9 ms·

Cholesterol and mortality: Evidence of a U-shape Relationship

121 points by hansmeierbaum 5y ago

pocw 5y ago
Can someone tl;dr? Not that the paper is too long, but I think I'd need to go back to university and major in biology or statistics to understand what they discovered and more importantly what it might mean.
- onlyrealcuzzo 5y ago
  When you have TC (total cholesterol) < 200 mg/dL (milligrams per deciliter) - each 1mmol/L (millimoles per liter) reduces mortality. When you have TC > 200 mg/dL - each 1mmol/L increases mortality. The confidence interval was high. > In the age groups of 18–34, 35–44, 45–54, 55–64, 65–74, and 75–99 years, each 1 mmol/L higher TC increased mortality by 14%, 13%, 8%, 7%, 6%, and 3%, respectively (P < 0.001 for each age group), for TC ≥ 200 mg/dL, while the corresponding TC changes decreased mortality by 13%, 27%, 34%, 31%, 20%, and 13%, respectively, in the range < 200 mg/dL (P < 0.001 for each age group). TC had U-curve associations with mortality in each age-sex group. TC levels associated with lowest mortality were 210–249 mg/dL, except for men aged 18–34 years (180–219 mg/dL) and women aged 18–34 years (160–199 mg/dL) and 35–44 years (180–219 mg/dL). The inverse associations for TC < 200 mg/dL were stronger than the positive associations in the upper range.
  - twoWhlsGud 5y ago
    Speculation in the discussion section is that while lower TC (below the limits cited above) is correlated with lower cardiac risk, it seems to be correlated with a higher risk of death. So the implication is there's something else bad for your health about being out of the sweet spot they observed in the data.
    - gumby 5y ago
      I remember reading about 20 years ago that low cholesterol was correlated with increased mortality due to increased incidence of suicide.
  - stavros 5y ago
    So basically the 170 mg/dL TC limit that my lab shows is very suboptimal, and I should go for 230 instead?
    - jeffbee 5y ago
      170 would be in the lowest quartile for American adults, no? Seems like an unreasonable limit.
      - stavros 5y ago
        I'm in Greece, but it seems fairly unreasonable here as well. Other labs have the limit at 200 (it varies per lab), but 170 seems too low.
        myle 5y ago
        Greeks tend to have higher "normal" cholesterol levels. In other labs I have seen in Greece, they write as the limit 200. I know of someone with TC around 240 and the doctor didn't prescribe statins. Not a medical advice.
    - sooheon 5y ago
      No. Please don't make health decisions off of incorrect inferences from observational studies. https://news.ycombinator.com/item?id=30893041 https://news.ycombinator.com/item?id=30893041
    - imtringued 5y ago
      Imagine you have container ships named HDL and it is loaded with containers called triglycerides. You don't know how many containers you have. You just know you have this many container ships. Do you have too many containers? Do you have too many ships? That question cannot be answered with just one absolute number. This is why the HDL to triglycerides ratio exists.
- SnowHill9902 5y ago
  There exists a non-zero total cholesterol (TC) concentration in blood which is correlated with the minimum all-cause mortality in human beings. Meaning: lower cholesterol is not always correlated with lower mortality.
- stavros 5y ago
  Here's the hazard graph for total cholesterol: https://www.nature.com/articles/s41598-018-38461-y/figures/2 https://www.nature.com/articles/s41598-018-38461-y/figures/2 230 mg/dL is associated with the lowest mortality, and anything below or above that increases mortality.
  - sooheon 5y ago
    > increases mortality Implies a causal relationship. In reality, it's much more likely that causality points the other way, and an underlying disease like cancer is causing low cholesterol: https://www.ahajournals.org/doi/10.1161/01.cir.92.9.2396 https://www.ahajournals.org/doi/10.1161/01.cir.92.9.2396
    - stavros 5y ago
      That's interesting, thank you.
  - tails4e 5y ago
    Is it correct that 230 mg/dl is 5.6mmol/l? We've always been told that we must keep the number below 5 at all costs for health, but this seems to be as bad as being above 6.3. Am I reading this correctly? If so, current medical advice is way off.
- sooheon 5y ago
  TLDR: this observational study replicated the known phenomenon that (seemingly paradoxically) low cholesterol is correlated with increased risk of mortality. It's an ongoing debate whether low cholesterol is directly bad for you, or it could itself be a marker of underlying disease like cancer. The authors admit this study is unable to shed further light on that debate due to lack of data on specific cause of death.
tmaly 5y ago
Am I the only one that seems to think there is some correlation is not causation here with the numbers?
- slacka 5y ago
  Agreed. I'd bet money that 20 years from now, the anti-cholesterol fad will be viewed just like the anti-fat fad. Cholesterol is an essential building/repair block that our body makes, with very little absorbed from diet.[1] Since cholesterol responsible for repairing damaged tissue in the body[2], how do we know know that inflamed, unhealthy individuals don't generate high cholesterol amounts for repair and not from an unhealthy diet? .... Time will tell. [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257636/#:~:text=The%20solubilization%20of%20cholesterol%20is,on%20partitioning%20into%20bile%20micelles https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257636/#:~:tex.... [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630197/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630197/
- sooheon 5y ago
  No, scientists have studied this phenomenon for decades. This is a study specifically interrogating the direction of causality for low cholesterol and mortality: https://www.ahajournals.org/doi/10.1161/01.cir.92.9.2396 https://www.ahajournals.org/doi/10.1161/01.cir.92.9.2396
