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

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