Monday, September 17, 2012

Familial hypercholesteromia: Why rely on cholesterol levels when more direct measures are available?

There are two forms of familial hypercholesteromia (FH), namely heterozygous and homozygous FH. In heterozygous FH only one copy of the gene that causes it is present, inherited either from the father or the mother. In homozygous FH, which is the most lethal form, two copies of the gene are present. FH is associated with early-onset cardiovascular disease (CVD).

Homozygous FH may happen if both the father and mother have heterozygous or homozygous FH. If both the father and mother have heterozygous FH, the likelihood that at least one in four children will have homozygous FH will be high. If both parents have homozygous FH the likelihood that all children will have homozygous FH will be high.

In fact, in the latter case, homozygous FH in the children is almost certain. One case in which it won’t occur is if the combining FH gene from the father or mother mutates into a non-FH gene before it is used in the assembly of the genome of the child. A gene mutation in a specific locus, only for the father or mother, is an unlikely event, and would lead to heterozygous FH. Two gene mutations at once in the same locus, for the father and mother, is a very unlikely event.

By the way, despite what many are led to believe based on fictional characters in movies and series like the X-Men and Hulk, mutations in functional genes usually lead to harmful traits. In our evolutionary past, those traits would have been largely removed from the gene pool by selection, making them rare or nonexistent in modern humans. Today we have modern medicine; a double-edged sword.

Mutations leading to super-human traits are very, very unlikely. The myostatin gene, for example, suppresses muscle growth. And yet the mutations that lead to little or no secretion of the related myostatin protein are very uncommon. Obviously they have not been favored by selection, even though their holders are very muscular – e.g., Germany’s “Incredible Hulky” ().

Okay, back to FH. Xanthelasmas are relatively common among those who suffer from FH (see photo below, from Globalskinatlas.com). They are skin deposits of cholesterol, have a genetic basis, and are NOT always associated with FH. This is important – several people have xanthelasmas but not FH.



FH is a fairly rare disease, even in its heterozygous form, with an overall incidence of approximately 0.2 percent. That is, about 1 in 500 people in the general population will have it. Genetically related groups will see a much higher or lower rate of incidence, as the disease is strongly influenced by a genetic mutation. This genetic mutation is apparently in the LDL receptor gene, located on the short arm of chromosome 19.

The table below, from a study by Miltiadous and colleagues (), paints a broad picture of the differences one would typically see between heterozygous FH sufferers and non-FH controls.



The main difference is in total cholesterol and in the relatively large contribution of LDL to total cholesterol. A large difference is also seen in Apolipoprotein B (indicated as "Apo B"), which acts as a LDL transporter (not to be confused with a LDL receptor). The LDL cholesterol shown on the table is calculated through the Friedewald equation, which is notoriously imprecise at low triglyceride levels ().

Looking at the total cholesterol row on the table, and assuming that the numbers after the plus/minus signs are standard deviations, we can conclude that: (a) a little more than two-thirds of the heterozygous FH sufferers had total cholesterol levels falling in between 280 and 446; and (b) a little more than two-thirds of the non-FH controls had total cholesterol levels falling in between 135 and 225.

Keep in mind that about 13.5 percent {calculated as: (95-68)/2} of the non-FH controls had total cholesterol levels between 225 and 270. This is a nontrivial percentage; i.e., these may be a minority but are not rare individuals. Heterozygous FH sufferers are rare, at 0.2 percent of the general population. Moreover, about 2 percent of the non-FH controls had non-pathological total cholesterol levels between 270 and 315. That is not so rare either, amounting to an “incidence” 10 times higher than heterozygous FH.

What would happen if people with heterozygous FH were to replace refined carbohydrates and sugars with saturated fat and cholesterol in their diets? Very likely their already high total cholesterol would go up higher, in part because their HDL cholesterol would go up (). Still, how could they be sure that CVD progression would accelerate if they did that?

According to some studies, the higher HDL cholesterol would either be generally protective or associated with protective factors, even among those with FH (). One of those protective factors may be a more nutrient-dense diet, as many foods rich in cholesterol are very nutrient-dense – e.g., eggs, organ meats, and seafood.

