A recent piece in The Wall Street Journal addressed this topic in an article titled: “I Was in Great Health. So Why Were My Arteries Clogged?” The author led an active and healthy lifestyle, playing multiple sports, running, and maintaining fitness into his 60s. He transitioned from running to using an elliptical machine due to joint issues but remained committed to fitness. Despite no prior heart-related problems and no family medical history due to being adopted, the author was diagnosed with severe coronary artery disease after a routine cardiac calcium CT scan.
The scan revealed a high calcium score of 2,424, well above the threshold for coronary artery disease. Follow-up tests, including a second calcium scan and cardiac catheterization, confirmed significant but stable calcium deposits in his arteries. The author was initially prescribed a diet rich in nuts, vegetables, and certain oils, inadvertently worsening his condition due to their high levels of plant sterols. A lipidologist diagnosed the author with sitosterolemia, a rare hereditary disease in which plant sterols accumulate in the bloodstream, forming calcified plaque.
Sitosterolemia is a metabolic disorder in which the body absorbs and accumulates plant sterols (e.g., beta-sitosterol, campesterol, stigmasterol) at abnormally high levels. These plant-derived compounds, similar in structure to cholesterol (Figure 1), are typically excreted by the body in healthy individuals. Sterols are hydrophobic compounds possessing a distinctive fused four-ring structure (Figure 1) with hydroxyl (-OH) groups at specific positions. They are a key component of cell membranes and precursors for the synthesis of the closely-related steroid hormones.
The most severe cases arise through mutations in the ABCG5 or ABCG8 genes, which encode for proteins involved in regulating the excretion of plant sterols and cholesterol into bile and the intestinal tract. Loss-of-function mutations in the proteins prevent plant sterols from being secreted into the intestines after being absorbed leading to a dramatic increase in plant sterol levels in the blood. If a child inherits two copies of the mutant gene (homozygous) then the phenotype is more severe and may appear in childhood. If only one mutant copy is inherited (heterozygous), then the phenotype is milder without early symptoms.
As a reminder, cholesterol can be packaged into low density lipoproteins (LDL or bad cholesterol) which is ingested by macrophages forming cholesterol-engorged foam cells that build up on the walls of arteries promoting atherosclerosis. Presumably excess plant sterols can act in a similar fashion.
The most serious long-term consequences of sitosterolemia are atherosclerosis and coronary heart disease. These can lead to heart attacks, stroke, or sudden cardiac death, especially in cases with undiagnosed or untreated disease. Other symptoms include xanthomas, yellowish growths on the skin or tendons caused by fat deposits, and arthralgia or arthritis, i.e. joint stiffness and pain. Misdiagnosis may be common as it can be confused with other conditions like familial hypercholesterolemia.
Some subjects such as the author of the WSJ piece become aware of their condition from imaging the heart. A cardiac CT (Computed Tomography) scan is a noninvasive imaging test that uses X-rays to create detailed images of the heart and its blood vessels. One common type of cardiac CT is a coronary artery calcium (CAC) scan, which measures the amount of calcified plaque in the coronary (heart) arteries which is a sign of atherosclerosis. The scan does not require an injected dye and takes about 15 min overall (the scan itself is about 30 seconds).
The result of the CAC is expressed as an Agatston Score, which reflects both the density and area of calcified plaque with values between 0 and more than 400. Any score over 100 means that you are likely to have heart disease. The higher the score, the greater the chance of having a heart attack:
| Calcium Score | Risk Level | Interpretation |
|---|---|---|
| 0 | Low | No calcified plaque; very low risk of coronary artery disease. |
| 1–10 | Minimal | Small amount of plaque; low risk, but lifestyle adjustments may still be beneficial. |
| 11–100 | Mild | Some plaque is present; mild risk of CAD. Preventive measures (diet, exercise, possibly medication) recommended. |
| 101–400 | Moderate | Significant plaque; moderate risk of a heart attack or cardiovascular event. More aggressive management needed. |
| >400 | High | Extensive plaque; high risk of heart attack. Further testing or treatment strongly recommended. |
The primary disadvantage of cardiac CT is the radiation dose which can potentially induce cancer (the lifetime risk is very low, ~0.02%). The dose is roughly ten times more than a typical mammogram, and so it is safe but not insignificant. The author's Agatston Score was 2424 which is very high.
A more definitive diagnosis is made through specific blood tests for phytosterols (plant sterols) like beta-sitosterol. This test uses mass spectrometry (GC-MS) and so is not as routine as a standard lipid panel. It can be ordered by a specialist.
Fortunately if recognized early and managed properly, sitosterolemia has a good prognosis because of effective treatments which include the following:
- Dietary Changes: Avoid foods high in plant sterols, including nuts, seeds, certain oils (canola, olive), and fortified plant sterol products. Focus on low-sterol vegetables, meats, and other low-plant-sterol foods.
- Ezetimibe (Zetia): Blocks the absorption of plant sterols in the intestines, reducing levels in the bloodstream.
- Regular Monitoring: Periodic blood tests and imaging to track plaque buildup and disease progression.
The author was prescribed Zetia, which reduces sterol absorption, and shifted to a low-sterol diet. Zetia acts by inhibiting sterol absorption in the small intestine. In particular, it selectively blocks the Niemann-Pick C1-like 1 (NPC1L1) protein, which is responsible for the absorption of dietary sterols cholesterol and the reabsorption of sterols excreted in bile. The original focus was on cholesterol but it turns out NPC1L1 is also involved in absorbing phytosterols.
Sitosterolemia is considered to be rare, but it is likely underdiagnosed. The homozygous form (two mutant alleles) is extremely uncommon, with fewer than 100 documented cases worldwide. The heterozygous form (one mutant allele) is more frequent but remains poorly understood and under-recognized. In addition, sitosterolemia is almost certainly a multi-factorial trait with multiple genetic and environmental factors contributing to its expression which is likely to span a broad range of phenotypic severity.
Thus, its misdiagnosis is not surprising given the limited understanding of disease etiology, and that the diagnostic tests are not routine. In the future, cardiac CTs may become more prevalent and even may be used to screen patients in the same way as mammograms. For now cost and perhaps the radiation dose may restrict this possibility.
Misdiagnosis of sitosterolemia is especially dangerous because it is often mistaken for cholesterolemia whose treatment often is trying to consume more phytosterols (replacing cholesterol) which would make the condition worse.
Because the possibility of misdiagnosis is a fact of life, the patient must be alert and proactively advocate for their health, especially in the face of unclear diagnoses. Recommendations include regular screenings, seeking second opinions, and leveraging medical research databases to explore potential conditions. Medical expertise saves countless lives and forms the basis of a mostly sound healthcare system which continues to improve, and so it deserves our respect. However, there are gaps in medical understanding that patients need to be vigilant about.
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Figure 1. The chemical structures of the sterols cholesterol (left) and beta-sitosterol (right) which are similar. Both when present in the blood stream at high levels can lead to atherosclerosis.
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