Saturday, October 18, 2008

Familial Hypercholesterolaemia; heterozygous survival

When you sit here with an LDL cholesterol which makes a cardiologist's trigger finger itch for a reflex prescription of lovastatin, you get quite interested in the fate of others with high LDL cholesterol levels. I found this familial hypercholesterolaemia paper by accident while looking for a paper on blood insulin levels by some big noise in USA cardiology.

BTW: That hunt was triggered by Michael Eades' post (back on line here) on ITT (intention to treat) analysis and the murkier aspects of statistical techniques. The insulin paper was mind boggling. Their limit of detection for plasma insulin was 2.0microIU/ml. A big chunk of their patient base had insulin levels below this, SO THEY MADE UP A DATASET, based on an assumed distribution. Duh. Wish I could find it! Plus I remember them as obese USA citizens, non of whom were type 1 diabetics or were at the end stage of type 2 diabetes. No healthy person runs a fasting insulin below 2.0microIU/ml. So the assay was probably rubbish anyway!

Anyway, back to heterozygous FH. It's another paper by Sijbrands on the mortality of patients with untreated FH.

Here's the first paragraph of the discussion:

"In the present study, mortality was highest in families which were ascertained through cases with a premature onset of CAD. These families — in particular the male patients in middle age — had high excess mortality. This high excess mortality underscores that our results do not detract from the older finding of increased mortality in families in whom the disorder was clinically recognised. These old studies described a decreased life expectancy in families with familial hypercholesterolaemia that were investigated because the probands — or even multiple family members — had presented themselves with premature cardiovascular disease"


This translates as: In families with FH and premature heart disease there is premature heart disease. Yes, that's what it says.


"Presumably these families — and our families with a premature onset of CAD — were characterised by clustering of risk factors. In the present study, a lot of families were not ascertained by clinical outcome but by routine measurement of cholesterol and they had a life expectancy similar to the Dutch population, suggesting the presence of protecting factors or the absence of additional risk factors"


Translation: In families WITH heterozygous familial hypercholesterolaemia, but WITHOUT premature heart disease, life expectancy is NORMAL (rather, the phrase is "similar to the Dutch population"). There is no premature CVD. There are a lot of these families. I wonder if they are all on statins? If so, why?


"Others also observed normal survival of some familial hypercholesterolaemic patients [3 and 4]. The factors involved in this reduced risk of mortality from the disorder are yet unknown and their identification is needed to enable prediction of longevity"


What I feel is missing from the paper is the inclusion, taken from the normocholesterolaemic Dutch population, of a group of people with normal cholesterol receptor genetics but WITH premature heart disease. There are plenty of families with this predicament. Then do some comparisons with the various FH groups discussed by Sijbrands... That might put FH in to perspective.

Peter

24 comments:

Paul said...

Hi Peter,

I have a fasting insulin below 2.0microIU/ml (at least my result was listed as 'below detection threshold' and I remember the threshold value was a '2' if not the units, so I think this must be the same thing). I googled around at the time of my test without getting any useful info about its significance. Can you tell me how it is unhealthy?

Thanks,
Paul.

(p.s. I am not obese like the people in the study, my BMI is 20.5 and I am physically fit.)

gunther gatherer said...

hi Peter,

So sorry to hijack, but I don't know where else to post this. I'm wondering what you know about getting TSH levels down. Mine is currently 3.5, which is considered "normal", but from what Dr. Davis and other more forward thinking docs are saying, this should actually be closer to 1 for optimal health.

Do you know yours offhand? Is there any info on pre-agricultural peoples and their TSH levels? What is the best way to get this lower to optimise thyroid function, as I'm starting to think the sluggish weight loss problems I was having on JK were related to this...

Thanks, and btw the BSE studies were fascinating!
Gunther

Paul said...

Peter,

Sorry for clutter when I already posted once, but I cannot help but notice you are becoming everyone's favorite MD! A comment on conventional healthcare and its close ties to the pharmaceutical corporations maybe...

Paul.

