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Comment by karzeem | Hacker News Reader

Your expectation is a worthwhile ideal, but it's very far out of the reach of modern medicine. Doctors are pretty good at treating symptoms, but when it comes to root causes of serious diseases, they're pretty bad at treating them without inflicting collateral damage on some other body system. Especially if the treatment involves disrupting a body process designed by evolution.

The body owes as much of its function to the ways its systems interact as it does to the individual systems. And we're pretty much at a loss when it comes to tracing the mechanism of those interactions.

In other words, I strongly suspect that until we're all flying around Mars in hover cars, any "don't worry about sugar anymore" treatment will end up being harmful in some insidious, not-discovered-until-years-later way.

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> Doctors are pretty good at treating symptoms, but when it comes to root causes of serious diseases, they're pretty bad at treating them without inflicting collateral damage on some other body system.

I'm sure this is true, but the examples that immediately come to mind don't fit. New tyrosine kinase inhibitors inhibit the fusion "always-on" tyrosine kinases that cause many cancers. Antibiotics kill bacteria. Statins stop the production of cholesterol. All of these get at the root cause of the problem and don't merely treat symptoms. When you say "good at treating symptoms," which things are you thinking about?

I'm in medical school and always want to improve my understanding of what thoughtful people see as symptomatic treatments that don't get at the root cause of problems. (Like I said above, I know that there are tons of these, but would really like to know which ones come to mind for you; perhaps these are the places where we, as a profession, are failing.)

You replied to this person:

>>are pretty good at treating symptoms, but when it comes to root causes of serious diseases, they're pretty bad at treating them without inflicting collateral damage on some other body system. [Especially bad when messing with systems designed by evolution]

saying:

>Statins stop the production of cholesterol .. these get at the root cause of the problem and don't merely treat symptoms.

No, statins do not treat the "root cause of the problem" and in fact, merely "treat" symptoms. In doing so they do great damage and kill people. Look up torcetrapib or clofibrate for examples.

0) Wikipedia http://en.wikipedia.org/wiki/Torcetrapib

1) pubmed http://www.ncbi.nlm.nih.gov/pubmed/6147641? ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

2) Pubmed Clofibrate http://www.ncbi.nlm.nih.gov/pubmed/20535009

Production of cholesterol is not the root cause of the problem. Starting from wrong axioms always produces wrong results. It's the kind of stuff that leads to blood-letting being the leading treatment of the age.

If you're in medical school I would urge you to read Gary Taubes' book -- the man makes some interesting observations about how medical textbooks have changed over the years (esp. in the fields of diabetes, iirc).

Also, sure antibiotics kill bacteria, but they also take a toll on the body (granted they get at the proximate cause of the problem).

You will do well to note that I said statins, not CETP inhibitors (torcetrapib) nor fibrates. There is an ocean of difference between them, so you can't just go around making it look like I endorsed a drug that never got FDA approval (torcetrapib), for example. After antibiotics, statins have the clearest risk-benefit profile of just about any drugs ever invented, and their effectiveness and safety have been under continuous study for decades. You assert that the production of cholesterol is not the problem. Since you claim that I am starting from the wrong axiom, what do you believe is the root cause of hypercholesterolemia? Since hypercholesterolemia is the canonical asymptomatic disease, I suspect you are misusing the term symptom.

Finally, it is natural for medical textbooks to change as our knowledge changes. I haven't read the book you are referring to but if he says that drug companies are having an evil influence, I wouldn't be surprised and I'd probably agree.

>You will do well to note that I said statins

I did note that, and in my reply said that they (statins) don't treat the root cause.

However, I used the example of torcetrapib and clofibrate merely to point out that "reduction in cholesterol" is done most efficaciously by other compounds too. (I don't know if the overall mortality was because of alternate toxicities of the compounds in question, other fibrates are still under consideration).

I did not mean to imply that you endorsed either T or C, and I hope I didn't sound like I did. I may as well have accused you of promoting thalidomide...

The intent was to show that treating lipoprotein numbers was unproductive... ie that the lipoprotein numbers are merely a symptom [2]. More on this below in the coronary calcification note below..

> statins have the clearest risk-benefit profile of just about any drugs ever invented

I do not believe this to be true. For example, statins have well known effects in "worsening"[1] the lipoprotein profile (especially VLDL or Lp(A) -- can't find the reference at this moment)

If dyslipidemia is a symptom, what accounts for Coronary arterial disease? What about coronary calcification? For example look at this:

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=S...

From the abstract: We did not observe a relationship between on-treatment LDL cholesterol levels and the progression of calcified coronary atherosclerosis.

>Finally, it is natural for medical textbooks to change

Of course I agree, with the proviso that the change is "as our knowledge changes". But what if the medical advice changes for political or commercial (drug company) reasons?

So, if (let's assume) lipoproteins aren't the problem, what is? Here's an intriguing possiblity:

http://www.ncbi.nlm.nih.gov/pubmed/17606264?ordinalpos=1&...

