Low Cholesterol Part 2: Genetically Low Cholesterol Levels

Follow-up to Low Cholesterol Part 1: Stroke and Depression.

There are a number of different types of people with genetically low LDL cholesterol levels, which normally results in somewhat lower total cholesterol (much lower in some individuals) and much less heart disease. Whether these people suffer from depression, stroke, failure to thrive, or low steroid hormones cannot necessarily be extrapolated to people who have very low cholesterol due only to diet. I also don’t know that rates of these conditions have been measured in such people (none were in the studies below), though there apparently hasn’t been an alarming amount.

It is my understanding that the people with familial hypolipoproteinemia have an inability to produce the protein fraction of the LDL, not the cholesterol portion. They definitely have less cholesterol in their blood, but this doesn’t mean they have less cholesterol in their tissues. Whereas someone with very low cholesterol in their blood due to diet might have lower cholesterol levels in their tissues.

Some readers sent me links to show that people with genetically low LDL levels have longer life spans. I checked out all the links, and followed some of them even further. Unfortunately, none answered the questions I have, but I found the information interesting enough to pass on.

PCSK9 Genetic Variant

People with a mutation in the PCSK9 gene were followed for 15 years in the Atherosclerosis Risk in Communities study from the USA (1). There are at least two variants of this mutation and in the study, 2.6% of black people had one variant that lowered their LDL cholesterol levels by 26% and their risk of heart disease by 88%. This roughly lowered their risk of having a coronary event from 1 in 10 to 1 in 100 during the 15-year time interval. Another variant was found in 3.2% of white people and lowered LDL levels 15% and their risk of heart disease by about 50%.

One would think that this reduction in heart disease would lead to a reduction in mortality, but the authors state, “[I]t is not known whether the beneficial effect of decreased LDL cholesterol levels on cardiovascular disease results in an overall reduction in mortality rates.” Interestingly, the average total cholesterol of the white people with the genetic variant was a whopping 194 mg/dl. For the black people it was 172 mg/dl.

Familial Hypolipoproteinemia

One reader sent me some links to articles on people with familial hypolipoproteinemia which results in very low LDL levels. Here is a run down of the papers:

Steinberg D, Glass CK, Witztum JL. Evidence mandating earlier and more aggressive treatment of hypercholesterolemia. Circulation. 2008 Aug 5;118(6):672-7 (link)

This is a review article that says, “Third, in some kindreds with hypobetalipoproteinemia, LDL cholesterol levels can be < 15 mg/dL throughout life, yet the affected members show perfectly normal growth and development and actually have increased longevity. (40, 41)”

Citation 40, from that quotation directly above, is this paper:

Steinberg D, Grundy SM, Mok HY, Turner JD, Weinstein DB, Brown WV, Albers JJ. Metabolic studies in an unusual case of asymptomatic familial hypobetalipoproteinemia with hypolphalipoproteinemia and fasting chylomicronemia. J Clin Invest. 1979 Jul;64(1):292-301 (link)

It is an article describing one man, age 67, known as “HJB” with an unusual variant of hypobetalipoproteinemia and a total cholesterol level of 47 mg/dl. It doesn’t discuss longevity of such people in general.

Citation 41 is:

Young SG, Bertics SJ, Curtiss LK, Dubois BW, Witztum JL. Genetic analysis of a kindred with familial hypobetalipoproteinemia. Evidence for two separate gene defects: one associated with an abnormal apolipoprotein B species, apolipoprotein B-37; and a second associated with low plasma concentrations of apolipoprotein B-100. J Clin Invest. 1987 Jun;79(6):1842-51 (link)

This paper describes 19 members of HJB’s family (including HJB), whose total cholesterol levels ranged from 31 mg/dl (HJB himself, by this time) to 130 mg/dl, with an average of 84 mg/dl. The only mention of longevity was that HJB was in excellent health at age 75, one of his family members had lived to 95, and one was said to have lived to 105.

