Your gallbladder and why it’s important

Yesterday I had a video coaching session with one of my patrons, and the last thing we talked about was the gall bladder. They recently had an ultrasound done to check out the insides of the abdomen—obviously to make sure everything looks good. The kidneys looked good, the liver had a small benign lump of 1–2 mm  in size (angioma sounds so much more serious), and the gall bladder had a bunch of little stones. I asked what the doctor recommended.

“There’s nothing to worry about. Let’s check again in half a year.” That was it. Nothing more. So, they asked me if there was anything that could be done to help in some way.

What do you think? Is there not always something that can be done to help—to help the body cleanse itself, repair itself, heal itself, improve its physiological and metabolic functions?

We’ll take the time to study and explore the liver and its functions in greater detail later—the liver is a lot more complex. The gall bladder is quite simple, and so, I just wanted to share with you what I explained yesterday, and at the same time, take the opportunity to expand a little on that.

First the Anatomy

Looking at the abdomen from the bottom of the sternum (the bone between the pectorals) to below the hips, after having removed the skin and layers of muscle, cut out the front part of the ribs, and changed the appearance to make it cartoon-like, without any blood, veins, arteries, or nerves, and thus not so shocking to look at, we would see something like this:

abdomen-front-labels

Digestive system: front view with labels

The large, dark red organ that is the liver sits at the very top of the abdomen with its largest lobe located on the right side of the body. On the left, below the liver’s smaller left lobe, is the stomach that curves back towards the middle where it connects to the small intestine (duodenum). The gallbladder—the small dark green pouch—is nestled between the bottom of the liver’s right lobe and the first part of the duodenum. Below the stomach, sweeping across the abdomen from one side of the body to the other is the transverse part of the large intestine (colon). The entire lower portion of the abdomen is filled with the longest segment of the intestines.

If we zoom in on the upper abdomen,

upper-abdomen-front-nolabels

Upper digestive system: close up front view

and then hide the liver,

upper-abdomen-front-noLiver-nolabels

Upper digestive system: close up front view without liver to show bile ducts

we see all of the little green ducts embedded into the liver whose function it is carry the bile from the different parts of the organ to the main bile duct and gallbladder.

Taking a look at the same part of the abdomen from the back,

upper-abdomen-back-top-labels

Upper digestive system: close up back view with labels

we see how the gallbladder sits between the liver and duodenum, and how the main bile duct sweeps down behind the pancreas to connect to the main pancreatic duct such that the bile from the liver and gallbladder can be injected into the small intestine together with the enzymes, insulin, glucagon, and bicarbonate from the pancreas. We also see from this side the dark red, bean shaped, right and left kidneys, and the yellow adrenal glands sitting on top of them.

And then the physiology

Why do we need bile and what does it do? Why is there a gallbladder? And what is bile anyway?

Bile is 97% water, 0.7% bile salts (sodium and potassium), 0.5% cholesterol, fatty acids, and lecithin, 0.2% bilirubin, and a tiny bit of inorganic salts. In human adults the liver produces 400–800 ml of bile per day (Wikipedia).

The liver produces bile continuously but slowly. When we eat, depending on how much fat there is in the meal, the digestive system may need quite a bit of bile to handle the fat that was just ingested. Hence the need for storage and thus the function of the gallbladder.

The purpose of bile is to emulsify fat. Emulsifying means making into tiny droplets that can mix into another liquid to form a smooth homogeneous solution. For example, a bit of mustard works very well to emulsify the oil and vinegar that would otherwise not mix into a smooth creamy vinaigrette. After emulsification, fat droplets are typically 15–30 microns in size.

We need bile to emulsify the fats that we eat so that the pancreatic enzyme lipase can then break these triglycerides down into monoglycerides and free fatty acids. This is done in the small intestine where the bile and enzymes are secreted from the pancreas with the bicarbonate solution. This in turn allows the fat to be transported through the intestinal wall before being reassembled into triglycerides and absorbed into the lymphatic system. Without bile, fat could not be absorbed. It would go straight through the gut and be excreted undigested.

Why would stones form in the gallbladder? Is there a way to prevent the formation of gallstones? And what actually are these gallstones?