[1] worsening = causing a lipoprotein profile that is positively correlated with cardiac death (correlation is not causation, there could be an underlying common factor etc. disclaimer goes here). [2] an attempt to answer your question about where it is that people think medicine treats only the symptoms

Hmm, the point of torcetrapib was to increase HDL cholesterol, not reduce cholesterol. Most likely, it increased mortality via totally off target effects (see Rader's 2008 NEJM review on the topic).

Looking at coronary calcification is no better than looking at lipoprotein fractions; both are intermediate endpoints. I see no reason to trust calcification if you don't trust LDL. Reduction in LDL correlates so well with reduction in mortality (statin trials) that fibrates got licensed on those grounds without showing reduced mortality. That is a problem, but not the fault of statins. It's an FDA-got-bought-out-by-pharma sort of problem.

To reject the overwhelmingly data-backed LDL hypothesis, I'd need to see something much more compelling, I must say.

Edit: your pubmed article addresses insulin resistance. Hypercholesterolemia is usually independent of that. In fact, high LDL is not even part of the metabolic syndrome... It seems as though you and I are not so much in disagreement as we are talking about different things entirely. I've been focusing on high cholesterol.

> both are intermediate endpoints. I see no reason to trust calcification if you don't trust LDL.

I respectfully disagree. Cardiac deaths, including strokes, heart attacks etc., have many causes. One of the leading proximate causes is stenosis due to coronary atherosclerosis (which causes infarcts in heart muscle over time), and the mechanism involved there is the development of plaque in the intima of the coronary arteries: this plaque consists of [1] calcium deposits, fibrinogen and lipoprotein. It seems high CRP, fibrinogen and possibly homocysteine trigger calcium deposition and lipoprotein/platelet aggregation, thereby leading to plaque formation. Does insulin predispose cells to secrete calcium [2] (this would exacerbate the problem of inadequate vasodilation) ?

[1] http://www.ncbi.nlm.nih.gov/pubmed/20551578 (yes, I am aware they found a low correlate with CRP and others, but that they're investigating indicates that the hypothesis exists)

[2] http://www.ncbi.nlm.nih.gov/pubmed/17606264?ordinalpos=1&...

In other words, I see CAC scores (Agatston scores) as far better markers of cardiac events.

> Reduction in LDL correlates so well with reduction in mortality (statin trials) that fibrates got licensed on those grounds without showing reduced mortality. That is a problem, but not the fault of statins. It's an FDA-got-bought-out-by-pharma sort of problem. To reject the overwhelmingly data-backed LDL hypothesis, I'd need to see something much more compelling, I must say.

As for "reduction in mortality", what about this study.. http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=S...

In fact, if you would be so kind as to refer to some studies where, as you say "Reduction in LDL correlates so well with reduction in mortality (statin trials)", I would be very grateful, because, afaik usually those studies found "reduction in cardiac mortality", but all-cause mortality figures are more important (IOW, what if there are off-target effects with statins too, just not at the levels of clofibrate/torcetrapib?).

From the abstract:

> The J-curve association was observed between average TC or LDL-C concentrations and total mortality. Malignancy was the most prevalent cause of death. The health of patients should be monitored closely when there is a remarkable decrease in TC and LDL-C concentrations with low-dose statin.

Since they found a J-curve, IOW, reduction in LDL does not correlate well with reduction in mortality. If LDL caused heart disease one would expect a dose-dependent relationship. Also would you agree that if there is, for example a U-shaped curve, average reductions in mortality, P-values etc. mean nothing and are misleading? IOW, it's a case of the aggregation hiding a vast disparity in outcome?

It's a very interesting paper, and the full paper is available, which increases its value substantially.

> your pubmed article addresses insulin resistance. Hypercholesterolemia is usually independent of that.

Exactly. Hypercholesterolemia is independent of insulin resistance (IR), but IR (aka metabolic syndrome) is highly associated with cardiac mortality. IMHO this supports my point that in most cases, actual cholesterol numbers have very little to do with cardiac mortality (except for a few pathological cases of hypercholesterolemia as defined above some 500mg/dl etc).

> In fact, high LDL is not even part of the metabolic syndrome.

Again, that's exactly where I'm coming from. Metabolic syndrome (easiest identified by high triglycerides, low HDL, IR, intra-abdominal obesity [3]) is the "best" precursor/predictor for cardiac mortality.

[3] http://www.ncbi.nlm.nih.gov/pubmed/19839225

> not so much in disagreement as we are talking about different things entirely.

To loosely paraphrase Feynman, where there is unexplained data is where science has the potential to advance most. I think (and so do others, I'm not a lone loony) that IR, metabolic syndrome, diabetes, etc. have basically a common trigger, which is carbohydrate/omega-6 induced metabolic dysfunction (systemic dysfunction, I should add) -- this is basically a summary of the second part of Taubes' book.

> I've been focusing on high cholesterol.

What do you mean by cholesterol exactly? What method of assay do you refer to, and what do you consider as the significant numeric values?