Another study passed on by this reader:

Glueck CJ, Kelley W, Gupta A, Fontaine RN, Wang P, Gartside PS. Prospective 10-year evaluation of hypobetalipoproteinemia in a cohort of 772 firefighters and cross-sectional evaluation of hypocholesterolemia in 1,479 men in the National Health and Nutrition Examination Survey I. Metabolism. 1997 Jun;46(6):625-33. (link)

It doesn’t appear to be available in electronic form; so going by the abstract, this study measured the rates of genetically low LDL and total cholesterol levels among male firefighters in Cincinnati. It didn’t measure heart disease or mortality risk.

Finally, in the order they were presented to me, there is a study which actually does appear to suggest that people with familial hypolipoproteinemia live longer:

Glueck CJ, Gartside P, Fallat RW, Sielski J, Steiner PM. Longevity syndromes: familial hypobeta and familial hyperalphalipoproteinemia. J Lab Clin Med. 1976 Dec;88(6):941-57 (link)

It was a study of 26 different families with familial hypolipoproteinemia. The abstract says, “Expectation of life for males and females from kindreds with hypobeta lipoproteinemia was 9 and 12 years longer (p less than or equal to 0.002) than that indicated by population statistics for U.S. white populations, whereas expectation of life for males and females from kindreds with hyperalpha lipoproteinemia was 5 and 7 years longer (p less than 0.02).”

This paper was not available online or at my local university library (UC Davis), but I’m hoping to get a copy at some point. And there should be some caution here in suggesting this is proof that genetically low LDL increases life expectancy by 5 to 12 years. Comparing disease rates to the average population does not allow for much adjustment for confounding variables of which there could be many in these 26 families compared to the population at large. But even if such people do have longer life spans, it doesn’t shed much light on the questions I have. As I mentioned in Low Cholesterol: Part 1, I’m not debating whether low LDL prevents heart disease, there is good evidence that it does.

Hunter-Gatherer Populations

The above studies were done on people with genetic mutations, not your average people. The commenter who sent me those studies also said that “Optimal low density lipoprotein is 50 to 70 mg/dl; lower is better and physiologically normal” [my emphasis]. What does “physiologically normal” mean? Read on…it might mean the average cholesterol of people who are very active, eating a diet of about 20% fat.

As evidence, the commenter linked to:

O’Keefe J, Jr, Cordain L, Harris W, Moe R, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: Lower is better and physiologically normal. J Am Coll Cardiol. 2004;43(11):2142-2146 (link)

This is merely a review article that says, “Evidence from hunter-gatherer populations while they were still following their indigenous lifestyles showed no evidence for atherosclerosis, even in individuals living into the seventh and eighth decades of life (15,16). These populations had total cholesterol levels of 100 to 150 mg/dl…”

Citation 15 from the quotation above is a citation for yet another review:

Cordain L, Eaton SB, Miller JB, Mann N, Hill K. The paradoxical nature of hunter-gatherer diets: meat-based, yet non-atherogenic. Eur J Clin Nutr. 2002 Mar;56 Suppl 1:S42-52 (link)

It says:

“Over the past 64y, anthropological research has consistently demonstrated relatively low serum cholesterol and triacylglycerol levels among indigenous populations that derive the majority of their diet from animal products (Bang & Dyerberg, 1980; Biss et al, 1971; Corcoran & Rabinowitch, 1937; Day et al, 1976; Eaton et al, 1988a; Leonard et al, 1994; Scott et al, 1958; Shaper et al, 1961; Wilber & Levine, 1950).”

I obtained two papers from this list (and could find no abstract for a third, Bang & Dyerberg):

Biss K, Ho KJ, Mikkelson B, Lewis L, Taylor CB. Some unique biologic characteristics of the Masai of East Africa. N Engl J Med. 1971 Apr 1;284(13):694-9 (link)

The Masai, an East African Tribe that had intermingled very little with other African tribes, had a very interesting diet (when this paper was published). They ate mostly milk, 3 – 5 liters per day. They also ate cow’s blood, and the meat of cattle, goats, and sheep. Yet their cholesterol levels were very low, an average of 135 mg/dl. How did they do it?

The authors of the study did an experiment in which they challenged some of the Masai with 2,000 mg of cholesterol per day for 8 weeks! They did not have higher levels of cholesterol excretion (or lower absorption) but rather showed an impressive ability to decrease their internal cholesterol production in the face of eating such high amounts. Autopsies of some of the Masai showed them to have a “paucity of atherosclerosis.”

