a range. I remember thinking that the biochemistry could not possibly be this simple.

Having once worked in industrial R&D on blood glucose, I had some idea how biochemical systems behave. They are dynamic, complex, and hopelessly interdependent. The idea that a single concentration could dictate life expectancy always seemed naïve. I have read Ben Goldacre’s Bad Science, which convinced me that my distrust of tidy medical narratives was not misplaced.

The statin hypothesis sounded straightforward enough. High blood cholesterol correlates with heart disease. Statins lower cholesterol. Therefore, statins prevent heart disease. The simple logic appealed to the same instinct that drives us to fix a broken tap by changing a washer. The problem is that biology rarely works like plumbing. Over time, it has became clear that cholesterol is a passenger, not the vehicle.

What we casually call “cholesterol” in the bloodstream is not cholesterol, the molecule, at all but a family of microscopic transport particles, vesicles, called lipoproteins. They are colloidal assemblies of lipids and proteins that shuttle fats around the body. Low density lipoproteins, LDL, deliver cholesterol and triglycerides from the liver to tissues. High density lipoproteins, HDL, carry excess lipids back to the liver for disposal. Together they form a continuous feedback loop. If the loop stays balanced, arteries remain clean. If not, small dense LDL particles can slip beneath the arterial lining, oxidise, and trigger an inflammatory chain reaction. The immune system sends macrophages to clean up the oxidised fats. These cells fill up, burst, and spill their contents, causing lesions that harden and narrow the arteries. This is atherosclerosis in slow motion.

But the critical point is that not everyone with high levels of LDL develops this problem. Some people carry elevated cholesterol levels their entire lives without cardiovascular disease. My own family is an example. The men and women all have high cholesterol and live into their nineties. For years that seemed like an anomaly. It is not. Modern research now shows why.

First, not all LDL particles are created equal. The large, buoyant ones are relatively benign. The small dense ones are the real culprits. These smaller particles are more likely to oxidise and adhere to vessel walls. Standard cholesterol tests do not distinguish them. They report a total LDL cholesterol concentration, not the number or size of the particles themselves. Two people with identical LDL readings can have entirely different risk profiles.

Second, inflammation matters more than concentration. Atherosclerosis is as much an immune disorder as a lipid disorder. When inflammation is low, even a high LDL burden may do little harm. Chronic inflammation, however, primes the immune system to overreact to oxidised lipids. Families like mine that stay lean, active, and relatively uninflamed can carry high cholesterol with little consequence.

Third, genetics play a significant role. Some people inherit variants of the APOE, PCSK9, or CETP genes that alter the way cholesterol circulates and clears. These variants can produce high measured LDL but also faster recycling or more efficient repair of damaged vessels. Conversely, some people with normal cholesterol have fragile arterial linings and develop plaques early. The medical system struggles with this diversity because it prefers a universal threshold to individual kinetics.

The way cholesterol is measured has not kept up with the science. Traditional lab tests still rely on the Friedewald equation, a 1970s shortcut that estimates LDL as total cholesterol minus HDL minus triglycerides divided by five. It assumes everyone’s lipid chemistry is identical. The method was designed for speed, not precision, and breaks down when triglycerides are elevated or patients are not fasting. Modern assays can measure LDL directly, yet many clinics still report estimated values. The result is a mix of rounding errors, lab drift, and statistical illusions.

More accurate markers now exist. The best known is apolipoprotein B, or ApoB, the structural protein on every LDL particle. Counting ApoB molecules gives a direct measure of the number of potentially atherogenic particles, which correlates far better with heart disease than total LDL cholesterol. Another key marker is lipoprotein(a), or Lp(a), a genetically determined variant of LDL that carries an extra protein tail. High Lp(a) increases risk regardless of diet or lifestyle. Measuring these two gives a much clearer picture of cardiovascular risk than the traditional cholesterol panel ever could.

The dietary side of the story has also evolved. In the past, trans fats produced by partial hydrogenation of vegetable oils were the main culprit in distorting LDL particle size and increasing small dense fractions. They have been banned in many countries, but their replacements—inter-esterified fats—may not be much better. These engineered lipids alter the physical structure of triglycerides in processed foods and can confuse the liver into releasing smaller, more numerous LDL particles. Natural fats, whether saturated or unsaturated, are metabolised more predictably. The modern consensus is that refined carbohydrates and industrial fats together are the most harmful combination. They raise triglycerides, lower HDL, and inflame arterial walls.

Statins still have their place. They lower LDL cholesterol by inhibiting HMG-CoA reductase in the liver, reducing the production of cholesterol molecules and prompting cells to express more LDL receptors. This increases clearance of LDL particles from the blood. But the benefit appears to go beyond lipid reduction. Statins also dampen inflammation, stabilise arterial plaques, and improve endothelial function. Their effectiveness is strongest in people who have already had a cardiovascular event or have very high baseline risk. For low-risk individuals, the absolute benefit is modest, and the side effects are more noticeable. Muscle pain, fatigue, elevated liver enzymes, and in some cases insulin resistance are now well-documented.