We have so many better markers now, ApoA/B ratios, HDL/Triglyceride ratios, homocysteine, inflammation factors and fibrinogen. Cholesterol by itself has been recognized as a completely inadequate explanatory factor, heck, everyone now knows that eating eggs and their cholesterol has no effect (other than a small beneficial one) on cardiac events.

Tangential at this point:

I agree with you overall, that it seems fibrates sneaked in under the wire, but (conspiracy hat on) if the pharmas are devious enough for that, are they not devious enough to also massage data and corrupt researchers? :-)

One hopes not, but I am trying to point out that the fibrates fiasco (again, other fibrates are still, afaik, under consideration, though it's probably harder now that they have the clofibrate rap to contend with) is a symptom of the pervasive "treat the numbers" mentality. I wish they would adopt a "find the mechanism" attitude instead.

At one point you say that the metabolic syndrome is correlated with insulin resistance, and at another point you use IR as another word for the metablic syndrome. It's important to be clear, as you pointed out. (Btw, when I say "high cholesterol," I mean elevated LDL-C.) The correlation coefficient between ApoB and repeat LDL-C measurements is high enough as to make the (more expensive) ApoB not worth measuring except for research purposes; though I'd be happy to measure ApoB directly, doing so would change very little. It's certainly not "much better." There is actual research, and then there is clinical junk like taking ratios of different lipoprotein species; that doesn't help you get to the heart of the problem. And you are extrapolating out too far from the papers that you are citing; the medical literature merits a bit more of a cautious reading than I think you're giving it, IMHO. Making super-bold claims like "Metabolic syndrome ... is the "best" predcursor/predictor for cardiac mortality" from a paper entitled "Evaluation of some markers of subclinical atherosclerosis in Egyptian young adult males with abdominal obesity" is a perfect example of over-interpreting.

In conclusion, your level of belief of well-established science (such as statin trials; >100,000 people, total) is too low, and your willingness to extrapolate from very small studies (50 people, total) is too high. I would urge you to recalibrate your beliefs in proportion to the weight of each study, instead of in proportion to your desire for the study to be true. It's hard for all of us to do, but it's the hallmark of the scientific approach.

> Making super-bold claims like "Metabolic syndrome ... is the "best" predcursor/predictor for cardiac mortality" .. example of over-interpreting.

That is an unfair charge, the claim is not based solely on that study. Taubes reviews 50+ years of observations and research on this. Besides, that claim is my hypothesis, which is yet to be tested.

I in no way present it as anything other than a theory.

> In conclusion, your level of belief of well-established science (such as statin trials; >100,000 people, total)

Citation?

> is too low, and your willingness to extrapolate from very small studies (50 people, total) is too high.

I will grant that this is the case. It's because the large scale studies for the hypothesis I put forward do not exist yet. I would like to see NIH funded diet-intervention studies at the same scale, even n=200 would be a great thing.

> each study, instead of in proportion to your desire for the study to be true. It's hard for all of us to do, but it's the hallmark of the scientific approach.

Nice burn in the last sentence!

While I agree that my hypothesis has not been tested, it has not been negated either.

I would like to see well funded and well designed studies to settle the issue conclusively, therefore the charge about the scientific approach is a bit off the mark: I am not holding on to a belief in the face of overwhelming evidence against it, I merely postulate an alternative hypothesis which has the potential to neatly (in the Occam's razor sense) explain several inconsistencies in the current model (and should be tested for merely on that basis, if for no other).

The ApoB issue was raised as there were some pubmed papers that discussed the test and what advantages it had over others in predictive power. I cannot find the ref. right now, but it should be easy to search for. In any case, that was a tangential point I made and you spend a lot of time addressing it, while not addressing other tests like homocysteine levels etc.

MS is a catch-all term for several coincidentally occuring symptoms, as far as I can tell. IR is one of them, abdominal obesity is another, prevalence of LDL and high triglyceride counts are yet more markers. For all I know, IR is the major symptom, that's why at one point I refer to IR and then say "aka MS". Again, this point is tangential.

When you said "Cholesterol" I naturally assumed "Total Cholesterol". I note that you have clarified that. Also, LDL-C I presume includes the VLDL counts? That raises another possible issue: what if the symptoms observed in these studies actually indicate that VLDL is highly correlated with mortality, and that due to some confounding factor, the subjects in these studies have very high VLDL? In that case LDL would be unfairly blamed. Do you agree?

> Looking at coronary calcification is no better than looking at lipoprotein fractions; both are intermediate endpoints. I see no reason to trust calcification if you don't trust LDL. Reduction in LDL correlates so well with ... FDA-got-bought-out-by-pharma sort of problem.

You did not address the Agatston score point, which iirc was the main rebuttal I'd made to your earlier comment. As this discussion is threatening to run off on another tangent, I will end here.

> To reject the overwhelmingly data-backed LDL hypothesis, I'd need to see something much more compelling, I must say.

Perhaps GCBC may itself be compelling?

I will state that most of my stance is covered in GCBC (to the extent that you could say I got it from there) and it should be quite easy to test the alternative hypotheses laid out in that book. Perhaps we can revisit this thread when the issue is settled to our satisfactions and marvel at the different positions we took.