In other ways, the Masai are (or were) not doing so well with high rates of malaria and tuberculosis.

I don’t think the Masai’s situation can shed much light on what normal physiological cholesterol levels would be for people not in their genetic situation. I didn’t bother looking up the older citations from Cordain et al, but did check out the one from 1994:

Leonard WR, Crawford MH, Comuzzie AG & Sukernik RI (1994): Correlates of low serum lipid levels among the Evenki herders of Siberia. Am. J. Hum. Biol. 6, 329 – 338 (link

The Evenki had an average total cholesterol level of 139 mg/dl for men and 148 mg/dl for women. Despite eating large amounts of animal products, their diets were only 18-19% fat.

The researchers thought that the Evenki’s low cholesterol levels were primarily due to their high activity; the men were more active in herding than the women, cholesterol increased with age in the men only, and the men who lived in the village rather than the herding areas had higher levels. The differences in cholesterol levels could not be explained only by differences in body weight.

The authors said, “Among the African pastoral groups, only the Masai have lower total cholesterol levels than the Evenki.” Longevity and heart disease were not mentioned. Unlike the Masai, the Evenki do not appear to have a genetic propensity for keeping cholesterol low (though this cannot be ruled out).

Interestingly, Cordain also says:

“For the majority (53% n=122) of the world’s foraging cultures the dietary fat intake would lie between 36 and 43% of total energy (Cordain et al, 2000a), values not dissimilar from current Western intakes (McDowell et al, 1994). Despite this dietary characteristic, the available evidence suggests that hunter-gatherers were generally free of the signs and symptoms of [cardiovascular disease].”

I didn’t track down the citations for that statement.

Citation 16 from O’Keefe (above) is to another paper by Cordain and I decided not to track down any more of Cordain’s references as this was taking too much time and shedding very little light on my question of whether a cholesterol of ≤100 mg/dl, caused by diet and not genetic variants, could result in some vegans not thriving.

I have not answered the question about low cholesterol levels (from diet) and steroid hormone production. None of the studies I reviewed in these posts addressed those questions and I hope to look into it more after going through the backlog of other studies I intend to post about.

I don’t mean to dig my heels in and be hyper-skeptical, but I just don’t think these populations exclude the possibilities of very low cholesterol being a problem in failure to thrive for some people.

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References

1. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006 Mar 23;354(12):1264-72. | link

19 Responses to “Low Cholesterol Part 2: Genetically Low Cholesterol Levels”

  1. Dan Says:

    In JUPITER, 4,154 patients had an LDL concentration less than 50 mg/dL (median was 44 mg/dL in this group – pre-treatment it was 103 mg/dL). Here is what they write about this group: “Rates of myalgia, muscle weakness, and myopathy were not significantly different among rosuvastatin-allocated patients with and without LDL-C <50 mg/dl. Diabetes mellitus as an adverse event was reported more frequently among rosuvastatin-allocated patients attaining LDL-C <50 mg/dl than among rosuvastatin-allocated patients who did not attain LDL-C < 50 mg/dl, but this difference was not significant (1.6 vs. 1.2 per 100 person-years, p = 0.70). Rates of psychiatric adverse events, fatigue, peripheral neuropathy, cancer, hematuria, proteinuria, and renal failure did not differ between the rosuvastatin and placebo groups. Reports of hematuria were more frequent (p = 0.03) in rosuvastatin-allocated patients with LDL-C <50 mg/dl when compared with placebo, whereas depression (p =0.005) and colon cancer (p = 0.04) were reported less frequently."

    These patients also experienced significantly less all cause mortality and CV events.

    In the discussion section, they state: "Depression, anxiety, aggression, fatigue, cognitive impairment, and insomnia have been ascribed to statins through a variety of proposed mechanisms, including localized low cholesterol levels in the brain, transient hypoperfusion, impairment of blood-brain barrier function, and mitochondria-mediated effects (9,13,33). In the JUPITER study, rates of psychiatric adverse events were similar in the placebo and rosuvastatin groups, and in subjects with and without LDL-C <50 mg/dl."