Peter said...

Hi Paul,

I almost specified "excluding LC eaters" (if you eat that way). In a young fit healthy weight stable LC eater it's possible. On the SAD a fasting insulin this low is a marker of problems, probably reactive hypoglycaemia. On other whole food diets I'm not sure, probably if you are eating real foods it's fine. Again, like FBG, you have to put it in context...

Peter

Peter said...

Gunther,

Yes, 3.5 is a bit high nowadays. The opinion on LC and thyroid function is that (Barry Groves and Lutz talk about it) it usually improves. Be careful starting supplements as you then cannot track recovery (if it happens) as exogenous T4 suppresses thyroid function for some time after you stop taking it.

But you don't want to stay hypothyroid as that is bad news on many fronts, CVD obviously included.

Not seen any HG data on thyroid function.

There is a particular person (female) who's name escapes me who is encyclopaedic on thyroid deficiency and has a useful book on it (not read it myself). If you wander the forum of Dr Berstein's site there is a poster called Georgette who will point you in the right direction. Just search on her posts and you'll get there.

Peter

Anna said...

Gunther,

I am someone who had slowly rising TSH between 2.5 and 5 for more than a decade, with it rising over 3.5 after 2004, when I began low carbing, then more rising more rapidly after that, being almost 5 by the time I found a doc who would take my concerns seriously. I don't blame LC for causing this, as the trend started long before LC. I had a lot of TSH tests done because of two rounds of infertility testing as well as reporting to my doctor so often that I was exhausted and cold all the time, with worsening sleep patterns. I had a *lot* of worsening hypothyroidism symptoms (too numerous to mention) throughout this time (though at the time I had no understanding of their origins) (you don't seem to mention more than weight instability as a symptom, which I had, too, onsidered the least of my worries). So when I clued in to the sluggish thyroid as a common factor, I opted for supplementing with T4 and T3, and overall, I feel much improved. After my doses were adjusted a few times the first year or so, my TSH has remained fairly stable in the 1.0 range (+/- .1 or so). Some symptoms recur as seasonal daylight diminishes, so I tend to need a very slight dose adjustment in fall/winter.

I know many don't like to take Rx thyroid hormone for this (I don't usually like to take medications, either), but I don't mind taking the thyroid hormone supplement because I don't really see it as a drug, more like a vitamin. It made a huge difference in my ability to function and "get myself" back; the hardest part was finding a doc to help me get to that point. I had tried everything I thought possible to do on my own that seemed safe, but it wasn't nearly enough.

But not long ago, Dr. Eades commented on his blog that my TSH situation and struggle was all too common and had I been his patient, he would have tested for iodine deficiency first, before trying thyroid hormone treatment; he and his wife both tested with low iodine levels (he didn't mention if they had any symptoms) and his wife noticed improvements with iodine supplementation, though he didn't notice any difference. But noticeable or not, it's probably a good idea to have enough iodine. I haven't ever had any iodine levels tested. The info I found back when I was learning about thyroid conditions, I interpreted as a risky experiment to do on my own with supplemental iodine, as too much can be as bad as too little, especially with autoimmune thyroiditis (which is very common).

But perhaps iodine deficiency is a possibility in your case, especially since you don't mention any of the symptoms that I had. There is, of course, the "conventional" widespread belief that iodized salt eliminated deficiency in industrial populations (well, I haven't bought iodized salt in almost 20 years and I don't consume much processed food or the SAD, so my iodine intake could very well be low). I think this view is parallel to the belief that Vit D deficiency is rare in sunny mild climates, yet I keep learning about more and more Vit D deficient people in my So California region now that testing is becoming more routine and common.

So if you haven't had your iodine levels tested, you might start with that. I plan to take this up with my new primary care doc the next time I go in, because he seems more open to that sort of thing.