>That is an unfair charge

No, it's completely fair. We have objective criteria for evaluating "best", and expert opinion is Grade C evidence (different groups use different lettering conventions, but suffice it to say that expert opinion is not regarded highly since it is, in fact, not evidence).

>Citation?

Looking at only those without CVD at time of enrollment, see http://www.ncbi.nlm.nih.gov/sites/pubmed (70,000 participants in that meta-analysis alone).

LDL is not VLDL. LDL-C is different from VLDL measures. Since this isn't that popularly known, let me explain a bit: people rarely measure LDL-C directly. Instead, they assume that virtually all serum TG is carried by VLDL; they measure HDL; and then they infer LDL-C. It turns out that this inferred LDL-C correlates well enough with directly measured LDL-C for the vast majority of people that it hasn't been worth the cost of implementing a direct test except for research purposes (Canadians will differ on this).

I'm not exactly sure where you are going with the VLDL vs LDL discussion, however, since VLDL is the precursor to LDL. It is always a formal possibility that a confounder is modifying or even inverting the relationship between X and Y, but typically one would expect some evidence in support of that. The LDL-MI association holds up in every population tested - so unless this postulated confounder is present in every population, it's not likely. Plus, most people expect that both VLDL and LDL will correlate with MI risk, though the best studied one is LDL.

>You did not address the Agatston score point, which iirc was the main rebuttal I'd made to your earlier comment. As this discussion is threatening to run off on another tangent, I will end here.

My point isn't that the Agatston score is bad; it's that you're rejecting the intermediate endpoint with the best evidence (LDL-C, which has prospective randomized trials supporting it) and then endorsing an intermediate endpoint that's far less accepted (coronary calcification). I rebutted your Agatston score comment in a couple of ways previously and without actual evidence supporting its importance in the causal chain for MI, I see it merely as a biomarker (unlike LDL-C, which is causal).

>Perhaps GCBC may itself be compelling?

No. Since the GCBC is a book that expresses its author's expert opinion, I do not find it to be evidence. When I hear "evidence," I expect data, not opinion.

Clarification edit (damn you HN):

As for "reduction in mortality", what about this study.. http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=S....

From the abstract:

>The J-curve association was observed between average TC or LDL-C concentrations and total mortality. Malignancy was the most prevalent cause of death. The health of patients should be monitored closely when there is a remarkable decrease in TC and LDL-C concentrations with low-dose statin.

IOW remarkably low LDL concentrations increase death rates.

>IOW remarkably low LDL concentrations increase death rates.

Since you must have read the article, given that you're citing it, what were your thoughts on the following things that I found troubling:

(1) People were stratifed according to post-treatment TC, not according to any baseline measure, LDL-C, or an appropriate compound measure of risk. In other words, this is all post hoc, and highly suspect.

(2) The group with low on-treatment TC was overwhelmingly male (>60%, vs 30-40% in other groups) at baseline.

(3) The groups with low on-treatment TC had higher blood pressure (53-58% vs 39-48%) at baseline.

(4) The groups with low on-treatment TC were overwhelmingly more alcoholic (45% vs 28%) at baseline.

(5) The groups with low on-treatment TC were overwhelmingly more burdened by liver disease (11-16% vs 8%) at baseline.

(6) The groups with low on-treatment TC were overwhelmingly more likely to smoke (30% vs 15%) at baseline.

In other words, there are plenty of reasons at baseline! for the low TC group to exhibit increased risk of all-cause death. Perhaps the most interesting conclusion is that the statins appeared to protect these hypertensive male smokers from cardiovascular disease!

Your conclusion is almost certainly incorrect (and probably inverted, in fact), due to the confounders that I've enumerated above.

>Reduction in LDL correlates so well with reduction in mortality (statin trials) that

Citation please.

From my other comment:

Harrison's 17th edition has an entire chapter summarizing all statin trials to date; there is a dose-response curve between LDL and mortality, with no lower limit. Or try a recent meta-analysis of statin trials looking specifically at all-cause mortality (PMID 20403481). Or see (PMID 19067719) if you want another statins + all-cause mortality meta-analysis.

In another post you pointed to one article asking about the risk of cancer in statin-treated patients. That was a scare a few years ago; now, in contrast, the NIH is funding statin trials for cancer prevention (specifically colorectal and skin cancers).

> You assert that the production of cholesterol is not the problem. Since you claim that I am starting from the wrong axiom, what do you believe is the root cause of hypercholesterolemia?

The issue is cardiac mortality. I assert cholesterol is not the cause [1]. I further claim that assuming that it is, and orienting research that way, is equivalent to starting from the wrong axiom.

I don't say you particularly start from the wrong axiom, rather that the general approach does.

Your counter is "Since you claim that I am starting from the wrong axiom, what do you believe is the root cause of hypercholesterolemia?"

This is orthogonal because we are not concerned with cholesterol.

Here is a corrected version of the question I assume you meant to ask.

"what do you believe is the root cause of the current sudden cardiac mortality epidemic?"