  - rpmisms 5y ago
    But perhaps low cholesterol points to having less inflammation/other minor repair work the body has "backed up", and thus begs the question of why people have low or high cholesterol.
- imtringued 5y ago
  Consider the following scenario. "Bad chemical compound" (which is a close variant of "good chemical compound") exists in a concentration of 1% when your total level of "good chemical compound" exceeds Y. Therefore a high level of "good chemical compound" correlates with the harmful effects of "bad chemical compound". Does "good chemical compound" cause the harmful effects? No. Does it correlate? Yes. Now "good chemical compound" is the evil compound that must be lowered. Now imagine that there is a product that has a high degree of "bad chemical compound". So suddenly there are lots of people with low levels of "good chemical compound" but they suffer from the very same harmful effects that higher levels would predict! "Bad chemical compound" has been found in the product itself and therefore the product was banned. However, the fact that "good chemical compound" isn't the problem hasn't been recognized because detecting "bad chemical compound" in products is very easy due to the extremely high concentration but difficult (read expensive) to detect in the blood due to the much lower concentration. So the only "reliable" indicators that exist must be based around correlations because measuring the "bad chemical compound" isn't done. That was a long winded way of saying oxidization of cholesterol causes inflammation and the formation of plaque in blood vessels. Detecting oxidized LDL is possible but almost no lab does it. Instead you get spurious correlations, the most reliable of which is HDL to triglycerides.
osrec 5y ago
I wonder how this would look if we consider LDL, HDL and triglycerides individually... Perhaps that would be more telling than just considering total cholesterol.
- Terry_Roll 5y ago
  Diet is also a factor. Nicotinic Acid (vitamin B3) will lower Cholesterol because it converts cholesterol into hormones starting with Pregnenolone, 500mg of nicotinic acid on an empty stomach or fat free meal is the fastest cheapest way to get a growth hormone boost, if you can handle the prostaglandin 9sun burn) flush! https://en.wikipedia.org/wiki/Steroid_hormone#/media/File:Steroidogenesis.svg https://en.wikipedia.org/wiki/Steroid_hormone#/media/File:St... Manganese also affects cholesterol. https://pubmed.ncbi.nlm.nih.gov/3705654/ https://pubmed.ncbi.nlm.nih.gov/3705654/ "a favourable influence of manganese was shown which effected a decrease of the cholesterol content of serum, liver and aorta and inhibited the entry of lipids into the aorta. The influence of the manganese on various enzymes as well as a manganese-copper interaction are discussed as possible causes." Manganese is one of those minerals in constant decline from birth when Reactive Oxygen Species starts, before then we all get about 9months to build up levels in the body, provided the mother is healthy and has an healthy diet. And there isnt much discussion on the content of HDL. https://en.wikipedia.org/wiki/High-density_lipoprotein#Overview https://en.wikipedia.org/wiki/High-density_lipoprotein#Overv... And on the point of macrophage accumulation, no mention of how vit K1 keeps calcium out of tissue which prevents elastic fibres from hardening and thus causing their own problems. Thing is whatever science looks at can be portrayed in a positive or negative light.
  - awiesenhofer 5y ago
    The part about B3 sounds very interesting but whats a prostaglandin flush?
    - johncearls 5y ago
      Your skin turns read and feels hot, like a sunburn. It's the number one side effect of high dose niacin. There are some prescription extended release prescription niacins to reduce that effect, but it still happens. It's very uncomfortable, which is a real problem for something you take daily.
sooheon 5y ago
This is not a new finding. It's common enough to have a name: the cholesterol paradox (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374572/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374572/). Also replicated in a more recent n=100k Denmark study: https://www.bmj.com/content/371/bmj.m4266 https://www.bmj.com/content/371/bmj.m4266 These are all observational studies, meaning cause and effect is not established. It's relevant that people with some cancers will have very low cholesterol (the cancer apparently using it as fuel source), which reverts to normal in remission. Other medical conditions can lower serum cholesterol, from IBD to chronic liver disease (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271321/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271321/). If low cholesterol is inherently mortality inducing, lowering it directly in otherwise healthy people should cause more deaths. This is a testable hypothesis. The Denmark study found that people on statins (cholesterol lowering) did not die more, even when they were on the lower side of the U curve. There have also been countless RCTs with statins (or other cholesterol reduction drugs) being the only controlled intervention, finding that low TC improves total mortality. A long term study tracking change in total cholesterol found that people who always had low TC (genetically) did not have a higher risk of death, but those whose TC suddenly dropped from normal to low had a higher risk of cancer: "We observed a significant risk of cancer, noncardiovascular noncancer, and all-cause mortality in men whose TC levels changed to low (<180 mg/dL) from the middle (180 to 239 mg/dL) level at baseline." (https://www.ahajournals.org/doi/10.1161/01.cir.92.9.2396 https://www.ahajournals.org/doi/10.1161/01.cir.92.9.2396) These points together point to the low cholesterol -> high mortality link as being a biomarker of underlying disease, not a direct causal link. (Info taken from this video: https://www.youtube.com/watch?v=CxX51n2Z0vc https://www.youtube.com/watch?v=CxX51n2Z0vc) --- edit: skimmed the paper, authors mention everything in this post but have some counterpoints. They point to other longitudinal studies where consistently low cholesterol was a risk factor for death (a point against the sudden lowering due to cancer hypothesis). There are many studies like this, but the problem is while we have shown the link b/w cardiovascular death and high cholesterol through RCTs, there are no strong theories for the diseases caused by low cholesterol, while we know cancer and chronic liver disease cause low cholesterol. It could just be a marker of general frailty in old age.