Gallstones are basically little hard lumps of cholesterol. One of the functions of the gallbladder is to concentrate the bile which comes in quite diluted, as we saw earlier, being 97% water. But when the concentration grows too high, then cholesterol precipitates out and forms little lumps. These are what we call gallstones.

Given that we know that stones form out of precipitated cholesterol when the concentration of the bile is too high in the gallbladder, it is simply logical that if the concentration can be kept low enough, below the threshold at which cholesterol will precipitate, then no stones would form. But why does the concentration of bile grow to the point of precipitation?

Let’s ask another question: what happens if we don’t eat much fat? The liver produces bile continuously, between 400 and 800 ml per day. This bile is stored into the gallbladder until it is needed after a meal in which fat was ingested. If we don’t eat much fat in a meal, then, naturally, not much bile will be needed, and most of the available bile will therefore remain in the gallbladder. Because the liver continues to produce it, the gallbladder needs to make room for it, and thus concentrate its contents further.

So, what happens if we never eat very much fat, and if actually, every meal is a relatively low fat meal? Well, what happens in a pool of water if the water does not flow out, and is by this not renewed by fresh water? Stagnation. In the case of the pool of water, we all know what happens: it grows dirty, then thick, then greenish, then totally filled with lumpy green gelatinous stuff. In the case of the gallbladder, we can imagine that something analogous takes place, and that the lumps of cholesterol are like the lumps of green gelatinous stuff in the water.

The solution is simple: eat plenty of fat on a regular basis. This way, the gallbladder can empty itself out regularly, and the bile does not stagnate, grow more concentrated, and eventually lumpy with gallstones.

Your gallbladder and why it’s important

Here’s what we learned:

The gallbladder sits between the right lobe of the liver and the first part of the small intestine. It stores and concentrates bile which is mostly water with small amounts of salts, bilirubin, lecithin, and cholesterol. The liver produces bile continuously in the amount of 400 to 800 ml per day.

The function of bile is to emulsify the fat we eat to make it absorbable. Without bile, fat just go through and gets excreted undigested. The same is therefore true for all fat-soluble minerals and vitamins, including some of the most important of them all, the crucial vitamins A, D, E, and K2.

If we don’t eat fat, there’s no need for bile. If we don’t eat much fat for a long time, the bile will get more and more concentrated. Eventually, the concentration will be high enough for cholesterol to precipitate out of the bile and form little lumps. These lumps of cholesterol are called gallstones.

Imagine that this continues for years and even decades, following a good “heart-healthy” low-fat diet. What do you think will eventually happen based on what we’ve just discussed? More stagnation, more highly concentrated bile, more gallstones, and then at one point, this whole thing explodes into acute infection, acute inflammation, excruciating pain, and emergency surgery to remove the infected gallbladder.

And then what? I’ll you finish this exercise in deductive reasoning which you now have all the necessary background to complete.

 

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Why every undigested protein is an allergen

We come out of our mother’s womb, and we are very soon thereafter given a bottle to suckle on. In the bottle there’s a powdered ‘infant formula’ mixed with water, or milk, or both. “The most commonly used infant formulas contain purified cow’s milk whey and casein as a protein source, a blend of vegetable oils as a fat source, lactose as a carbohydrate source, a vitamin-mineral mix, and other ingredients depending on the manufacturer” (source: Wikipedia). The water is municipal tap water with residues of agricultural and industrial chemicals, of prescription drugs of various kinds, fluoride that suppresses the immune system and makes the bones and teeth brittle, and chlorine that kills the bacteria and destroys the flora of the gut. The milk is most likely UHT, which stands for ultra high temperature pasteurised, cow’s milk from cows that have never set food outside, have never eaten a blade of grass, have only ever eaten soy, oats, and corn, and have their whole lives received antibiotics preventatively to lower the probability infection due to the fact that they are sick and immunosuppressed from the living conditions they are subjected to. How’s that for a start?

We start teething and we are given ‘teething cookies’ to nibble on. Cookies, like Gerber’s classic arrowroot cookie, made wheat and arrowroot flours, dairy proteins and solids, vegetable oils, sugars, and other stuff like stabilisers, preservatives, texture and flavour enhancers, and some added vitamins and minerals, of course.