Answer: carbohydrate/omega-6 induced Metabolic Syndrome.

If this seems like begging the question [2], I will make it plainer: carbohydrate overfeeding coupled with excessive omega-6 consumption. Our bodily mechanisms necessarily mean it will lead to Syndrome X / Type 2 diabetes / early-onset cardiac mortality.

[2] because Metabolic syndrome is so ill-specified as to really be just a combination of symptoms.

[1] except pathological cases above, say 500mg/dl

Do you have any evidence to support this, or is just an idea?

Also, how does your idea square with the fact that cardiac mortality has decreased at the same time that the diet you are blaming has increased?

I'm in medical school and always want to improve my understanding of what thoughtful people see as symptomatic treatments that don't get at the root cause of problems.

A huge amount of medicine is essentially treating the symptoms of aging.

What do you see as "aging," and do you see that as a disease process?

Decreased physical and often mental capabilities, and increased susceptibility to other diseases and incidents like heart attacks and strokes. Whether aging itself is a disease is just a matter of definition, but preventing it or undoing its effects would substantially reduce the need for other medical treatments, as well as saving tons of money and greatly increasing quality of life. It may not be possible, or may require currently unavailable capabilities like advanced nanotechnology, but I believe it's worth seriously investigating.

The cause of the constellation of symptoms that we associate with aging remains outstanding. Perhaps it is environmental; perhaps it is genetic. Certainly, one cannot expect us to treat the root cause of that which we don't even have more than a rudimentary understanding. Gaining that understanding will (hopefully) be one of the defining achievements of the 21st century -- most likely too late for you and me, but of tremendous import for those to come later.

If we had advanced nanotechnology that could do whatever you asked to ameliorate the root cause of aging, what would you ask it to do? I submit that we don't know yet, so trying to choose the right technology for the job (such as nano) at this point is a bit like putting the cart several feet in front of the horse.

The above notwithstanding, I honestly fail to see how making people live longer would save any money. Presumably it would just delay the inevitable, expensive end-of-life care by a few (or many) years. Do you not see it that way? I would love to have a more optimistic view.

Certainly, one cannot expect us to treat the root cause of that which we don't even have more than a rudimentary understanding.

Agreed; gaining that understanding is the first step, and I believe it should be a top priority.

The above notwithstanding, I honestly fail to see how making people live longer would save any money.

If you have the physical health of a 25 year old indefinitely, your medical expenses per year would be far less. Yes, you'd still occasionally get sick and eventually die of something, but a greater percentage of your life would be healthy and productive.

> If you have the physical health of a 25 year old indefinitely, your medical expenses per year would be far less. Yes, you'd still occasionally get sick and eventually die of something, but a greater percentage of your life would be healthy and productive.

Having the health of a 25-year-old indefinitely seems unlikely ever to be achieved. If we can achieve that, then we will have eliminated virtually all inherited causes of death, and I would agree that we would save money. It seems more likely to me that we will continue to expand the gains that we had in the 20th Century: people will live better, longer, but will still ultimately age and suffer the consequences (though perhaps at 150-200 years instead of 65-100). If the former is true, then we'll save tons of money because we'll have eliminated chronic disease and aging. If the latter is true (which would fit with past experience), then we'll truly just have delayed the costs by a few years. If people are willing to work longer since they live longer, this won't be a problem. But if people were so noble, then we'd already be delaying Social Security and Medicare benefits until age ~75, since the average lifespan has widened since the programs were conceived decades ago.

At any rate, I wholeheartedly agree it would be a huge net benefit; I suppose whether or not money gets saved is dependent on how society decides to partition out the costs and benefits.

Jack LaLanne managed to have the health of an athletic 25 year old into his 50s. And the health of an athletic 50 year old until his 70s. I have a great uncle who followed LaLanne's advice and is 84 and looks like a 45 year old bodybuilder with a 65 year old face. In contrast his brothers are dead, except for my grandfather who is fat and has diabetes and mild alzheimer's and is basically confined to his retirement apartment. I would say we already know how to be a 25 year old for much longer than than expected - the key is to exercise a lot more and a lot differently than you would think, and eat a diet similar to that of a 7th day adventist. Unfortunately this lifestyle is in opposition to pretty much every cultural and marketing trend in every society on the globe today.

Personally, I would prefer to have the health of a 25 year old until I'm 90 and then croak, rather than live like an 80 year old until I'm 150.

Outward appearances of health are poor indicators of internal physiological conditions; just ask anyone with hypertension or hypercholesterolemia. But I think it's great that you know people who do right by their bodies. There's no reason everyone shouldn't do that, if that's what they care about. There's also no reason that everyone should, if they don't.

I used to have hypertension and it went away after I lost 55 pounds. Most fat people are hypertensive.

I intended that to be interpreted in the context of your specific point about healthy-looking people. A healthy-looking exterior does not indicate a healthy interior. An unhealthy-looking exterior almost certainly does indicate an unhealthy interior.

So my point is not that your obese self could have been healthy; there is almost no way it could have been. The pathophysiology behind obesity-induced hypertension is not that hard to imagine. In contrast, the fact that someone looks healthy doesn't mean that they don't have hypertension or hyperlipidemia.