- stavros 5y ago
  That's very informative, thank you.
wtetzner 5y ago
It’s high levels of _oxidized_ LDL that’s problematic. https://youtu.be/DXKJaQeteE0 https://youtu.be/DXKJaQeteE0
- flenserboy 5y ago
  Yes. There's also evidence that longer-lived people tend to have higher cholesterol levels.
elevenoh 5y ago
As a medical field outsider: Instead of basic linear / bell/U curve type ways of describing impact of biomarkers, are new ways of describing complex biomarker relations emerging into the vernacular? e.g. optimums within clusters/sets of biomarkers
- sooheon 5y ago
  There are efforts to study multivariate, nonlinear biomarkers, especially with the advent of deeper molecular profiling (i.e. transcriptome, proteome).
sacrosancty 5y ago
Why is most of that abstract not a graph, or at least a table? Is there some ridiculous constraint to prevent them making it legible?
- projektfu 5y ago
  Figures and tables are just usually not part of an abstract.
  - sacrosancty 4y ago
    They wrote it badly because everyone else does that too? I wonder if scientists will ever improve their illegibility problem. They work so hard to write in such a terrible way for no apparent reason.
twofornone 5y ago
>This suggests that a low cholesterol level should be interpreted as a biomarker of illness severity. What if we are just looking at genetic variations? I feel like medical science in general does not appreciate the magnitude of confounding likely caused by unevenly distributed alleles of all sorts, which would explain a lot of the conflicting papers. And this comes from a reluctance to assign people to genetic groups - because they would almost certainly map at least somewhat to what we call races, and that would have other, potentially uncomfortable implications. It's a deeply seated bias that is so totally normalized as to be virtually undetectable by those who suffer from it, but in some ways it holds back extremely beneficial progress in medical acience.
- kuhewa 5y ago
  I reckon accounting for generic variation in observational studies is more common then you are letting on, see mendelian randomisation. Also, in this type of research, race isn't the 'elephant in the room' that it seems you are implying, I mean it is already one of the most common stratifications used and disparities across racial lines in health outcomes are well recognised. The real barrier to a genetic understanding is with few exceptions, the affect of genes is really complicated.
owenversteeg 5y ago
I am personally convinced that we have an extremely primitive understanding of human biology and that we use the biomarkers we have (such as cholesterol) in grossly inappropriate ways. We've seen this story play out time and time again, with everything from vitamin D to HDL/LDL. Low levels of vitamin D are related to everything from depression to heart disease to diabetes, but a recent study gave people over 300% of their daily value of vitamin D every single day for 10 years and found zero improvement on a giant list of health metrics. The same with LDL/HDL: bad LDL/HDL numbers give you dramatically higher risk for heart disease and stroke, so people designed a drug that improves those numbers, but of course it does nothing for your actual health. We need to fix the actual, underlying causes of disease - lifestyle and diet - not hack the various biomarkers higher or lower until the numbers look good. I'm actually working on a startup to help with this, so if anyone's curious (about using it or just to discuss) my email's in my profile.
- mrslave 5y ago
  > not hack the various biomarkers higher or lower until the numbers look good Goodhart's law is an adage often stated as "When a measure becomes a target, it ceases to be a good measure". (Wikipedia)
- kkfx 5y ago
  The classic Italian/French MDs schools told simply 5 time HDL must be lower than LDL, but nowadays people want absolute numbers and interests around diets and meds just push debatable practice that might hold a bit of truth but are so vaporous to be a nonsense. Also about diet remember that just in the recent history we are shifted, without really scientific proofs behind, from saying "eggs are good, eat them at least one a day" to "egg are bad, limit them"; "blue fish are the protein of the see, eat them much" to "blue fish are pollutants collectors of the see, avoid them| etc, mostly following some lobbyist PR campaign dressed as science so just talking about diet it's complex. Again, the old school when medicine was not that much a business say: all animal foods help lower the LDL, so eggs, fish, cheese, meat help. Starchy foods (from potatoes to beans, rice, ...) do the opposite. Taking a global look from countries with more animal protein based diets and others with starchy foods based diets confirm that well, but such simple observations is considered flawed because there are too many variables in the middle, while no one really criticize modern studies that actually tend to fail proving anything, just claiming...