    If having a low cholesterol is causal for depression or fatigue, this very well-powered trial certainly fails to support that hypothesis. Admittedly they studied statin and not diet for inducing dramatic cholesterol drops, but in the end the intermediate outcome (total cholesterol) would be similar to your cases with very low cholesterol and failure to thrive on vegan diets. But here we have hard statistical numbers, with a large sample size (http://www.ncbi.nlm.nih.gov/pubmed/21492764).

  2. AFD Says:

    Sorry, off-topic.

    Can you please give some information about defatted peanuts? They are said to contain more than 50% protein. Are they the same as peanut flour? Can you eat them the way they are or only use them for baking?

  3. Jack Norris RD Says:

    AFD,

    That’s a job for Google!

  4. idan Says:

    Jack can you elaborate on this :
    “They definitely have less cholesterol in their blood, but this doesn’t mean they have less cholesterol in their tissues. Whereas someone with very low cholesterol in their blood due to diet might have lower cholesterol levels in their tissues. ”

    Why do you think there is a difference – Is it because you think that the genetic variant might influence only the blood cholesterol (effect only the liver?) and therefor other tissues will be ok , While with a diet that lower cholesterol it might effect every kind of tissue ? Or is it something else ?

  5. Jack Norris RD Says:

    Idan,

    > Why do you think there is a difference – Is it because you think that the genetic variant might influence only the blood cholesterol (effect only the liver?) and therefor other tissues will be ok

    I will try to look into this as soon as I can, but these genetic variants are not a lowered ability to produce cholesterol, they are a lowered ability to produce the protein that transports the cholesterol.

  6. Dan Says:

    iDan, the brain has its own HMG-CoA reductase to manufacture (synthesize) local cholesterol. Statin drugs that cross the blood brain barrier reduce cholesterol manufacturing in both the brain and the liver, yet rarely cause severe depression or dementia (actually, there’s evidence they’re protective against both). This is despite very large reductions in cholesterol that are sustained for years. No signal of major brain toxicity has emerged with these drugs which have been in use now since 1987.
    Jack, I finished reading Chapter 15 in your book (chapter titled ‘Why vegan?’). Very powerful stuff. I would like to know what I can do to better promote veganism and reduce animal suffering. Does one go to vegan outreach and order brochures/pamphlets (do you ship to Canada)? I can hand these out on my university campus, right outside the student gym……thoughts?

  7. Jack Norris RD Says:

    Dan,

    > the brain has its own HMG-CoA reductase to manufacture (synthesize) local cholesterol. Statin drugs that cross the blood brain barrier reduce cholesterol manufacturing in both the brain and the liver, yet rarely cause severe depression or dementia (actually, there’s evidence they’re protective against both).

    Why didn’t you tell me this a long time ago?! But do the statins prevent the production of cholesterol in the brain, or just the production of LDL? I assume it’s all cholesterol, but I want to be sure.

    > Does one go to vegan outreach and order brochures/pamphlets (do you ship to Canada)? I can hand these out on my university campus, right outside the student gym……thoughts?

    Yes, we ship to Canada. You can order here:

    http://www.veganoutreach.org/catalog/index.html

    Hand them out wherever you’re allowed to and there is the most students. You can look up the info for your college to see if we have any suggestions in the School search box in the sidebar at the Adopt a College site:

    http://adoptacollege.org/

    LMK if you need anything else and let us know how it goes!

  8. AFD Says:

    That’s fine. You may use whatever source you want for your article 😉

  9. Jack Norris RD Says:

    AFD,

    I have to admit I laughed at that one! 🙂

  10. Mike Says:

    Hello everyone!
    I believe I have familial hypobetalyoproteinemia. I only say “I believe” because I have not had any genetic tests done. My last total cholesterol test was 80 mg/dL.
    LDLcalc was 24 mg/dL.. HDL was 39 mg/dL. Triglyc was 132 mg/dL . Vitamin D was 35 in a 30-100 ng/mL range. Apo B was 30 in a 52-109 mg/dL range. My question is this.. besides vitamin supplementation, is there anything I can do to raise my cholesterol? I believe with certainty this is the cause of depression, anxiety, low testosterone, etc.. The only thing I have seen to possibly raise cholesterol is :

    http://www.nbnus.net/shopexd.asp?id=399

    It is mostly marketed towards children with autism as they have found that autistic kids have lower than normal cholesterol levels.