Many patients make the mistake of thinking that what cured them will cure others. Sure, losing all of your excess weight will cure many cases of diabetes and hypertension. But not all people with diabetes have it because of their obesity; not all people with hypertension are obese. You won't see me telling a 70kg 5'10" male to drop some weight to cure his hypertension. But there is basically no diagnostic dilemma when you see a 100kg 5'10" male with hypertension, and the cure is clear.

I would wager that most people with hypertension have it because they are fat. I would also wager that if someone looks healthy, like a soccer player, there is a good chance they don't have any of the conditions now classified as "metabolic disorder." They might have brain cancer, or a cold, or even type 1 diabetes, but they probably don't have high blood pressure or type II diabetes. High cholesterol I know nothing about, so I wouldn't make any bets about that. I have other wagers about skinny people with hypertension, but it's getting too far off topic now.

I agree with your instinct about the cause of most hypertension. Most Americans are fat; obesity causes hypertension; therefore, most Americans who are hypertensive are so because of their obesity. With regards to your point about the soccer player, I cannot agree. You listed plenty of fine caveats to your point - in fact, the caveats outweigh your argument, in my opinion. These caveats only increase as you transition from a 25-y/o soccer player to a 50-y/o soccer player who "looks" 25. But perhaps that is just my American physician-style bias - to err on the side of caution. Most diseases that you and I will ever need to worry about do not have dermatological findings, so just looking at a person and noting a lack of obesity or other derm findings is a pretty poor screening test for ruling out disease.

High cholesterol primer: it is the most important disease based on the objective criterion of "causes the most deaths," has no physical findings, except for the 1/1000 who have recessive mutations that will cause them to have a heart attack in their 20s-30s unless they take statins. 80% of the cholesterol in your body is produced by your body, so you cannot typically blame diet for hypercholesterolemia.

Your post seemed to imply that Type II diabetes is caused only by obesity; this is not true, but it feels true because the recent obesity epidemic has made obesity the most important cause of T2D. Unfortunately for the patients, it's not the only cause.

The metabolic syndrome is a rule-based diagnosis: you must meet 3 out of 5 criteria, only one of which is obesity. Thus, you can have the metabolic syndrome without being obese. These patients are actually very interesting, because it suggests that they naturally have the same maladaptive gene expression profile that is caused by obesity. This is an opportunity for research into the molecular biology of obesity-induced diseases.

As an aside, we do treat obese hypertensives with ACE inhibitors and other proven medications, even though we know their hypertension is caused by obesity. Doing so still reduces their cardiovascular disease and kidney damage. If they lose weight and are no longer hypertensive, then we stop the meds. In the meantime, we do what we can to protect their vital organs.

Oh, also - congrats on losing so much weight! Most people have a devil of a time losing even 1/3 of that (and keeping it off for an appreciable amount of time is another story entirely.) What was your trick for losing it, and for keeping it off?

My trick for losing weight was that I stopped eating cheese, pasta, burritos, and pizza. I also quit drinking beer. I kept it off by not eating or drinking those things.

> I have other wagers about skinny people with hypertension, but it's getting too far off topic now.

I would like to hear this. I have read that hypertension may be caused by renal failure to excrete salts and is not connected with intake.

Those examples do fit: Tyrosine kinase inhibitors turn an always-on enzyme into an always-off one, when the normal behavior is for it to act as an on/off switch according to the cell's immediate environment.

http://en.wikipedia.org/wiki/Erlotinib#Side_effects

http://en.wikipedia.org/wiki/Imatinib#Tolerability_and_adver...

Once the gene mutates in a cancer cell, it's never going to work properly again (unless all the cancer cells are killed, or the gene is somehow replaced). It's just less harmful if it's disabled than if it's permanently active.

Antibiotics tend to kill good bacteria in the body, too. Most people are willing to take a week or two of GI problems and some extra servings of yogurt in exchange for survival, but still, that's some collateral damage.

The common problem is, once one part of a system in the body begins malfunctioning, it's very difficult to fix that part without affecting the surrounding system, or other parts that work similarly but aren't malfunctioning.

Neoplastic TKs are not on/off switches; they are always on. Once you inhibit effectively, they are always off, like you said. But you still have a copy of the normal TK, so most likely things could be perfectly normal if you identified a highly specific TK inhibitor. The current -inibs just aren't specific enough yet, so they have serious side effects.

I argue that antibiotics get to the heart of an infection, not that they only kill the bacteria you want to kill. Is it possible to create a drug or engineer a phage to do wo? Yes, sure. But the cost tradeoff is not worth it, on balance. Very few people develop any side effects from most antibiotic treatment, much less weeks of GI discomfort. It definitely happens, but you outlined the treatment for it -and eating yogurt is much cheaper than paying for a theoretical, patented, new superantibiotic that causes mo GI problems.