121 points by hansmeierbaum 5y ago

pocw 5y ago

Can someone tl;dr? Not that the paper is too long, but I think I'd need to go back to university and major in biology or statistics to understand what they discovered and more importantly what it might mean.

onlyrealcuzzo 5y ago
When you have TC (total cholesterol) < 200 mg/dL (milligrams per deciliter) - each 1mmol/L (millimoles per liter) reduces mortality. When you have TC > 200 mg/dL - each 1mmol/L increases mortality. The confidence interval was high. > In the age groups of 18–34, 35–44, 45–54, 55–64, 65–74, and 75–99 years, each 1 mmol/L higher TC increased mortality by 14%, 13%, 8%, 7%, 6%, and 3%, respectively (P < 0.001 for each age group), for TC ≥ 200 mg/dL, while the corresponding TC changes decreased mortality by 13%, 27%, 34%, 31%, 20%, and 13%, respectively, in the range < 200 mg/dL (P < 0.001 for each age group). TC had U-curve associations with mortality in each age-sex group. TC levels associated with lowest mortality were 210–249 mg/dL, except for men aged 18–34 years (180–219 mg/dL) and women aged 18–34 years (160–199 mg/dL) and 35–44 years (180–219 mg/dL). The inverse associations for TC < 200 mg/dL were stronger than the positive associations in the upper range.
- twoWhlsGud 5y ago
  Speculation in the discussion section is that while lower TC (below the limits cited above) is correlated with lower cardiac risk, it seems to be correlated with a higher risk of death. So the implication is there's something else bad for your health about being out of the sweet spot they observed in the data.
  - gumby 5y ago
    I remember reading about 20 years ago that low cholesterol was correlated with increased mortality due to increased incidence of suicide.
- stavros 5y ago
  So basically the 170 mg/dL TC limit that my lab shows is very suboptimal, and I should go for 230 instead?
  - jeffbee 5y ago
    170 would be in the lowest quartile for American adults, no? Seems like an unreasonable limit.
    - stavros 5y ago
      I'm in Greece, but it seems fairly unreasonable here as well. Other labs have the limit at 200 (it varies per lab), but 170 seems too low.
      - myle 5y ago
        Greeks tend to have higher "normal" cholesterol levels. In other labs I have seen in Greece, they write as the limit 200. I know of someone with TC around 240 and the doctor didn't prescribe statins. Not a medical advice.
  - sooheon 5y ago
    No. Please don't make health decisions off of incorrect inferences from observational studies. https://news.ycombinator.com/item?id=30893041 https://news.ycombinator.com/item?id=30893041
  - imtringued 5y ago
    Imagine you have container ships named HDL and it is loaded with containers called triglycerides. You don't know how many containers you have. You just know you have this many container ships. Do you have too many containers? Do you have too many ships? That question cannot be answered with just one absolute number. This is why the HDL to triglycerides ratio exists.
SnowHill9902 5y ago
There exists a non-zero total cholesterol (TC) concentration in blood which is correlated with the minimum all-cause mortality in human beings. Meaning: lower cholesterol is not always correlated with lower mortality.
stavros 5y ago
Here's the hazard graph for total cholesterol: https://www.nature.com/articles/s41598-018-38461-y/figures/2 https://www.nature.com/articles/s41598-018-38461-y/figures/2 230 mg/dL is associated with the lowest mortality, and anything below or above that increases mortality.
- sooheon 5y ago
  > increases mortality Implies a causal relationship. In reality, it's much more likely that causality points the other way, and an underlying disease like cancer is causing low cholesterol: https://www.ahajournals.org/doi/10.1161/01.cir.92.9.2396 https://www.ahajournals.org/doi/10.1161/01.cir.92.9.2396
  - stavros 5y ago
    That's interesting, thank you.