This brings me to my main point in this post. It is mainstream practice to diagnose people with FH based on total and/or LDL cholesterol levels. But the main problem with FH is that it leads to early onset of CVD, which can be measured more directly through simple tests, such as intima-media thickness and related ultrasound plaque tests (). These are noninvasive tests, done in 5 minutes or so, and often covered by insurance.

Even if simple direct tests are not perfect, it seems utterly nonsensical to rely on cholesterol measures to diagnose and treat FH, given the possible overlap between pathological and non-pathological high total cholesterol levels.

32 comments:

  1. Very interesting (I am one of those on low carb/paleo with TC and calculated LDL that freaks out my doctor).

    But don't those "direct" tests you mention also suffer from low specificity when conducted on populations not already known to have a high pre-test probability of CVD?

    In other words, doesn't agreeing to such "direct" tests as a seemingly healthy person bear a high risk of false positive results and even overdiagnosis?

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  2. Hi William. False positives can indeed happen with IMT/plaque tests, but they seem far more likely with TC-based tests. I’d argue that a reduction in plaque is way more reliable as an indicator than a reduction in TC, if one is trying to slow down CVD progression.

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  3. As a 22-year old with heterozygous FH I have been confronted with the dogma of lowering my total LDL levels for the past 10 years.

    I can give an example of my personal lipid panel from 13/07/2012 in mg/dl:

    Total: 296
    Trigs: 76
    HDL: 80
    LDL 201
    Apo A: 184
    Apo B: 135
    Lip A: <3.0

    I have been on/off a statin for three years now. I now take 10mg of Atorvastatin. I am of the opinion that in my special case the anti-inflammatory benefits of taking a low-dose statin outweigh its potential risks.

    I have done ultrasound calcium plaque test and the thickness of the plaque was virtually non-existent.

    I have also had my Lp-PLA2 score tested which stood at 225 ng/ml with a reference value <235 ng/ml.

    Ever since changing from a vegan to a Paleo/WAP diet with roughly 20-30% carbs, 55% fat, rest protein, my HDL has gone up by 20 points. Despite a sharp spike of total cholesterol (506 mg/dl) in the beginning, this value has leveled out quite significantly.

    My father has had a cardiac infarction at an age of 47 but within a context of much more worrying parameters than mine.

    My personal takeaway from the all the testing I have done and continue to do is that I consider myself at a low to moderate CVD risk. I will continue the way I do and keep looking for new and improved methods of quantifying CVD risk.

    Any suggestions on what I could still tinker with would be greatly appreciated.


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  4. carbs max 15%
    protein max 15% ;10-12% animal prot, offal, cheese, egg yolks etc
    fat rest 70-80%

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  5. Thanks for sharing Stephan. Your Apo B is low compared with the hetFHs on the table.

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  6. It is also interesting to point out that both the hetFHs and the non-FHs have low BMIs.

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  7. Ned,

    Because of their high cholesterol, FH patients were the first humans approved by the FDA for statin trials. In the statin trials, patients with 100% defective LDL receptors experienced a 50% INCREASE in serum LDL while patients with 50% defective LDL receptors experienced significantly reduced serum cholesterol. The trials were the first clue that statins reduce serum cholesterol by triggering an increase in the number of LDL receptors, NOT by "inhibiting endogenous cholesterol synthesis" as widely believed.

    Statin drugs do disable existing cellular reductase thereby blocking the mevalonate pathway, the source of cholesterol and other vital isoprenoids ("cell foods") but the deprivation of cellular nutrients triggers increased cellular reductase synthesis and simultaneously increases the number of LDL receptors to provide cells with a second source of vital nutrients. Thus FH patients with 100% defective LDL receptors experience an increase is serum LDL while cholesterol is lowered in those with 50% defective receptors.

    The foregoing is set forth in detail in the recent book "How Statin Drugs Really Lower Cholesterol by James B Yoseph and Hannah B. Yoseph MD.

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  8. @ Stephan R.

    One thing I suggest you tinker with is coenzyme Q10 (CoQ10) which is one of the many isoprenoids, in addition to cholesterol, that is reduced by statin drugs.

    Coenzyme Q10 is vital for mitochondrial energy production. Fatigue due to reduced CoQ10 is perhaps the most most common side effect of statins. CoQ10 synthesis diminishes with age so the elderly are the most adversely effected by statin-induced CoQ10 inhibition.