I can think of three categories helpfull when looking for "root causes medicine": 1.Better more in-depth information, using tools like genetic medicine and new bio-markers that can give us a more precise diagnosis(using genetic medicine , hypertension can be classified into more then 10 categories , each with his own preferred treatment). with more precise diagnosis , the chances are greater that we treat the core problem.

2. In many cases, we know the core problem, but the tools we can only treat symptoms. For such diseases , a good place to look is emerging technologies focus on the core problem. for example today we treat diabetes type 2 mostly symptomatically, but the core problem is that pancreas cells die or stop functioning. Stem cell therapy is offers big hope as a cure for diabetes type 2 by replacing the bad pancreas cells with new cells.

3.i wonder if prevention, in the general case, is relatively more focused on the core mechanisms, simply because when you prevent something , you have no symptoms and symptoms never appear.

I agree with 1 and 3. I disagree with point #2. The root problem with Type II diabetes is insulin resistance peripherally. The damage done to the pancrease is actually a secondary problem. If you cure the peripheral resistance to insulin, you fix the problem. If you add back pancreas, you simply end up becoming hyperinsulinemic and, while that will work for awhile, it doesn't get at the core of the problem. In other words, what you are proposing is more symptom oriented than current cause-oriented treatments.

"If you add back pancreas, you simply end up becoming hyperinsulinemic and, while that will work for awhile, it doesn't get at the core of the problem. "

That's pretty much what we do now with sulfonylureas and other insulin secretagogues, not to mention insulin therapy.

Agreed. That's why diabetes treatment sucks so badly (yes, better than nothing). The PPAR agonists seem promising, in theory. In practice they don't seem quite so awesome. I'm still hopeful; GWAS has offered us some new targets that should be exploited in the near future.

The PPAR agonists stimulate adipogenesis - one of their main effects is to make you fatter so that you have a dumping ground for excess sugars. This doesn't seem like a very good idea, and I'm not surprise that it turns out that they suck (kill people).

Well, yeah, insulin sensing leads to adipogenesis. Since the PPAR agonists increase insulin sensitivity, you're going to become fatter if you continue overeating. This sort of brings us back to the root cause of most DM (overeating). And while some of the PPAR agonists kill people, it does not seem to be a class effect; pioglitazone looks OK. (CHF is a class effect of the thiazoladinediones, but it's a more balanced tradeoff with diabetes.)

One could perceive antibiotics alone as ignoring a deeper root cause, such as the patient engaging in risky behavior (not washing hands, eating rotten food, etc.). A prescription for statins doesn't necessarily address why the body is producing excess cholesterol.

But, of course, I am not in the medical field.

Over 50% of the variability in cholesterol levels is attributable to genetic factors. The root cause of high cholesterol will typically be an unlucky genetic profile.

Hundreds of genes participate in cholesterol metabolism, and since cholesterol is a complex trait, most people will have various polymorphisms in multiple lipid genes, each of which confers only a modest effect. Consequently, while the root cause(s) will ultimately become known in the next few years, it seems unlikely to change the standard of care: statins. Sure, this knowledge will help us develop new cholesterol lowering drugs, but the fact remains that it will be impossible and, in general, pointless to target a specific therapy to a specific genetic profile (at least for LDL).

I don't think that patient behaviors are a good example of medicine's failures. A rational actor may decide to value many things over their own personal health. It's like saying that intravenous drug use and unprotected sex are the root causes of AIDS. That's more a public health viewpoint. I see HIV as the root cause of AIDS, and I find treatments or cures as a far more interesting medical problem. Likewise, the public health perspective on bacterial infection is to avoid it (clean clothes thoroughly to reduce staph transmission between wrestlers). From a medical perspective, the interesting question is, once you have staph, can we cure it? Killing the causal bacterium is basically the definition of a treatment aimed at the root cause. I don't think that redefinition of "root cause" makes the problem more interesting; it just makes it less medical.

I see your point, and concede that some "root causes" should be out of scope for the medical field. I believe that solutions to problems should be sought by the appropriate groups at every stage of progression and every level of abstraction. However, during an actual patient/doctor visit, public health "root causes" should probably be at least discussed.

Definitely. Studies have shown that discussion with a physician is effective (just not very much). But better than nothing. I just don't want to depend on physicians talking people out of eating too much as being the only solution; this is simply not effective enough given the severity of the problem.

the patient engaging in risky behavior (not washing hands, eating rotten food, etc.).

I see where you're going, but this may not be the best example. I believe it's currently thought that exposure to some bacteria and other uncleanliness is essentially exercise for your immune system, especially in childhood.

One of the most common symptomatic treatmeants that doesn't get at the root cause of the problem is prescribing meds for high blood pressure.

I think this is a good point; in fact, we don't know the root cause for most cases of hypertension (idiopathic). In fact, >90% of people who are normotensive at age 50 become hypertensive before they die. This is an astounding stat. We're not going to be able to fix this, IMHO, until we understand the genetic (and/or environmental) basis for HTN.

Nevertheless, treatments for HTN also reduce the sequelae, such as cardiomyopathy, so these are better than just "symptomatic treatments."