- tails4e 5y ago
  Is it correct that 230 mg/dl is 5.6mmol/l? We've always been told that we must keep the number below 5 at all costs for health, but this seems to be as bad as being above 6.3. Am I reading this correctly? If so, current medical advice is way off.
sooheon 5y ago
TLDR: this observational study replicated the known phenomenon that (seemingly paradoxically) low cholesterol is correlated with increased risk of mortality. It's an ongoing debate whether low cholesterol is directly bad for you, or it could itself be a marker of underlying disease like cancer. The authors admit this study is unable to shed further light on that debate due to lack of data on specific cause of death.

tmaly 5y ago

Am I the only one that seems to think there is some correlation is not causation here with the numbers?

slacka 5y ago
Agreed. I'd bet money that 20 years from now, the anti-cholesterol fad will be viewed just like the anti-fat fad. Cholesterol is an essential building/repair block that our body makes, with very little absorbed from diet.[1] Since cholesterol responsible for repairing damaged tissue in the body[2], how do we know know that inflamed, unhealthy individuals don't generate high cholesterol amounts for repair and not from an unhealthy diet? .... Time will tell. [1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257636/#:~:text=The%20solubilization%20of%20cholesterol%20is,on%20partitioning%20into%20bile%20micelles https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257636/#:~:tex.... [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630197/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630197/
sooheon 5y ago
No, scientists have studied this phenomenon for decades. This is a study specifically interrogating the direction of causality for low cholesterol and mortality: https://www.ahajournals.org/doi/10.1161/01.cir.92.9.2396 https://www.ahajournals.org/doi/10.1161/01.cir.92.9.2396
- rpmisms 5y ago
  But perhaps low cholesterol points to having less inflammation/other minor repair work the body has "backed up", and thus begs the question of why people have low or high cholesterol.
imtringued 5y ago
Consider the following scenario. "Bad chemical compound" (which is a close variant of "good chemical compound") exists in a concentration of 1% when your total level of "good chemical compound" exceeds Y. Therefore a high level of "good chemical compound" correlates with the harmful effects of "bad chemical compound". Does "good chemical compound" cause the harmful effects? No. Does it correlate? Yes. Now "good chemical compound" is the evil compound that must be lowered. Now imagine that there is a product that has a high degree of "bad chemical compound". So suddenly there are lots of people with low levels of "good chemical compound" but they suffer from the very same harmful effects that higher levels would predict! "Bad chemical compound" has been found in the product itself and therefore the product was banned. However, the fact that "good chemical compound" isn't the problem hasn't been recognized because detecting "bad chemical compound" in products is very easy due to the extremely high concentration but difficult (read expensive) to detect in the blood due to the much lower concentration. So the only "reliable" indicators that exist must be based around correlations because measuring the "bad chemical compound" isn't done. That was a long winded way of saying oxidization of cholesterol causes inflammation and the formation of plaque in blood vessels. Detecting oxidized LDL is possible but almost no lab does it. Instead you get spurious correlations, the most reliable of which is HDL to triglycerides.

osrec 5y ago

I wonder how this would look if we consider LDL, HDL and triglycerides individually... Perhaps that would be more telling than just considering total cholesterol.