    CoQ10 is also a powerful antioxidant and, further, revitalizes other antioxidants such as vitamin C and vitamin E.

    All statins reduce CoQ10 levels. Because of your youth and relatively low dose of statins you may not have felt the effects yet, but it would be worth checking on.

    CoQ10 is a natural substance and cannot be patented. For that reason the 17 step method of testing serum CoQ10 has never been automated and there are very few labs that can accurately measure CoQ10. Six years ago I got my CoQ10 level tested at the laboratory of Dr. Peter Langsjoen, a cardiologist in Tyler, Texas, who has one of the few labs in the country that can do that test accurately. (The blood sample was overnighted from a local hospital) Dr. Langsjoen also advised me on dealing with my aortic valve stenosis, a condition which increases the work load on the heart and increases CoQ10 utilization. He charges only a nominal fee for the test.

    Since you are on statins, CoQ10 would be a worthwhile thing to tinker with.



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  9. Apo B?
    How many
    B-48? exogenous fat (butter,lard)

    B-100? endogenous fat (liver,adipose tissue)

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  10. Jack C., good point regarding CoQ10 as a possible input to be manipulated.

    Changing subject a bit, but still on the same general topic of FH: one anecdotal piece of evidence often cited is that CVD from FH is nonexistent in hunter-gatherer (HG) populations.

    I wish that were the case, because then we could look at key differences between HG and non-HG populations and see if they were strongly associated with FH. For example, BMI tends to be significantly lower in modern HGs compared with non-HGs. (Btw, this is not the case in the study from which the table shown on this post was taken – both hetFHs and non-FHs had low BMIs on average.)

    However, with FH having such a low rate of incidence in the general population (0.2 percent), how can we assume with certainty that it does not occur in HGs? For example, ischemic heart disease among the traditional Inuit is presented as fairly low, ranging from 0.1 to 1.1 percent depending of the study and how the results are interpreted.

    While these rates are indeed low, a rate of 0.65 (in the middle of the range) would be significantly higher than 0.2 percent. Based on this, one could reasonably conclude that several instances of ischemic heart disease in HGs (e.g., the traditional Inuit) may be due to FH.

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  11. Jack said "The trials were the first clue that statins reduce serum cholesterol by triggering an increase in the number of LDL receptors, NOT by "inhibiting endogenous cholesterol synthesis" as widely believed."

    But surely the latter would cause the first? A law of supply and demand applies; restricting the supply of cholesterol causes an increase in LDL-R numbers.
    This is the exact strategy the Hepatitis C virus uses to increase the number of hepatocytes it infects.
    HCV, especially geno 3 (which specialises in this strategy) prevents distal cholesterol synthesis; it monopolises cholesterol and associates with VLDL.
    (DAGT1 is required for virion completion)
    This causes LDL-R numbers to increase; so there are more opportunities for the LDL-associated virions to be taken into naive cells.
    (the virus uses elements of the LDL-R complex like NPC1-L1 to enter cells)
    Of course consuming a cholesterol-rich, low-carbohydrate diet, and restricting PUFA, thwarts this strategy.
    This is a virus that can really exploit our ideas about "healthy eating" as well as our taste for junk food and sweet drinks.
    I cover the cholesterol- monopolizing strategy in this blog post http://hopefulgeranium.blogspot.co.nz/2012/08/recent-blood-tests-hcv-genotype-3-and.html

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  12. Ned.,, since statins lower serum CoQ10 it makes sense supplement with CoQ10 to restore CoQ10 levels at the very least.

    There is a great deal of evidence that oxidized cholesterol, not native cholesterol, is that primary cause of heart disease. For example, a recent study found that removal of oxidized cholesterol from rats that had high LDL and high TG completely prevented atherosclerotic progression. It is therefore not surprising that many with FH do not get atherosclerosis.

    "LOX-1 is an endothelial receptor for oxidized low density lipoprotein (oxLDL), a key molecule in the pathogenesis of atherosclerosis." (Pubmed 21805404)Primary contributors to increased LOX-1 expression include (1) excess intake of linoleic acid (LA from vegetable oil), and (2) high circulating levels of TG. Most people who avoid modern vegetable oils and maintain a low carbohydrate diet (no more than 30% of calories as carbs) including those with FH, will have low TG and high HDL which indicates a low level of inflammation and low risk of heart disease.