There is a lot of controversy about treating a TSH level like yours if asymptomatic, but the emerging research also seems to indicate that higher than truly "normal" TSH (over the 1.0-2.0) range is associated with some negative health outcomes long-term. So while you might not need to address this immediately, looking into all your possible options is probably a good idea. I know a British woman who has a TSH of 12 or more, yet she says she feels fine and won't take thyroid hormone as her doctor has recommended. It's so strange that she is asymptomatic with a much higher TSH but if my TSH is between 2.5 and 5.9 it feels like walking through quicksand with my knuckles dragging, a head full of cotton (or alternately sharp pins), and I'm perpetually numb and feel cold in So California. Go figure.

Some people swear by coconut oil, too, which may be helpful in very, very mild elevated TSH situations, too. I didn't notice any benefit, though, nor do I know of any research on this.

Please keep us posted on what you learn and try, and any results/lack of results.

Paul said...

Peter,

Yes I am LC and high-fat. If you are collecting anecdotal evidence, you may be interested to hear that I just had my yearly cholesterol test, after my first year of changing from 'semi LC' to a truly optimal-type diet. My LDL went from 130 to 178, my HDl from 78 to 88. You blogged very recently about temporary increase in LDL for LC adopters, so I am waiting to see what happens next. I must say there is an uncomfortable difference from having a theoretical interest in cholesterol-statin misinformation, and actually finding oneself with elevated LDL.

One question this raised for me - Kendricks' book shows a graph of total mortality against LDL with a smooth curve and a minimum at an LDL of 130. Taubes' book says there are multiple different types of LDL and only the small dense LDL is dangerous. My question - if there are multiple different types of LDL (Taubes mentions a paper which talks about six types), I would expect that the sum of them - i.e. the conventional LDL measurement - would not be a smooth curve against anything. More likely the graph of total mortality against LDL would have multiple minima.

If I explained myself properly, do you see how to square Kendricks' smooth curve against Taubes reporting that LDL is an umbrella for multiple LDL molecules, all with different effects?

Paul.

Peter said...

Hi Paul,

It's the triglycerides which tend to rise during the transition which has been mentioned in various places over the last few months. JK suggests TC and LDL can rise then fall. It strikes me that they can rise then stay high (again, personal anecdote!).

When you look at the U shaped TC (which will probably parallel LDL) against mortality curves you have to bear in mind that these are from people on the SAD or the equivalent. We have no idea about what is in the lipoproteins or what their glucose control is like.

Six seems a modest number of types for LDL subtypes. I doubt there are so few and in all probability there is a spectrum from small dense to large bouyant. The more sugar you eat the iller you get and the more small dense LDL you make. Which matters? I know Chris Masterjohn is sure that small dense LDL is both the stickiest and the most coated with lip(a). But until you can get a human to have small dense LDL without eating sugar, how can you tell which matters?

It also strikes me as difficult to get an LDL cholesterol measurement as high as mine is (100mg/dl above yours) if they are all small dense particles. They could be I suppose, but I doubt it. Again, if you are in to HDL being protective (Kendrick isn't) you must be phenomenally protected at HDL of 88mg/dl!

Overall your numbers come over as someone eating a high saturated fat, LC, minimal PUFA diet. I don't see as you could do better.... (but I know what you mean!).

Peter

gunther gatherer said...

Hi Peter and Anna.

Thanks for your tips regarding TSH. I'm going to try to handle my low thyroid as naturally as possible, and I agree with Anna that iodine deficiency could always be a factor when you grow up in the western world. My symptoms were more than just sluggish weight loss, also perenially cold hands (much better now after OD), low body temp, bad sleep quality, hair loss, generally thick skin, etc. Even periodic TMJ and jaw pain associated with thyroid (as I read it).

There are other factors such as adequate minerals and Vit D, and although I've been an Optimal Diet advocate for several months now, it's only recently that I've started to eat offal regularly, even in lieu of muscle meat altogether (thanks to Stephen for nudging me in the right direction on that). I guess only time will tell.

But I'll have bloodwork done once I'm a full year into OD, and will be sure to post the new TSH results. Thanks again.

Anna said...

