生物与医学2019nature.com
总胆固醇与全因死亡率：一项针对 1300 万成年人的研究
Total cholesterol and all-cause mortality – a study among 13M adults
进阶 · 约 30 分钟读完前置知识：流行病学基础、观察性研究设计、胆固醇与脂蛋白基础
导读
这项研究利用约1300万成年人的大规模数据，考察总胆固醇水平与全因死亡率的关联，报告了U型关系：总胆固醇过低和过高都与较高的全因死亡率相关。但这是观察性分析，不能直接推断因果，且是否校正他汀使用等混杂因素成为讨论焦点。
HN 关注点：大规模观察性研究里的U型曲线是否只是反向因果或混杂（尤其未校正他汀使用）的产物，以及总胆固醇这个复合指标是否真有解释力。
HN 评论精选
这几条评论里：质疑 3 补充 1
质疑未校正他汀使用会造成适应症混杂，使研究结论不可靠。
研究方法似乎没有说明是否对使用他汀类药物做了调整！如果未考虑他汀使用，就会因适应症混杂得出错误结论。补充：我找到了——他们确实没有校正他汀使用！因此他们的结论似乎都不成立。
carbocation查看英文原文
The study methods don't seem to indicate whether they adjusted for statins! If they failed to account for statin use, then they will get the wrong answer due to confounding by indication. https://twitter.com/skathire/status/1110909549811322880 Edit: Found it - they are not accounting for statin use! None of their conclusions seem warranted.
质疑低胆固醇与死亡率的关联可能是疾病导致的逆向因果，而非低胆固醇本身有害。
这不是新发现，已有名称叫“胆固醇悖论”，后续丹麦10万人研究也复现了。这些都是观察性研究，不能确立因果。某些癌症会使胆固醇很低（癌症似乎把它当燃料），缓解后恢复正常；IBD、慢性肝病等也会降低血清胆固醇。如果低胆固醇本身会致死，那么健康人降胆固醇应导致更多死亡，这是可检验假设；但丹麦研究发现服他汀者即使处于U型低端也未死亡更多，大量他汀RCT也显示低总胆固醇改善总死亡率。长期追踪还发现天生低TC者死亡风险不更高，而TC从正常骤降到低者癌症风险更高。
sooheon查看英文原文
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/). Also replicated in a more recent n=100k Denmark study: 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/). 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) 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) --- 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.
质疑U型曲线可能反映逆向因果：低胆固醇者是因病而低，而非低胆固醇导致死亡。
我的疑问是，这里的U型曲线是否和酒精的J型曲线类似：不喝酒的人往往已有病或是戒酒者，造成不喝酒反而更不健康的假象。这里是否也可能低胆固醇与患病个体相关？我们不知道本研究中个体低TC的原因。
dnhz查看英文原文
My question is that whether the U-shaped curve found here is caused by similar phenomena as the J-shaped curve previously found for alcohol. That is, for alcohol, individuals who drank no alcohol tended to have disease or be recovering alcoholics, and so that association made it seem that drinking no alcohol was less healthy than drinking some alcohol. Here too, is it possible that having low cholesterol is associated with individuals with disease? We don't know what caused different individuals to have low TC here.
补充总胆固醇是复合指标，不能反映脂蛋白组分和颗粒数，临床解释力有限。
我觉得奇怪，如此大规模研究只看一个复合指标。总胆固醇包含HDL（apo A-I）、LDL、VLDL、IDL（apo B）等，决定心血管健康的是各组分比例而非总和；而且浓度不如颗粒数重要，但颗粒数不易测量。测总胆固醇就像测医院平均体温。发现U型不错，但会促使患者和医生只盯着TC数字，而不理解脂蛋白组成对健康的影响。
keymone查看英文原文
I find it strange that research of this scale is looking exclusively at a compound metric. TC is HDL (apo A-I), LDL, VLDL, IDL (apo B) and few more things. Its different proportions of these things that define how healthy your cardiovascular system is, not the total sum. To complicate even more - those things are usually measured as concentrations (mass/volume) while much more important metric is particle count, but that’s not easy/cheap to measure. Considering how complex this system is, measuring TC is like measuring average body temperature in the hospital. It’s cool that they found a U-shape but this approach just makes patients(and doctors) hack the TC number without understanding how that affects lipoprotein composition and, subsequently, patient’s health.
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