We don’t need to have teeth to have ice cream. In fact, parents are encouraged to give cold things like ice cream teething infants to soothe their gums aching from the teeth pushing through them. And we love it, of course! We’re still far from being able to speak, but we eagerly await the next spoonful, which, if delayed too long, makes us impatient, and soon angry enough to cry out and let our parents know we want more.

Naturally, we never make a fuss when we are fed apple sauce, or pear sauce, or pureed bananas, peaches, or apricots, nor when we are are given mixes like banana-strawberry, or strawberry-kiwi, or even apple-carrot-parsnips. We also like sweet potatoes, squash, and even regular mashed potatoes with our pureed meals. But the green things like mashed pees or broccoli, that we like less—quite a lot less.

We always start the day with orange juice. In fact, this is so much a part of our upbringing that we can’t even imagine a morning with having orange juice. And as soon as we can chew, our breakfast is made of those delicious, sweet and crunchy cereals served in a big bowl of milk. This is another part of our upbringing that is so much a part of us that we  often consider it a normal part of life, and can’t imagine a life with it.

We snack on cookies, on muffins, on granola bars, and particularly like the chocolate covered ones. We snack on chips, crunchy and salty—on Doritos, Pringles, and all sorts of different kinds of chips—and we love them too. We love our regular home pasta dinners, our pizza dinners, our hot dogs, our burgers, our fries. When we’re hungry in the afternoon, we make ourselves those delicious peanut butter and raspberry jam sandwiches on ultra moist slices of white bread, and they’re so good we have a hard time to stop eating them one after another. And what about our Nutella, that amazing chocolate spread we can never have enough of? We really could eat the whole jar if we didn’t force ourselves to stop. It’s so delicious we even eat it by the spoonful when we don’t feel like having bread with it. And they tell us it’s good for us, that’s a good source of nutritious milk and hazelnuts. Wow! How great!

We get sick pretty often as school children, but not more than anyone else, about ten times a year or so. Our parents seem to get colds less often than we do, only about 4 or five times per year. Sometimes it’s worse than others, and we are given antibiotics. We take them because our parents give them to us. And they give them to us because our family doctor tells them to. We get loose stools for a while, and we don’t understand why. After some time, things kind of get back to normal.

We go on like this for years. Actually, usually for at least two or three decades. Everything we do destroys our gut flora. All the foods, the chemicals, the drugs, destroy the essential health-promoting bacteria and the balance between the different varieties that are meant to populate the gut, and at the same time promote the overgrowth of specific kinds of pathogenic bacteria and yeasts that take over our gut.

All the foods we eat are loaded with lectins that damage the lining of our gut, making it thinner, less functional, less protective, and more vulnerable to further damage. This damaged gut with its damaged lining and damaged glycocalyx becomes leaky. Not only do we not digest food properly, not only do we not absorb nutrients properly, not only do we not excrete wastes properly, but all sorts of stuff starts leaking from our gut into our blood. And possibly the worst thing that can happen is to have a leak into our bloodstream of undigested proteins.

The reason is that undigested proteins in the blood trigger the immune system that responds to them as allergens. As this is the result of a degenerative process, and is therefore a chronic condition that grows more severe with time, the dysfunction eventually manifests itself into auto-immune disease conditions. Those ‘incurable’ disease conditions on which modern conventional medicine has given up. This is how serious it is.

Proteins from out food are not meant to enter the bloodstream—ever. So much so that the kidneys will completely clog themselves up trying to remove proteins from the bloodstream to the point of kidney failure. Proteins are meant to be broken down into the much smaller units of which they are made called amino acids. And breaking down proteins into amino acids is meant to be done by the stomach before entering the intestines. Hence, having not fully broken down proteins in the gut can only really happen if they haven’t been broken down while they were in the stomach. Clearly, it isn’t therefore only the gut that is dysfunctional and damaged: the stomach must also be dysfunctional in some way to allow these undigested proteins to pass into the intestines in the first place.