    I believe there are many types of hypob and I do not believe it affected me in my youth but only later in life. I would say around turning 16 or 17 it all went downhill. I am 33 now.

  11. Jack Norris RD Says:

    Mike,

    Increasing saturated fat intake, though I don’t know if that can increase cholesterol in someone with familial hypobetalipoproteinemia.

    It sounds like you are depressed. I wouldn’t automatically assume it’s because of low cholesterol – you should probably see a health professional who is an expert in depression about your situation.

  12. Zeleni Says:

    Mike,

    I wad diagnosed with familial hypobetalipoproteinemia after having undetectable levels of LDL. I ate a tablespoon of coconut oil and quickly brought my LDL up to 40 mg/dl. Avocado, other saturated fats, and exercise are supposed to help. FHBL makes it more difficult to absorb fats and fat soluble vitamins – fats and vitamin supplements can help. Interestingly, my doctor told me my vegan diet is probably a good fit, since I would likely have a hard time absorbing animal fats. Good luck!

  13. Mike Says:

    Zeleni,

    Did you add the coconut oil to your foods? And was this something you did daily? I do take vitamins A,D,E and K and I am currently on TRT because testosterone was so low. Did you find that this affected your hormone levels at all?

  14. Zeleni Says:

    Mike,

    I typically ate coconut oil with food. Sometimes I’ll just eat it straight, add it to my coffee, cook with it instead of olive oil, etc. I did take it daily before getting my levels retested. I’m also supplementing with vitamins – the coconut oil is supposed to help with absorption. I didn’t get tested for hormone levels, so I’m not sure of its impacts.

  15. Kristy Says:

    Jack, do you know if it’s possible to have familial hypolipoproteinemia if HDL is high? My HDL is 78, LDL is undetectable, and triglyceride level is 45. I am a (seemingly) healthy 36 year old female although I have had bouts of anxiety/depression throughout my life. Just wondering if I should see a doctor about my cholesterol levels because the doctor that took the test seems to think I should just be thankful for low cholesterol.

  16. Jack Norris RD Says:

    Kristy,

    Familial hypolipooproteinemia can be specific to LDL. Are you vegan?

    20-50 ng/ml is considered the healthy range according to the Institute of Medicine, so I wouldn’t worry too much about your vitamin D level. Maybe supplement during the winter since it’s on the lower side of healthy.

  17. Kristy Says:

    I just wanted to add that I also have low vitamin D (24 ng/ml) despite being outdoors for many hours a week in the middle of summer in the southern U.S.

  18. Kristy Says:

    Thanks for the info! No, I’m not vegan. I have a pretty standard diet, but without many processed foods. I have been educating myself about the vegan lifestyle and have just recently begun to move in that direction.

  19. Rick Says:

    For whatever it is worth, I have just been diagnosed with FHBL as well. I was made to feel like a hypochondriac by family members, and also told to be thankful for the low cholesterol and longevity it may bring.
    I also have low testosterone (in the 220s at the age of only 47 when it was first discovered). I am also on TRT. If you are a man with low LDL (mine is under 20, and measured 2 last time around), you DEFINITELY need to get your T levels checked! It is vital to much more than your sex life! It will help with fatigue, bone density, etc.
    I had my kids tested after the diagnosis. My 11 year old daughter is almost the same as I – total 83, HDLs in 50s, LDLs in 20s. My 9 year old son is at 155 total with an HDL in upper 70s.
    I have fatty liver, idiopathic chronic pancreatitis, and low testosterone. My memory seems to be getting reeaally bad, and I believe it is related.
    I could feel pressure in my liver area, and was unable to sleep on my right side without discomfort. I am now on a low fat, low carb diet (pre-diabetic) and that has made a huge difference. I can now lay on my right side w/out much irritation.

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