    I think it is reasonable to expect that HGs on traditional diets would not have significant heart disease even if they had 50% inoperable LDL receptors.

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  13. George Henderson said "A law of supply and demand applies; restricting the supply of cholesterol causes an increase in LDL-R numbers."

    It appears that the statin blockade of the mevalonate pathway is not an occasion that the body has evolved to cope with, for it results in an increase in cellular reductase production and a simultaneous increase in the number of LDL receptors. As a consequence cells are stuffed with more cholesterol than it can metabolize. In normal cells, the LDL receptors are reduced in number when celluar needs are met but in statin treated cells the the number of LDL receptors is not reduced even when cells are stuffed with cholesterol crystals.

    It appears that it is the depletion of isoprenoids other than cholesterol (CoQ10, GGPP etc) that triggers the increase in reductase for when cholesterol alone was added back to cells the increase in reductase synthesis did not diminish, but adding back mevalonate did stop the increase in reductase synthesis.

    The way I see it, the function of the LDL receptors is to provide nutrients, including cholesterol, to cells, not to control Serum LDL levels. The reductase in cells produces cholesterol and other isoprenoids and the LDL is simply a secondary source designed to respond to fluctuating needs for nutrients. Statins simply make the function of the LDL receptors go haywire for the receptors no longer respond to the cellular cholesterol requirements of the cells.

    I look forward to reading your post about HCV.

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  14. i loved coming to your website, from now on i will be always coming back here to visit.

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  15. @ Jack,
    that's interesting. Does the extra cholesterol load cause any side effects?
    In HCV there is upregulation of the reductase, but inhibition of the CYP450s required to complete lanosterol and cholesterol, resulting in hypocholesterolaemia without HMG-CoA reductase inhibition.
    "The way I see it, the function of the LDL receptors is to provide nutrients, including cholesterol, to cells, not to control Serum LDL levels"
    Nutrients including phospholipids, fat soluble vitamins, essential fatty acids and antioxidants, as well as cholesterol and fats.
    Supplying many of these in diet and supplements seems to lower LDL, perhaps by decreasing hepatic lipid output in a supply-and-demand type scenario.

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  16. George Henderson said: "Does the extra cholesterol load cause any side effects?"

    There are two schools of thought on that question. The scientists who developed statins say the cholesterol load causes no side effects. Scientists for the Japanese drug company that abandoned statin development when they discovered the un-metabolized cholesterol in cells thought it was a problem. I suspect that the depletion of vital isoprenoids is a greater problem than the increased cellular cholesterol.

    Yeah, LDL does transport a lot of stuff including CoQ10 and vitamin K2. Most vitamin K1 is carried by TG to the liver.

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  17. Interesting discussion! It reminds of a China Study analysis post here suggesting that not only TC was protective against heart disease, but also LDL-C:

    http://bit.ly/dksAfm

    The above was in the context of the Chinese population in general, not FH groups. It is consistent with LDL’s role as a nutrient-transport particle and precursor to important compounds (e.g., hormones).

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  18. Stephan R. said “I am of the opinion that in my special case the anti-inflammatory benefits of taking a low-dose statin outweigh its potential risks.”

    It has long been recognized that statin drugs reduce inflammation by an unknown mechanism unrelated to cholesterol lowering. Evidence from recent studies suggests that statins decrease vascular inflammation and attenuate the development of atherosclerosis by disabling reductase which blocks the mevalonate pathway and results in reduced synthesis of isoprenoids (cell food). In particular, inhibition of the isoprenoid geranylgeranylpyrophosphate (GGPP) synthesis leads to inhibition of Rho and its downstream target, Rho-kinase (ROCK). The inhibition of ROCK by statins leads to up-regulation of endothelial nitric oxide synthase, decreased vascular inflammation, reduced atherogenic plaque formation and reduced expression of the ox-LDL receptor LOX-1 thereby reducing risk of cardiovascular disease.