We have previously looked in detail at the process of digestion in Understanding digestion. The essence of what we need to know is that the stomach has specialised cells whose purpose is to secrete hydrochloric acid to break down proteins; that acid is produced when these cells detect the presence of protein in the stomach; that as proteins are broken down, the pH rises and the stomach secretes more acid to keep the pH low in order to continue breaking down the protein; that when the pH stays low for a few hours or so, this signals that all the proteins have been properly broken down, and that the chyme (the processed contents of the stomach) can be transferred to the small intestine; and that at which point the stomach valve opens, the acidic chyme moves through, and the pancreas injects into the small intestines a concentrated solution of bicarbonate to neutralise the acid which would otherwise damage the lining of the intestines. This is how it’s supposed to work.

But if there isn’t enough bicarbonate in the system, the pancreas cannot do this properly. If there isn’t enough water, the pancreas cannot do this properly. If the stomach doesn’t produce enough acid, the proteins are not broken down properly. And if the acid producing cells of the stomach are not regularly exposed to high concentrations of hydrochloric acid, they lose their ability to produce it. This happens when little or no concentrated sources of protein are eaten, like when we are vegetarian or vegan for a long time. But it also happens when the lining of the stomach, which is supposed to be protected by a thick layer of mucus while digesting protein, is instead exposed to and damaged by its own hydrochloric acid. This happens when there isn’t enough water to make that protective layer of mucus, and it is why we should drink water before meals.

So, here’s what we get: not enough water or bicarbonate—loss of acid-neutralising function of pancreas, and damage to intestines; not enough protein in the diet—loss of acid production ability, and undigested proteins; not enough water—damage of stomach lining, loss of acid production ability, and undigested proteins; undigested proteins—chronic immune response to circulating allergens and autoimmune disease conditions. This is compounded with the damage that results from exposure to chemicals and antibiotics, from the overload of sugars and starches, and from the destruction of the cells lining the gut by the lectins in our diet.

The end result is, as expected, precisely what we observe: a population where basically everyone has, to some extent, compromised digestion, and therefore, a population where everyone is, to some extent, sick. Because we don’t know any of this, because we don’t know how food affects the body, because we don’t know how the organs of the body function, because we don’t now how digestion works, and because nobody else around us knows any of it either, we believe everything is normal and everything is just fine, just as it should be, just as it always has been. But the truth is that it isn’t.

What’s actually hard to believe is how simple the solution is: 1) avoid as much as possible exposure to chemicals and antibiotics, and adopt measures to systematically help the systems of the body cope with and recover from the exposure we cannot entirely avoid; 2) avoid as much as possible the overload of sugars and starches, and focus on animal protein and fats from free range animals, and green vegetables. This will automatically lead to a nutrient-dense, whole foods diet that also minimises exposure to gut-damaging lectins; 3) drink plenty of clean water to ensure good hydration, especially with enough time to replenish the stomach’s and pancreas’s reserves before meals, and take a little extra bicarbonate on an empty stomach with your first glass of water in the morning to maintain a good alkaline buffer and balance.

 

This strategy is so simple, and yet it is both preventative and curative. The extent to which we need to be strict depends on the extent of the damage from which we need to recover. And as it true for everything, it’s far easier to prevent damage than to recover from it. That’s obvious but it’s good to remind ourselves of it when our motivation weakens or strength of will falters. The amazing news is that, as shown by doctors Terry Wahls and Steven Gundry who specialise in the treatment of autoimmune disease conditions, recovery from even the most severe cases is virtually guaranteed and only a matter of consistency, patience, and time. I hope this is enough of a motivation for you. Enough of a motivation to at least start to make the effort to regain and then preserve the health of your gut and digestive system—the system on which everything about your health depends.

Oh, and breakfast? Just skip it and have your first meal at lunchtime. Breakfast is not, as we have been told over and over again, the most important meal of the day. It’s actually the most important meal of the day to skip. We’ll get back to this point some other time.

Every undigested protein is an allergen

If someone asked you what you thought was the most fundamental, the most essential, the most important health challenge that we face as modern human beings living in industrialised countries, what would you tell them?

Take a moment. Shift your gaze away from this text, and think about it.

When we read or hear something about health and nutrition in the news, on websites, on blogs, on social media, or even in books, the information we encounter is almost always biased and directed  in some way. It is also always restricted in scope. In fact, it is usually very restricted in scope. All this is perfectly natural and expected: whenever we sit down to write, it is usually about something in particular, something specific, some topic we want to address or explore. It’s hard to think of circumstances where this would not be the case.

