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 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.

Friday, September 14, 2012

More Thoughts on Macronutrient Trends

I had a brief positive exchange with Gary Taubes about the NuSI post.  He reminded me that there's an artifact (measurement error) in the USDA data on fat consumption in the year 2000 when they changed assessment methods.  Here are the USDA data on macronutrient consumption since 1970, corrected for loss (28.8%) but not corrected for the artifact:
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Wednesday, September 12, 2012

Nutrition Science Initiative (NuSI)

Some of you may have heard of an ambitious new nutrition research foundation called the Nutrition Science Initiative (NuSI).  In this post, I'll explain what it is, why it matters, and how I feel about it-- from the perspective of an obesity researcher. 

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Monday, September 10, 2012

Calories and Carbohydrate: a Natural Experiment

In the lab, we work hard to design experiments that help us understand the natural world.  But sometimes, nature sets up experiments for us, and all we have to do is collect the data.  These are called "natural experiments", and they have led to profound insights in every field of science.  For example, Alzheimer's disease is usually not considered a genetic disorder.  However, researchers have identified rare cases where AD is inherited in a simple genetic manner.  By identifying the genes involved, and what they do, we were able to increase our understanding of the molecular mechanisms of the disease.

The natural experiment I'll be discussing today began in 1989 with the onset of a major economic crisis in Cuba. This coincided with the loss of the Soviet Union as a trading partner, resulting in a massive economic collapse over the next six years, which gradually recovered by 2000. 

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Wednesday, September 5, 2012

A Late Summer Harvest

It's been a good year for gardening in Seattle, at least in my garden.  Thanks to great new tools* and Steve Solomon's recipe for homemade fertilizer, my house has been swimming in home-grown vegetables all summer.  I'm fortunate that a friend lets me garden a 300 square foot plot behind her house.  Here's a photo of part of today's harvest; various kale/collards, zucchini, tomatoes and the last of the pole beans:

Perfect for the Eocene diet.  

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Monday, September 3, 2012

Daniel Suelo, the man who quit money, seems remarkably healthy

Daniel James Shellabarger (better known as Daniel Suelo) is portrayed in the bestselling 2012 nonfiction book by Mark Sundeen titled “The Man Who Quit Money” ().

Apparently Suelo stopped using money in 2000, and lives in a cave near the city of Moab in Utah. His diet comprises primarily wild vegetables and fruits, insects, and road kill; as well as discarded or donated food he gets from others when he visits the city. The photo below is from a recent BBC documentary. An interesting 2006 YouTube clip on Suelo is titled “Moneyless in Moab” ().

Suelo is listed as having been born in 1961 (), and the photo above appears to have been taken in 2012. If these dates are correct, he is 51 in the photo above. I cannot help but think that he looks remarkably healthy. The 40-50 age period is one that often sets the stage for many diseases of civilization in urban societies.

Suelo’s decision seems like a radical one, at least to me. There are always complex motivations behind radical decisions. In the case of Suelo, some of these motivations are captured in the comment below, which is part of a review of the book “The Man Who Quit Money” posted on by a reader.

[…] a picture of Suelo not as an untarnished hero, but a man who has wrestled with heartbreak, depression, disillusionment with his family's faith, and his repugnance to working for the pure sake of making money and buying things. Whether or not you are inspired to follow Suelo's example, this book will make you think.

Many people have been inspired by Suelo’s story, to some extent because they see that adopting a radical form of “simple living” () may not only be possible but also liberating. Obviously Suelo’s lifestyle, as it is now, would not be possible without the help of others who adopt a more “traditional” lifestyle. Below is a critical review by a reader of the book, posted on, which harshly reflects this perspective.

Any infantile mentality charmed by this inane story should simply generalize the message - visualize a world in which all of us live like the parasitic protagonist. How fortunate for Suelo that there are still people who engage in productive work and indirectly and unknowingly keep the human sponge alive […] Suelo never quit money he simply quit contributing anything and continues to survive simply as a parasite.

Still, Suelo’s story is interesting, including from a human health perspective. An article on by Christopher Ketcham provides a glimpse at what a day in Suelo’s life looks like (). It seems that on most days he has one main meal per day.

It is hard to get a sense of the nutrient composition of his diet. It looks like his diet is limited in but not devoid of industrial foods, and one in which food consumption is sporadic, opportunistic, and driven primarily by hunger and availability – not by stress or set meal times, for example.

He probably walks a lot; his cave is one hour away from Moab by foot, and it looks like he goes to Moab often. Apparently he almost never gets sick.

Suelo also writes a blog (), which has many followers, and also maintains other websites, from the Public Library in Moab. His first blog post has over 1,000 comments under it ().