    A Harvard study on the subject (PMID 19754385) includes the statement: “These cholesterol-independent effects are predominantly due to their (statins) ability to inhibit isoprenoid synthesis” which statement portrays the statin blockade of the mevalonate pathway as a GOOD thing. Not mentioned, however, are findings that the statin blockade of the mevalonate pathway causes many adverse effects due to depletion of many vital isoprenoids such as GGPP, CoQ10, dolichol and isopentenyl adinine. The depletion of the GGPP alone has been found to be the cause of (1) Statin-induced mitochondrial damage and consequent contractile dysfunction of skeletal muscles (21127387), (2) neuro-degeneration and neuron cell death. (15030380), and (3) inhibition of cell cycle progression and DNA synthesis in human lymphocytes. (9425279)

    The anti-inflammatory benefits of statins might outweigh the risks for the majority of Americans who consume an inflammatory diet that is high in carbohydrates and contains excessive lineolic acid from modern vegetable oils. The risks associated with statin-induced depletion of vital isoprenoids, however, are likely to exceed the meager benefits of those who follow and anti-inflammatory diet and have low levels of inflammation.

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  19. Ned Kock said “It reminds of a China Study analysis post here suggesting that not only TC was protective against heart disease, but also LDL-C”

    Along that same line, the foregoing post it was noted that statins “have the ability to inhibit isoprenoid synthesis. -- In particular, inhibition of geranylgeranylpyrophosphate synthesis leads to inhibition of Rho and its downstream target Rho-kinase (ROCK)--the inhibition of ROCK by statins leads to up-regulation of endothelial nitric oxide synthase, decreased vascular inflammation, and reduced atherosclerotic plaque formation.

    Inhibition of Rho also reduces lectin-like oxidized LDL receptor-1 (LOX-1) which has been recognized in recent years as a major contributor to heart disease.

    Linoleic acid (LA) stimulates synthesis of Rho which increases expression of LOX-1 thereby increasing heart disease risk. ((15855339, 22124782)

    Cholesterol attenuates linoleic acid-induced endothelial cell dysfunction thereby decreasing heart disease risk! (12701065)

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  20. Yes, linoleic acid decreases nitric oxide, which maintains the tone of vascular endothelial cells. As does uric acid - so fructose plus omega 6 = vascular problems.
    In fact, look for nitric oxide anywhere and you will find it. It's the best little free radical we've got. Niacin works because it maintains NO. (by reducing formation of ADMA), ginkgo, any number of herbs and supplements that improve circulation; nitric oxide was there!
    Just say NO.

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  21. What does it feel like to be on statins? How do the benefits manifest subjectively?
    I know if I take Co-Q10 I have more stamina, I get breathless only after significantly more exercise.
    I've seen someone on statins be hopelessly short of breath after climbing one set of stairs.
    But how do the positive effects of statins manifest themselves?

    For such a popular drug, there don't seem to be any positive stories about feeling good - or are there?

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  22. Maybe this is the former drug addict speaking, but I won't take anything if I don't notice feeling better as a result. I certainly won't take anything that makes me feel worse.
    Is there a statin for me?

    Do studies about statin benefits control for Co-Q10 use by patients?
    Some are told to take it by doctors or pharmacists, but it's not supplied on Rx so might be missed.
    Especially if the doctor poo-poos it but the patient sneaks it anyway.

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  23. George Henderson said: "What does it feel like to be on statins? How do the positive benefits of statins manifest themselves?"

    The primary benefit of statins seems to be the lowering of serum cholesterol which results in instant gratification of both patient and doctor who are cured of cholesterol neurosis that has developed due to the incessant propaganda about the dangers of cholesterol. Whether or not there is any benefit beyond that is debatable.

    A 2009 study French scientist Michel de Lorgeril noted that almost all recent clinical trials failed to show any benefit. Prior to 2004 there were more than a dozen major statin trials that reported beneficial effects of statins. Around 2004 a controversy erupted within the FDA when drug safety reviewer Dr. David Graham was prevented by his supervisors from publishing his findings that Merck's pain killer Vioxx had caused 30,000 premature heart attacks. A big stink developed which resulted in new Clinical Trial Regulations which requried that investigators comply with demanding regulations or face criminal proceedings. After the new regulations were in place there were more than a dozen trials that failed to show any significant effect of statins in the prevention of CHD. There was one exception, JUPITER, which reviewers found so seriously flawed that its conclusions were called "extreme and exagerated."