Medicine is still very reductionist and that is not going to change for a while, even though we know that isn't the right way to go about doing it. The thing is that I am not sure that we will necessarily be able to fix the impact of "bad behavior" even at a systems level, because no two perturbations, even with the same behavior are going to be alike. Yes, we'll be able to detect a lot earlier and thus fix things, but in the end, the responsible thing to do is either to take a "I will be better with my body" approach or bear the consequences.

Being reductionistic is the source of all of medicine's success in the past 100 years, and I don't see that changing - ever - without evidence that another approach is superior. Which non-reductionistic approach do you see as supplanting reductionism?

Behavior isn't really a medical problem so much as it is a series of choices between different 'goods' - both medical and nonmedical. I see it as a public health problem. Want people to eat less McDonald's? We know that counsel from your doctor is very modestly effective. We also know that price changes are very effective. So tax McDonald's food at 100% and subsidize produce with that extra money. People can still choose McD's, but you just made it a whole helluva lot easier to eat well. Large-scale systemic interventions are the only things that will be able to change behavior, and this is neither surprising nor particularly problematic.

Sorry, but for what reason should the state intervene here? I could see the point in a system where everybody has state-run health care, but even then a junk food tax would probably attack the problem at the wrong end.

Never mind that the criteria for additional taxes would be pretty hard to specify and justify...

The state's interest here is about as obvious as it gets. The state already intervenes. It pays (entirely) for the training of all physicians during their residencies. It determines physicians' reimbursements. It runs Medicare. It runs Medicaid. In other words, if the state could reduce the usage of Medicare by improving the health of its citizens with targeted taxation, it could save itself money.

Oh, and let's not forget that the state intervenes on the other side of the argument, too: it subsidizes high fructose corn syrup, etc. The state is already intervening every step of the way. I'm just showing you the way it could do so to the benefit of people, instead of to their detriment.

My major point in that post was that behavior is not a medical problem. I'm not actually saying that I think the state should do this (in fact, if it just stopped subsidizing the bad stuff, we'd be much better off already). I was just giving an example of what one could do to effect large-scale behavioral change, which is not a medical problem but instead a political one. If one opposes statist interventions, as you seem to, then one would not like this solution. Large-scale private solutions to effect behavioral change could be just as effective. To reiterate, my point is that behavioral change is not a medical problem.

Oh, as an aside -- taxing these products would be no harder than subsidizing them: a problem that has already been solved, unfortunately.

I'm not entirely against statist intervention -- especially if it would be prefixed by a more universal health care system to justify it. But speaking of justification, I am not sure whether we really reached a point where we could equate sugar with alcohol and tobacco, i.e. as a substance where any amount is hurtful, and so taxation can begin with the first milligram. Is there a substance where we impose fines for "too much" of it? Unless science is very, very clear here, I would fear to tread on that slippery slope.

But I don't see this as a truly solved problem on any side. I assume that "taxing McDonalds" is basically a simplication. Still, what would you tax? Products containing refined sugar? Anything above a certain cal/lbs ratio? (Of course, the problem doesn't arise as much if you really agree with the sugar/substance X = 100% badwrong assumption)

Of course, private efforts don't need to be held to the same standards as those of the government, but on the other hand are quite a bit less effective. I would be interested in how a group of "concerned citizens" would try to tackle this.

I agree that it would be really interesting to see a "concerned citizens" effort. One might pilot different ideas. Let's say that the Gates foundation all of a sudden became interested in this. Perhaps they could target one particularly obese place that's not too big (maybe a few tens of thousands of people). They could then subsidize produce, etc, by paying the local grocers X% of the total price for each of a predetermined selection of items. Broad health measures could be tracked over the years.

The problem is that my idea isn't very inventive; it's just replacing "government" with "some rich group." There must be something more creative that people can do.

I don't know where the general trend is heading. It seems like there's more awareness, but a lot of that is actually pretty trend-ish and a lot of the literature is akin to self-help books. It could mean that people are going to pay more attention to nutrition in the future, but it could also go the way of the hula-hoop and the Atkins diet... Apart from that, I would guess that there's a big divide between urban and rural areas, as well as between economic classes.

Public and private campaigns against alcohol or tobacco won't serve as an inspiration, as they're mostly of a prohibitive nature, whereas obesity requires a more pro-active approach.

Ireland has a Tidy Towns campaign, and I remember something similar in Germany and Austria. Maybe something like that would work for health, too... Something that combines health with economic advantages probably has the biggest chance of success in the end.

> I would guess that there's a big divide between urban and rural area

Bingo! 100% correct. Look at West Africa. Rural areas have a very low incidence of obesity/diabetes/HTN (though I think their rate of hyperlipidemia is about normal, which makes mechanistic sense). Urban areas have rapidly increasing rates of those diseases.

I agree that public health campaigns, though helpful for raising awareness, are unlikely to succeed (at least, to a degree that you and I would consider successful).

It's all about the money (economic advantages), which is why the tobacco tax appears to have worked so well. (Or, who knows, maybe it just takes 20 years of public health campaigns; I guess I can't honestly say for sure.)

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