Can a Guacamole Overdose Kill You?-Part 3
The Rules & Take Home Messages on Plant Sterols & Premature Atherosclerosis.
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Here is the final installment on sitosterolemia. Please refer to the previous posts for the introduction and when to consider overabsorption of plant sterols.
https://pauldthompsonmd.substack.com/p/can-a-guacamole-overdose-kill-you
https://substack.com/home/post/p-155631190
So, let’s finish with the most important question of all: Can heterozygosity for defective ABCG5 or 8 genes causes coronary artery disease, such as in the case discussed in Part 1 of this topic?
In the study by Kathiresan and colleagues (1) mentioned in the first of these posts, LCL-C was 24.7 mg/dl higher in heterozygotes for ABCG5 and this group had a doubling of CAD risk. LCL-C levels and CAD risk were not elevated in the ABCG8 heterozygotes. The authors’ opinion (3) was that the “substantial increase in blood LDL cholesterol levels among individuals with the sitosterolemia causes atherosclerosis.” In other words, it’s the LDL and not the sitosterol that produces the atherosclerosis, and if the LDL is not elevated, as it was not with their ABCG8 heterozygotes, then there was no increase in CAD risk. But, as evidenced by the observation that patients with full-blown sitosterolemia have early atherosclerotic vascular disease, the possibility of heterozygosity for ABCG 5 or 8 should be considered in others with unexpectedly severe vascular disease.
One last but interesting point: Ketogenic diets have been associated with marked increases in LDL-C, as reported by two of my friends, Ira Goldberg and Robert Hegele. (2). Dr. Ernie Schaefer from Boston Heart Labs thinks that some of these reports, may be related to ABCG 5 or 8 heterozygosity. Dr. Schaefer and colleagues reported a 51 year old woman with a body mass index of only 18.5kg who used a ketogenic diet for depression and anxiety. Her LDL increased from 142 to 555 mg/ml on the diet.(3) Her beta-sitosterol level was also increased to 12.8 mg/dl. Sitosterolemia is generally defined as a value of 15 mg/dl, so this woman’s sitosterol was at the upper end of normal. Genetic analysis showed a pathologic variant in ABCG5, but she also had 2 variants of unknown significance in the gene for apolipoprotein B. Ketogenic diets often contain a lot of dietary cholesterol from sources such as egg yolks. When she was treated with a low cholesterol diet and ezetimibe, her LDL decreased to 159 mg/dl. Her sitosterol also decreased but did not normalize. Dr. Scheafer thinks that the combination of her ABCG defect, which increased cholesterol retention, and her high cholesterol diet produced the high LDL. Consequently, a very brisk increase in LDL on a ketogenic diet might also suggest defects in the genes for sitosterolemia.
So, here are the take-away rules from these three posts on sitosterolemia:
· Over absorption of plant sterols is caused by defects in the ABCG5 and ABCG8 genes. The disease sitosterolemia, named after the most abundant plant sterol, requires homozygosity for the defect or two-gene heterozygosity.
· ABCG5 and ABCG8 are proteins that excrete plant sterols back into the intestine so the sterol is not absorbed.
· Defects in these genes are rare, but not extremely rare, and are present in 1 in 500 individuals.
· These genetic defects are associated with increased cholesterol levels and increased atherosclerotic disease probably because the defects lead to increased cholesterol absorption, but sitosterol deposition may also contribute to the atherosclerosis.
· The presence of a homozygous genetic defect in ABCG5 or ABCG8 can be suspected when a young person has xanthomata or premature atherosclerotic.
· The presence of homozygosity for a genetic defect in ABCG5 or ABCG8 should also be considered when there is hemolytic anemia or a platelet disorder.
· Genetic defects in ABCG5 or ABCG8 can also be suspected in atherosclerotic disease more advanced than expected given other risk factors, if statins are ineffective in lowering LDL or if the LDL response to a low cholesterol diet, bile sequestrant resins or ezetimibe is exceptionally good.
· Elevated sitosterol levels can be determined by a blood test, and the genetic defects can be determined by genetic analysis, but both are rarely required.
· The key clinical issue in preventing disease is reducing the increased blood cholesterol level (and possibly by reducing blood phytosterol levels) caused by the increased absorption of cholesterol.
· Ezetimibe is the drug of choice for both sitosterolemia and heterozygotes for the disease because it decreases the increase in intestinal sterols.
· Bile-sequestrant resins are also very effective in lowering LDL in patients with these genetic defects.
· It is still not clear to me whether it is the increased cholesterol retention that is responsible for the early atherosclerosis or if the increased sitosterol also contributes. The experts I spoke to primarily blame the increase in cholesterol.
I have found this whole exercise very interesting. Before the Wall Street Journal article and my review, I did not know that being heterozygous for the genes that cause sitosterolemia could also contribute to atherosclerosis, but now I do.
Dr. Ernie Schaefer, Founder and Medical Director of Boston Heart Labs, advised me in preparing this post, but is not responsible for the final product..
1. Nomura, K ... Kathiresan S. Heterozygous ATP-binding Cassette Transporter G5 Gene Deficiency and Risk of Coronary Artery Disease. Circ Genom Precis Med. 2020 Oct;13(5):417-423. PMID: 32862661
2. Goldberg IJ, Ibrahim N, Bredefeld C, Foo S, Lim V, Gutman D, Huggins LA, Hegele RA. Ketogenic diets, not for everyone. J Clin Lipidol. 2021 Jan-Feb;15(1):61-67. PMID: 33191194
3. Schaefer EJ, et.al. Marked Low Density Lipoprotein Cholesterol Elevation on a Ketogenic Diet, Cholesterol Absorption, Lean Mass, and Heterozygous Sitosterolemia; Case Report, Large Population Analysis, and Review. J Clin Lipid
#atherosclerosis #coronaryartery #cholesterol #phytosteral #sitosterol #ezetimbie #bile