Terry_Roll 5y ago
Diet is also a factor. Nicotinic Acid (vitamin B3) will lower Cholesterol because it converts cholesterol into hormones starting with Pregnenolone, 500mg of nicotinic acid on an empty stomach or fat free meal is the fastest cheapest way to get a growth hormone boost, if you can handle the prostaglandin 9sun burn) flush! https://en.wikipedia.org/wiki/Steroid_hormone#/media/File:Steroidogenesis.svg https://en.wikipedia.org/wiki/Steroid_hormone#/media/File:St... Manganese also affects cholesterol. https://pubmed.ncbi.nlm.nih.gov/3705654/ https://pubmed.ncbi.nlm.nih.gov/3705654/ "a favourable influence of manganese was shown which effected a decrease of the cholesterol content of serum, liver and aorta and inhibited the entry of lipids into the aorta. The influence of the manganese on various enzymes as well as a manganese-copper interaction are discussed as possible causes." Manganese is one of those minerals in constant decline from birth when Reactive Oxygen Species starts, before then we all get about 9months to build up levels in the body, provided the mother is healthy and has an healthy diet. And there isnt much discussion on the content of HDL. https://en.wikipedia.org/wiki/High-density_lipoprotein#Overview https://en.wikipedia.org/wiki/High-density_lipoprotein#Overv... And on the point of macrophage accumulation, no mention of how vit K1 keeps calcium out of tissue which prevents elastic fibres from hardening and thus causing their own problems. Thing is whatever science looks at can be portrayed in a positive or negative light.
- awiesenhofer 5y ago
  The part about B3 sounds very interesting but whats a prostaglandin flush?
  - johncearls 5y ago
    Your skin turns read and feels hot, like a sunburn. It's the number one side effect of high dose niacin. There are some prescription extended release prescription niacins to reduce that effect, but it still happens. It's very uncomfortable, which is a real problem for something you take daily.

sooheon 5y ago

This is not a new finding. It's common enough to have a name: the cholesterol paradox (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374572/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374572/). Also replicated in a more recent n=100k Denmark study: https://www.bmj.com/content/371/bmj.m4266 https://www.bmj.com/content/371/bmj.m4266 These are all observational studies, meaning cause and effect is not established. It's relevant that people with some cancers will have very low cholesterol (the cancer apparently using it as fuel source), which reverts to normal in remission. Other medical conditions can lower serum cholesterol, from IBD to chronic liver disease (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271321/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271321/). If low cholesterol is inherently mortality inducing, lowering it directly in otherwise healthy people should cause more deaths. This is a testable hypothesis. The Denmark study found that people on statins (cholesterol lowering) did not die more, even when they were on the lower side of the U curve. There have also been countless RCTs with statins (or other cholesterol reduction drugs) being the only controlled intervention, finding that low TC improves total mortality. A long term study tracking change in total cholesterol found that people who always had low TC (genetically) did not have a higher risk of death, but those whose TC suddenly dropped from normal to low had a higher risk of cancer: "We observed a significant risk of cancer, noncardiovascular noncancer, and all-cause mortality in men whose TC levels changed to low (<180 mg/dL) from the middle (180 to 239 mg/dL) level at baseline." (https://www.ahajournals.org/doi/10.1161/01.cir.92.9.2396 https://www.ahajournals.org/doi/10.1161/01.cir.92.9.2396) These points together point to the low cholesterol -> high mortality link as being a biomarker of underlying disease, not a direct causal link. (Info taken from this video: https://www.youtube.com/watch?v=CxX51n2Z0vc https://www.youtube.com/watch?v=CxX51n2Z0vc) --- edit: skimmed the paper, authors mention everything in this post but have some counterpoints. They point to other longitudinal studies where consistently low cholesterol was a risk factor for death (a point against the sudden lowering due to cancer hypothesis). There are many studies like this, but the problem is while we have shown the link b/w cardiovascular death and high cholesterol through RCTs, there are no strong theories for the diseases caused by low cholesterol, while we know cancer and chronic liver disease cause low cholesterol. It could just be a marker of general frailty in old age.