Moreover, basically everybody who writes anything, does so in order to be read, and therefore naturally attempts to appeal as much as possible to their readership, both in content and in style. But maybe the most influential factor is that we have grown accustomed to information packets, to bite-size bullets of information: quick-to-read, quick-to-scroll-through, and quick-to-either-share-or-forget. And this has above everything else shaped the way information is being presented by all those people out there trying to appeal to more readers. Little can be done to counter this tendency. It’s just how it is at this time.

As a consequence, for all these reasons, we are—the whole world is—migrating away from the mindset that encourages inquiry into the global, the general, the underlying aspects of things. Instead, we are migrating towards an evermore concentrated, focused, laser-beam approach to basically everything. This is true in all fields of study and inquiry to some extent. In matters of nutrition, it is particularly noticeable, and the reason is surely at least in part because we tend to be at the same time very interested and highly sensitive to advice about what we should or should not eat. We take such advice very personally, and often react strongly to it.

Our relationship to food is very deep because it is so constant and continuous, so intimately related to our survival. This relationship starts when we come out of our mother’s womb, and persists throughout each day, every day of our life, until this life of ours itself comes to an end. What in addition makes this relationship so close and so intense is that if we don’t drink or eat, usually even for a few hours, we get headaches and stomach aches, we get light headed, weak, and unable to concentrate and function, we get grumpy and irritable. It is very clear and naturally understandable that we therefore tend to be—that we are—very sensitive to advice about what to eat, but immensely more so to advice about what not to eat, especially if we happen to eat those foods about which the advice is given.

Hence the movement to superficial, non-contentious, bite size bullets of information: ‘blueberries are excellent: they are low in sugar and full of antioxidants’; ‘avocados are amazing: they are not only full of healthy fats but they are also alkalising’; ‘hydrogenated vegetable oils are very bad: they are full of toxic trans fatty acids.’

But what about the essential, the fundamental, the underlying aspects of things?

You have had more than a few minutes to think about it. What would you say, then, to this question of what is most fundamental to the health, to what constitutes the most fundamental health challenge we face? I would say it’s digestion.

Digestion is where everything about us begins and ends. It is in and through the digestive system that we absorb all the nutrients from our food and excrete all solid wastes. It is through the digestive system that we absorb all the constituents of everything that we call body, and excrete all that is toxic, be it produced from the environment or from within through healthy digestive and metabolic processes. Do you find this sufficient to illustrate why digestion is so fundamental? For me it is. But we can go a lot further.

Evolutionary considerations, arguments, and observational evidence, are always useful, and usually very powerful in guiding clear thinking about matters of health. One of the main questions that has and continues to preoccupy evolutionary biologists is that of the growth of the human brain. In this, one of the most compelling ideas put forward to explain its evolutionary history is called The Expensive Tissue Hypothesis. I plan to, in the future, devote much more time to it. But I must refer to it here because of its relevance to digestion.

The Expensive Tissue Hypothesis is based on the fact that there is a strict minimum to the amount of calories any animal requires to survive, the observation that the brain is the most metabolically expensive organ in the body, and the conclusion that it would be very hard for any large complex animal to sustain two systems as energetically expensive as the brain. Because the gut is the second most metabolically expensive, and because both the brain and gut together account for a disproportionately large fraction of the body’s caloric needs, an increase in the size of the brain would necessarily be at the expense of that of the gut, and vice versa. It simply would not be possible to sustain both a large brain and a large gut. And thus, the growth of the brain would have to be accompanied by a shrinking of the digestive system. This is what is observed.

However, it is important to emphasize that it is the shrinking of the digestive system that allowed for the growth of the brain; not the growth of the brain that precipitated the shrinking of the gut. The growth of the brain would only be possible with a surpluss of calories for it to growth and have its increased activity sustained. It is even more important to emphasize that this evolution was the unintended consequence of a shift from a high-fibre, nutrient-poor, plant-based diet, to one consisting mainly of low-fibre, nutrient-rich, animal-based foods.