Gunther,

TMJ & jaw pain? Wow, didn't know that one. I had TMJ troubles with aches in one ear way back in college into mid-20s, which I attributed to clenching during the cold NE US winters. That was during my very skinny/eat-anything-I-wanted days. Between a nightime bite guard, behavior-awareness and modification, and moving south to a milder climate, it mostly resolved itself. That was long before I had "the" big metabolic shift when I was 29-30 yo (suddenly "filled out" after being perpetually skinny and underweight) after some some extreme stress lasting a few months.

I was surprised to realize that some breathing related issues cleared up once on a stable T4/T3 regimen. I didn't even make the connections, my husband and son did. I used to have violent coughing fits, usually waking me (& my poor husband) at night (but sometimes in daytime, too, especially when I was pregnant - that was my strange version of morning sickness). The violent coughing doesn't happen unless my dose needs the fall season adjustment. I now think it was apnea, due to weak muscles in my soft palate. I don't have other symptoms of apnea (my weight is pretty much ok and I sleep on my side with my mouth closed, don't snore, etc.).

The other strange breathing thing is that for years it was a family joke about how I would start uncontrollable yawning and extreme sleepiness within a few minutes, every single time I read aloud to my son. My husband often had to take over with longer reading sessions. Didn't happen with ordinary talking (never a problem with that!). A few months after I started thyroid hormone, my son noticed the yawning had stopped (he of course had no idea about the T4/T3).

Also, in hind sight I think I wasn't converting carotenes well- I had noticed my palms were a funny color, sort of orangy; now the orange tinge is gone. Fingernails grow faster and stronger now, too.

Do you have any of these symptoms, Gunther?

I'm trying hard to get my Vit D levels out of the lower end of the reference range. It'll be interesting to see if that changes anything.

Anna said...

Paul,

I don't have the numbers in front of me, but my lipid profile is similar to yours and I don't fret about it (my endo does!). TC has gone up a bit and so has LDL, but then again so has HDL so the TC/HDL ratio has "improved" even more (which keeps my endo from arguing with me). Knowing that my diet makes numerous small dense LDL particles unlikely, I don't see any reason to worry. But a few years ago when I knew far less about the LC zkvbxqdietary influences on blood lipids, I would have been quite uncertain.

gunther gatherer said...

Hi Anna.

Yes, I believe TMJ is a symptom of thyroid issues, as is sleep apnea. I had that too! But now that's gone (well I may still snore, but nowhere near as bad as before, with morning headaches and waking myself up during the night, etc.).

I really sleep better on OD, along with adequate Vit D and some mild exercise (walking) and have started dreaming again for the first time in years. No more fatigue during the day and no more hitting the wall at around 3 o'clock with the necessary 5 cups of coffee to get me through the work day. All that is gone. It's really like a new me.

Given the above improvments, maybe my TSH has already gone lower over the past few months, but I won't know until I spring for the bloodwork. In any case, I've only JUST started to get the OD principles and diet right, so I'm looking forward to even more improvements over the coming year.

Cheers, G

Stephan said...

Excellent. The title of the paper should have been "Heterozygous LDL Receptor Loss-of-Function does not Associate with Excess Mortality Despite Elevated Serum LDL".

Instead, they tried to imply elevated LDL doesn't cause mortality due to "additional risk factors". Typical, unfortunately.

Matthew said...

You're mistaken, healthy people can have insulin levels below what you state. See
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15096581

Click on Table 2!

The average level of insulin for the CR group = Fasting insulin, mIU/ml 1.4 ± 0.8

O Primitivo said...

What about this thing called "LDL apheresis"? Here is an Youtube video with an example: http://www.youtube.com/watch?v=QnJvo6WlxXs

O Primitivo said...

Dear Petro, I really would like to see non-statinators commenting this study: http://www.ncbi.nlm.nih.gov/pubmed/18840879 Have you seen any post on other blogs about this? Regards, Ricardo.

Peter said...