    De Lorgeril concluded that the presumed preventive effects of cholesterol lowering drugs have been exaggerated and the time has come for a critical reappraisal of the lipid theory and of statin treatment for prevention of CHD complications.

    http://thrivewithdiabetes.com/doc/De_Lorgeril.pdf

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  24. A google search for "subjective benefits of statins" didn't seem to find any (in fact my comment here was near the top), but did turn up this review of memory loss:
    http://onlinelibrary.wiley.com/doi/10.1592/phco.23.7.871.32720/abstract

    Results. Of the 60 patients identified who had memory loss associated with statins, 36 received simvastatin, 23 atorvastatin, and 1 pravastatin. About 50% of the patients noted cognitive adverse effects within 2 months of therapy. Fourteen (56%) of 25 patients noted improvement when the statin was discontinued. Memory loss recurred in four patients who were rechallenged with the drug. None of the 60 reported cognitive test results. Two placebo-controlled trials found no benefits for statins on cognition or disability. One randomized controlled trial of simvastatin found no effects on cerebrospinal amyloid levels. In one small, randomized study, patients receiving statins showed a trend toward lower cognitive performance than those receiving placebo. Five observational studies found a lower risk of dementia among patients receiving statins.

    Conclusion. Current literature is conflicting with regard to the effects of statins on memory loss. Experimental studies support links between cholesterol intake and amyloid synthesis; observational studies indicate that patients receiving statins have a reduced risk of dementia. However, available prospective studies show no cognitive or antiamyloid benefits for any statin. In addition, case reports raise the possibility that statins, in rare cases, may be associated with cognitive impairment, though causality is not certain.

    Also:
    http://www.severehypertension.net/hbp/more/statin-side-effects/

    Of the 1,220 respondents who stopped taking statins, 62% cited side effects as the main reason, compared with 17% who cited cost and 12% who said the drug lacked efficacy,

    and this:
    Severe irritability associated with statin cholesterol-lowering drugs
    http://qjmed.oxfordjournals.org/content/97/4/229.full

    Not, then, a feel-good drug?

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  25. qjmed.oxfordjournals.org/content/97/4/229.full

    All patients experienced other recognized statin adverse effects while on the drug. Manifestations of severe irritability included homicidal impulses, threats to others, road rage, generation of fear in family members, and damage to property.

    Wow! Those are some happy pills!
    Just like methamphetamine, but without the pleasure; or like steroids, but without the muscles.

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  26. http://healthydietsandscience.blogspot.co.nz/2012/10/patients-hospitalised-with-mental.html

    Unexpectedly low cholesterol levels among New York State inpatients.
    Essock SM, Jackson CT, Kent L.

    This paper can be accessed at: http://www.ncbi.nlm.nih.gov/pubmed/22388541

    This paper compared cholesterol levels in:
    (i) 3,792 New York State Office of Mental Health Hospital patients, (from 17 hospitals) aged 18 and over, with severe and persistent mental illness.
    (ii) The general US public.

    The paper found:
    (a) The mental hospital patients with cholesterol levels over 200 mg/dL (5.1 mmol/L) ranged from 11% to 36% across the 17 hospitals.
    (b) US national data indicates that from 40% to 51% of the US public have cholesterol levels over 200 mg/dL (5.1 mmol/L), depending on their ethnic background.

    This paper shows that patients hospitalised with mental illness have lower cholesterol levels than the general public.

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  27. "Even if simple direct tests are not perfect, it seems utterly nonsensical to rely on cholesterol measures to diagnose and treat FH, given the possible overlap between pathological and non-pathological high total cholesterol levels."

    For me, much better if you must test your cholesterol level and then check for the great supplement to overcome it like CoQ10.

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  28. A couple of interesting points: I have three kids and all three have FH, (heterzygous, my husband is also heterzygous FH, as are his two siblings and his mother.) So, not sure why that would be, you would think at least one of his siblings, or one of my kids wouldn't have it. Other point, my understanding is that FH is associated with heart disease only in some families. My mother in law is 74 and has no heart disease at all, and my husband is 47 and also fine.

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  29. Oh, and to the person wondering what statins feel like: my mother in law and my husband were both in early statin clinical trials due to their FH. They both had HORRIBLE side effects and stopped taking statins very quickly. Depression, cracked lips and skin, low energy, and muscle pains were the main effects. My husband's lips would bleed they got so cracked. My mother in law said they made her forgetful and spacey as well. They both hated them.

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