stavros 5y ago
That's very informative, thank you.

wtetzner 5y ago

It’s high levels of _oxidized_ LDL that’s problematic. https://youtu.be/DXKJaQeteE0 https://youtu.be/DXKJaQeteE0

flenserboy 5y ago
Yes. There's also evidence that longer-lived people tend to have higher cholesterol levels.

elevenoh 5y ago

As a medical field outsider: Instead of basic linear / bell/U curve type ways of describing impact of biomarkers, are new ways of describing complex biomarker relations emerging into the vernacular? e.g. optimums within clusters/sets of biomarkers

sooheon 5y ago
There are efforts to study multivariate, nonlinear biomarkers, especially with the advent of deeper molecular profiling (i.e. transcriptome, proteome).

sacrosancty 5y ago

Why is most of that abstract not a graph, or at least a table? Is there some ridiculous constraint to prevent them making it legible?

projektfu 5y ago
Figures and tables are just usually not part of an abstract.
- sacrosancty 4y ago
  They wrote it badly because everyone else does that too? I wonder if scientists will ever improve their illegibility problem. They work so hard to write in such a terrible way for no apparent reason.

twofornone 5y ago

>This suggests that a low cholesterol level should be interpreted as a biomarker of illness severity. What if we are just looking at genetic variations? I feel like medical science in general does not appreciate the magnitude of confounding likely caused by unevenly distributed alleles of all sorts, which would explain a lot of the conflicting papers. And this comes from a reluctance to assign people to genetic groups - because they would almost certainly map at least somewhat to what we call races, and that would have other, potentially uncomfortable implications. It's a deeply seated bias that is so totally normalized as to be virtually undetectable by those who suffer from it, but in some ways it holds back extremely beneficial progress in medical acience.

kuhewa 5y ago
I reckon accounting for generic variation in observational studies is more common then you are letting on, see mendelian randomisation. Also, in this type of research, race isn't the 'elephant in the room' that it seems you are implying, I mean it is already one of the most common stratifications used and disparities across racial lines in health outcomes are well recognised. The real barrier to a genetic understanding is with few exceptions, the affect of genes is really complicated.

owenversteeg 5y ago

I am personally convinced that we have an extremely primitive understanding of human biology and that we use the biomarkers we have (such as cholesterol) in grossly inappropriate ways. We've seen this story play out time and time again, with everything from vitamin D to HDL/LDL. Low levels of vitamin D are related to everything from depression to heart disease to diabetes, but a recent study gave people over 300% of their daily value of vitamin D every single day for 10 years and found zero improvement on a giant list of health metrics. The same with LDL/HDL: bad LDL/HDL numbers give you dramatically higher risk for heart disease and stroke, so people designed a drug that improves those numbers, but of course it does nothing for your actual health. We need to fix the actual, underlying causes of disease - lifestyle and diet - not hack the various biomarkers higher or lower until the numbers look good. I'm actually working on a startup to help with this, so if anyone's curious (about using it or just to discuss) my email's in my profile.

mrslave 5y ago
> not hack the various biomarkers higher or lower until the numbers look good Goodhart's law is an adage often stated as "When a measure becomes a target, it ceases to be a good measure". (Wikipedia)
kkfx 5y ago
The classic Italian/French MDs schools told simply 5 time HDL must be lower than LDL, but nowadays people want absolute numbers and interests around diets and meds just push debatable practice that might hold a bit of truth but are so vaporous to be a nonsense. Also about diet remember that just in the recent history we are shifted, without really scientific proofs behind, from saying "eggs are good, eat them at least one a day" to "egg are bad, limit them"; "blue fish are the protein of the see, eat them much" to "blue fish are pollutants collectors of the see, avoid them| etc, mostly following some lobbyist PR campaign dressed as science so just talking about diet it's complex. Again, the old school when medicine was not that much a business say: all animal foods help lower the LDL, so eggs, fish, cheese, meat help. Starchy foods (from potatoes to beans, rice, ...) do the opposite. Taking a global look from countries with more animal protein based diets and others with starchy foods based diets confirm that well, but such simple observations is considered flawed because there are too many variables in the middle, while no one really criticize modern studies that actually tend to fail proving anything, just claiming...