Hi Ricardo,

There are two types of patient represented in this study, and it's impossible to tease out how many of each are represented. Obviously both groups have elevated TC and possibly also elvated LDL. The first group also have tendon xanthomata or have a relative with tendon xanthomata, the second either have established heart disease themselves or it is present in a close blood relative. That's how I interpret this section:

"Patients were classified as having either ‘definite’ or ‘possible’ familial hypercholesterolaemia. A diagnosis of definite familial hypercholesterolaemia in adults was defined as a pre-treatment or on treatment total cholesterol >7.5 mmol/L (or, when available, an LDL-C of >4.9 mmol/L) together with the presence of tendon xanthomata either in the patient or in a parent, child, grandparent, sibling, uncle, or aunt. Possible familial hypercholesterolaemia was defined using the same cholesterol criteria together with either a family history of myocardial infarction before age 50 in second degree relative or before age 60 in first degree relative or, alternatively, a family history of raised the total cholesterol concentration >7.5 mmol/L in the first or second degree relative"

My personal feeling, and I have no data to back it up, is that FH heterozygotes with xanthomata probably have heart disease. If they are depositing LDL in tendons they will be depositing it in their arteries too. I'd expect the pathophysiology to be the same or similar.

If this is accepted then we have a study which pre selects all subjects to be hFH carriers with CVD and notes a reduction is relative risk of about 37% for CVD death with statin usage. This is marginally better than par for the course for statin use in non FH patients with known CVD. So it's basically a secondary prevention trial with predictable results. The criteron for getting in to the study virtually converts it to a secondary prevention trial of statins and has nothing to do with LDL cholesterol. As you know, patients with heart disease are prone to heart disease events.

However elevated cholesterol has long been known to be associated with reduced cancer mortality at all ages and reduced all cause mortality in the elderly. Tweaking the CVD mortality using the pleiotrophic effects of statins in a CVD prone population allows the benefits of elevated cholesterol to show through. Really effective LDL lowering will obviously be expected to increase cancer risk as in the J-LIT statin studies.

People with hFH but without CVD should get the benefits of elevated LDL without needing the statin, but Sijbrands is the only person I am aware of who has looked at unselected heterozygous FH carriers.

Does this sound logical?

Re LDL plasma apheresis I would need to know what it did to the real factors which are implicated in CVD, particularly clotting factors. It's normal for apheresis to be carried out much more frequently than fortnightly and people get anticoagulated for the procedure. Of course you could just describe apheresis as a method for correcting the execrable dietary advice, especially linoleic acid consumption, foisted on FH carriers!

The other procedure you will find is liver transplantation for FH. As the clotting factors are made in the liver this is bound to be a marked confounding factor.

Peter

Peter said...

BTW sorry for the delay, too many shifts but they're all done now!

Peter

O Primitivo said...

Hi Petro, thanks for your detailed answer. I'm wondering if HF is a disease or if, instead, these LDL receptor genetic changes could be somehow related to the evolutionary advantage of being more protected against infections because of the higher cholesterol levels. Can science trace these LDLR genetic changes back to our paleolithic ancestors or, at least, to neolitic times? I've read in a paper that in the 19th century people with FH probably had lower total mortality than the general population. In other words, we need an evolutionary and biological explanation to the higher cholesterol levels we are seeing today. Exactly what biological advantage or forces are driving cholesterol to these upper levels of today? If I went to live with the Bushmen or the Hazda today would my cholesterol imediatelly drop to 150 mg/dl? - "Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study." - http://www.ncbi.nlm.nih.gov/pubmed/11325764

Peter said...

Hi Ricardo,

The paper you cite is Sijbrands and is one of the few publications to look at heterozygious FH without pre selecting for CVD.

My overall impression is that elevated LDL cholesterol is protective against sepsis problems but makes it harder for an individual to cope with what ever the modern triggers are for CVD. If you were to put an hFH person in to a HG diet and lifestyle pattern I suspect they would do well. Putting them in to Europe or the USA in the 1940s is probably not such a good idea if they have any tendency to metabolic syndrome...

