Cholesterol is a biochemical found in cell membranes and particularly abundant in the fatty sheaths that insulate nerve cells; 25% of the body's cholesterol is in the brain. It is also a precursor molecule to hormones such as oestrogen and testosterone. It becomes troublesome when it accumulates in the walls of arteries, where it provokes the formation of structures called plaques. These may rupture and create blood clots that block arteries, leading to heart attacks and strokes. A third of heart attacks and a fifth of strokes are blamed on too much "bad" cholesterol or too little "good" cholesterol, or both.
Cholesterol is packaged for transport in the bloodstream as nanoparticles called lipoproteins. These comprise various fats, proteins and other molecules and shuttle cholesterol between the cells that use it and the liver, where it is made. Low-density lipoproteins (LDLs) deliver cholesterol to cells in need; once they have dropped it off they return to the liver for disposal. High-density lipoproteins (HDLs) collect surplus cholesterol—mopping up the cholesterol from dead cells, for example—and carry it back to the liver. Together, LDLs and HDLs account for 80-90% of the cholesterol in circulation. Plaque formation happens when too much LDL cholesterol is deposited in arterial walls faster than HDLs can clear it away.
Medical understanding has evolved beyond the simple dichotomy of "bad" LDL and "good" HDL cholesterol. Several additional risks are now recognised.
Around a fifth of people carry a genetic variant that causes their bodies to make a troublesome protein called apolipoprotein(a), which attaches itself to standard LDLs to create lipoprotein(a), or Lp(a), particles. People with high levels of Lp(a) are several times more likely to develop premature heart disease. These high-risk patients often pass standard cholesterol checkups—which do not look for Lp(a)—with flying colours. Lp(a) levels are impervious to changes in diet or lifestyle, though drugs from Amgen, Eli Lilly and Novartis are on the horizon.
Remnants are leftovers of large lipoproteins such as chylomicrons that have delivered their cargo of other molecules. They typically carry several times more cholesterol than an ordinary LDL particle. Although remnants are larger than LDLs, making it harder for them to penetrate the arterial wall, the proteins and fats on their surfaces can do serious damage. On a per-particle basis, remnants are up to four times more likely to cause heart disease than LDLs.
Scientists now think the problem may be too many LDL-like particles rather than too much of their cholesterol cargo. Each potentially problematic lipoprotein is wrapped in a single strand of apolipoprotein-B (ApoB). Counting ApoB thus offers a simple measure of the number of dangerous particles. The European Society of Cardiology endorses ApoB as a better way to measure cardiac risk, but this has not yet trickled into the calculators used by most doctors in Europe and America. Some 20-30% of people have low LDL-cholesterol but also high ApoB; this group are falsely reassured by typical checkups.
In 2012 a research team led by Sekar Kathiresan of Harvard Medical School reported that people with gene variants raising HDL-cholesterol did not have lower rates of heart attacks. Both low and very high HDL-cholesterol are now understood as signs of trouble, with mid-range levels seen as healthy. Very high HDL-cholesterol—found in 3-10% of people—has been linked to diabetes, non-alcoholic fatty-liver disease, chronic kidney disease, age-related macular degeneration, Alzheimer's and cancer. Some scientists now think dysfunctional HDL may be as bad as LDL.
HDL's jobs in the body are many and varied: it picks up bacterial toxins, blocks harmful enzymes, supports the immune system, fights inflammation, prevents artery damage, supports tissue repair, reduces blood clots and helps control metabolism. Some 280 proteins and counting are thought to be part of HDLs, but each particle carries only a subset of two or three. Working out which proteins sit on the more dangerous HDL particles remains a challenge.
Statins, widely available since the 1990s, boost clearance of LDL by the liver, reducing the rate of heart attacks. A genetic variant carried by one person in 250, which blocks the clearance of LDLs by the liver, is linked to a 20-fold increased risk of developing heart disease, often before middle age.
Six Nobel prizes have so far marked the emerging understanding of cholesterol science.
O'Brian's Law: Everything is always done for the wrong reasons.