Fortunately, the pharmaceutical landscape has expanded. PCSK9 inhibitors, injectable antibodies that prevent the degradation of LDL receptors, can cut LDL levels by half again when added to statins. Bempedoic acid offers an oral alternative for those who cannot tolerate statins. Even more interesting are RNA-based therapies such as inclisiran and lepodisiran, which silence genes involved in cholesterol transport. One injection can maintain low LDL or Lp(a) for months. Trials of gene editing therapies targeting the PCSK9 gene itself are underway and may one day offer a permanent fix.

The new challenge is determining how low “cholesterol” should go. Cholesterol remains vital for hormone synthesis, nerve insulation, and cell membranes. Extremely low levels have been associated in some studies with mood disorders, diabetes, and even glaucoma, though causation remains uncertain. The mantra “lower is always better” is slowly giving way to “lower within reason.”

If there is a single modern insight that redeems decades of confusion, it is that cholesterol is not a cause but a context. The number on the blood test reflects a steady state between diet, metabolism, genetics, and inflammation. It tells part of the story but not the outcome. Some people with high LDL will never have heart disease because the rest of their system works efficiently. Others with average cholesterol will suffer early because inflammation, oxidation, or blood pressure overwhelms them.

The most informative test may not involve chemistry at all. Coronary calcium scans, which detect actual plaque formation, provide a direct picture of risk. A person with high cholesterol but zero calcium buildup is statistically far safer than one with perfect numbers and silent plaque.

Diet still matters, though not in the way we were taught. Cutting intake of food with cholesterol has virtually no effect on blood cholesterol because the liver controls production tightly. What matters is avoiding the foods that distort lipid metabolism: refined sugars, processed starches, and artificial fats. Diets based on whole foods, adequate protein, and natural fats tend to normalise triglycerides and raise HDL. Moderate fasting periods help too, allowing the body to clear triglycerides and reset insulin sensitivity. Exercise, sleep, and stress management reduce inflammation, which may be the true mediator between cholesterol and disease.

When I look at my family history, it seems obvious that a single biomarker could never explain human longevity. My relatives ate whatever they wanted, rarely stayed active, and smoked. Their arteries stayed clear not because their numbers were perfect but because their chemistry remained balanced. High cholesterol in that context was a benign adaptation, not a pathology.

The irony is that we still use cholesterol as shorthand for risk even though we now understand its limitations. The term itself is a historical accident, kept alive by habit. What the blood tests actually measure is the cholesterol contained within lipoproteins, not the molecule freely floating around. The assumption that this concentration predicts disease was always a stretch. The reality is more complex, but complexity does not sell pills.

Modern cardiology has begun to catch up with chemistry. Risk is now assessed through multiple markers: ApoB, Lp(a), triglycerides, fasting glucose, blood pressure, and inflammation. Treatments are chosen based on overall context, not a single threshold. For some, statins remain life-saving. For others, the wiser course is to fix diet, reduce inflammation, and leave well enough alone.

If I were to summarise the lesson of fifty years of cholesterol research, it would be this: biology does not reward reductionism. The cholesterol number is a proxy for a vast, self-regulating system. Trying to control it in isolation can help or harm depending on who you are. The right question is not how to lower cholesterol but how to maintain metabolic harmony. That means fewer processed fats, fewer refined carbohydrates, more physical activity, and less chronic stress. It also means resisting the temptation to turn every correlation into a cause.

We are finally beginning to see the outline of a more coherent picture. Cholesterol is one actor in a complex play involving oxidation, immunity, and time. It is not the villain medicine once imagined, nor the harmless bystander claimed by its defenders. It is a participant in the chemistry of life, shaped by every molecule we eat and every cell we repair. The better we understand that, the less we will need slogans like “good” and “bad” cholesterol and the more we can treat the human body as the subtle chemical reactor it is.

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A total cholesterol of 6.0 mmol/L looks high on paper, but the balance matters far more than the headline. The HDL is 2.23 mmol/L, which is excellent and well above the minimum target of 1.0. Triglycerides are 1.6 mmol/L, comfortably within range. That combination signals efficient lipid transport and low metabolic stress. The LDL figure of 3.0 mmol/L, calculated by the old Friedewald formula, sits in the moderate zone for someone without heart disease. These numbers describe a healthy system moving fats around, not one storing them.

Doctors often react to the total cholesterol figure alone, but modern research shows it is the ratio and inflammation status that count. A total to HDL ratio of 2.7 is excellent; anything under 4 is considered low risk. People with ratios like this and no other risk factors such as high blood pressure, diabetes, or smoking have a very low probability of cardiovascular events. Prescribing a statin for someone with these ratios would usually rely on a calculated 10-year risk score rather than a biochemical need.

If inflammation markers and lifestyle factors are sound, this profile does not justify panic or medication. It reflects a strong HDL system carrying excess lipids back to the liver and keeping arteries clear. Populations with average HDL around 2.0 mmol/L show the lowest rates of heart disease. In that light, a total cholesterol of 6.0 mmol/L with HDL at 2.23 mmol/L and triglycerides of 1.6 mmol/L is not a warning sign but an example of normal, balanced chemistry.