I still wonder how a sucrose free, linoleic acid free, trans fat free hFH person would cope without the wonder of statins. I doubt we are likely to find out in the near future... As we know the dietary advice for hFH patients is completely untested, and probably wrong!

http://www.ncbi.nlm.nih.gov/pubmed/11406018

Peter

Jana said...

Hi
I read many of your posted articles and I'm interested about them.
I'm 45 years old.
High level of cholesterol was found 15 years before. My cholesterol
level is 15 years in interval 7,9 - 9,5 mmol/l. My diagnosis is
Heterozigot familiar hypercholesteremia.

Here are my current values from October 2010:
TK:113/70 Weight:54 Height: 164 BMI:20.8 Total cholesterol: 8,800
mmol/l
HDL-C: 1,460 mmol/l
LDL-C: 6,699 mmol/l
Apo-B: 1,980 mmol/l
Apo-AI: 1,690 mmol/l
RI1: 4,588
RI2: 1,172
TG: 1,410mmol/l

High cholesterol level 7,4 mmol/l found also at my 20 years old dother.
My 82 year old father has cholesterol at level 7,0 mmol/l and 81 year
old mother has 6,4 mmol/I. There are healthly.
Dr.Davis wrote in Herth scan blog:
articles: Saturated fat and large LDL
If, on the other hand, your small LDL is genetically programmed, then
saturated fat will increase small LDL. In other words, saturated fat
ends to increase the dominant or genetically-determined form of LDL .
(eg, variants of the gene coding for cholesteryl-ester transfer
protein, or CETP).
This means that sacharids, also unsaturated oils and saturated oils are
bad for my genetic familiar hypercholesteremy ?
My question is simple. How to lower my cholesterol level without statins ? Does exists any natural way ?

Magarietha said...

hi, I stopped worrying about our family's heterozygous FH (homozygous is another story altogether!) - ok so we have one of the "off" genes. My mother will turn 83 this year and she only found out she had it in her sixties. Could never take statins (none of us can) as we get rhabdomyolisis within a week - we WILL get kidney failure on statins - fact! Now for my heartbreak - OMG - my beautiful gentle spirited, never angry, eldest son over this christmas period got QUNTUPLE bypass surgery. Apparently just in the nick of time. Without telling us, he had become weakened and out of breath with numbing fingers progressively the last few months. I got the fright of my life, cannot get over this. He is currently convelescing at home. Can one of you goodly doctors please tell me why the thoracic surgeon said he had unusually hard arteries (also blocked) but this hardness of the arthery wall seems to me disturbed them. HOW can we get them softened? Please help, since he cannot take statins and apparently the fibrates are not indicated in our collective "case". My son is 34. Apparently there is a new drug in the offing, but he doesn't qualify for trials as they only take ppl over 40. Wld appreciate any help. In myself a keto diet worked swimmingly, but I cannot get my 2 sons to go onto it and I feel we were thrown a lifeline with this diet. My numbers normalided on it!!! Hlp please. I am sobbing under the cover of darkness.

Peter said...

Hi Magarietha,

I'm sorry to hear about your son. I doubt anyone has any cast iron answers but if I had to have a guess I would, as you already know, suggest that unremitting normal blood glucose levels are essential. Along the lines of Dr Bernstein's concept of 4.6mmol/l, 24/7. I doubt this could achieved without a ketogenic diet and the ketones would go some way to normalising metabolism in the vascular wall cells. Avoiding elevated insulin levels would be helpful.

The problem is that people simply do not believe this, which is their prerogative, or simply do not wish to do it, preferring to await a drug which will allow them to run hyperglycaemic blood levels after meals without consequence. Needless to say, this will be a very long wait.

Ultimately each person needs to make their own decisions. I doubt something as fundamental as a ketogenic diet could be imposed by even the most well-meaning of mothers...

Good luck, best wishes.

Peter

Magarietha said...

Thank you so much for your kind words Peter! Have sent it verbatim to Michael and can only hope that good sense will prevail. Thanx again.