Number two Silverback Mountain Gorilla (Gorilla gorilla beringei) of Kwitonda Group, Akarevuro, Virunga Mountains, Rwanda

Male mountain gorilla of the berengei berengei subspecies of eastern gorillas in Ruanda (Source: Time). As you can see from the chest muscle definition, this adult male’s bodyfat is low. The huge bulging belly that is apparent when they are seated and relaxed is the consequence of having it hold the very long gut required to process each day approximately 20 kg of fibrous roots, leaves, and stocks of the plants they eat.

It is very interesting—and it is surely related to this evolutionary history—that the gut has by far the largest number of nerve endings, second only to the central nervous system. Moreover, unlike other organs and systems of the body, all of which are entirely controlled by the brain, it is the only one with directive nervous signalling to the brain. Because of this, it is the only organ with a direct influence on the brain. Thus, besides the physical implications, some of which we’ll explore soon, it is quite literally the case that a happy gut means a happy brain. And conversely, a sad, unhappy, depressed brain is very likely to be caused by a dysfunctional gut.

It is a sick, dysfunctional, damaged gut that is the primary characteristic underlying states of disease. This is why I would say that it is a sick, dysfunctional, damaged gut that is the most fundamental health challenge we face today as modern human beings.

I know this might leave you hanging. Especially because we have not yet made any reference to the title. But I promise, we’ll pick up from here next time.

 

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Understanding the role of vitamin K-dependent proteins in vascular calcification

What if the process of arterial calcification was regulated from within the cells of the blood vessels, and that it had nothing directly to do with what you ate and what circulated in the bloodstream because calcification takes place not anywhere near the surface but inside the blood vessel wall?

What if the process of arterial calcification was actually a process by which muscle is transformed into bone, a process by which vascular smooth muscle cells transform themselves into bone cells which then actually build bone tissue within the blood vessel wall?

And what if apoptosis preceded calcification, what if cell death was what triggered the process of calcification, and it was the apoptotic bodies of dead vascular smooth muscle cells within the blood vessel wall that served as the nodes around which calcium crystals formed?

Would you not find this shocking? Find it incredible that any of these could be true, let alone all of them? It’s entirely not at all what we’ve been told by “health experts” and “health authorities” for more than half a century!

All of these statements are hard to believe. It is especially unbelievable that muscle cells can change into bone-building cells, and begin to grow bone tissue within the artery wall. It sounds surreal, kind of like science fiction. But it isn’t. All of it is true. All of this has been observed.

Interesting, you may think, but what does any of this have to do vitamin K? Everything! It has everything to do with vitamin K.

How clever we are

The sophistication and precision of biochemical reactions and processes in animals and humans are mind blowing. Understanding how they work is a wonderfully noble endeavour that is certainly very fulfilling in its own right. In some cases though, it can be a matter of life and death. And in the case of the processes related to and regulated by vitamin K dependent proteins it definitely is.

This is not an exaggeration to push you to read on. It’s a statement of fact. And you’ll see how this is true by the time we finish. I believe it is essential, for each one of us to understand the details of how things in our body work and how they are related and connected in order to appreciate their significance and their importance.

We are so clever. We can figure out such complicated things when we put our minds to it. Things like complex biochemical pathways, or long chains of enzymatic reactions that, one step at a time, transform molecules from one form into another. And it is this kind of cleverness that has enabled us to develop the hundreds of different types of medications we can find today in drug stores.

We have designed medications to address basically every symptom we can think of. If it’s a symptom we’ve had, it’s most likely a symptom that many others have or have had. And if many have the same or a similar symptom, we can be sure that at least one pharmaceutical company will have made a drug for it.

Warfarin was developed in the 1950s to prevent or at least suppress coagulation, and in so doing help prevent or at least reduce the number of strokes and heart attacks. Because so many people either suffer from, are susceptible to, or are at risk of cardiovascular disease, many people take warfarin.

And what I mean by many in this case is between 20 and 30 million prescriptions per year in the United States alone. The number went up to 35 million in 2010 and dropped back to 20 million in 2015. That’s a lot of warfarin pills! You can see the stats here (http://clincalc.com/DrugStats/Drugs/Warfarin). Warfarin is in the top 50 drugs. It’s 42nd down the list. Just below aspirin at 39, insulin at 36, and ibuprofen at 34, as you can see here (http://clincalc.com/DrugStats/Top200Drugs.aspx).

Surely close to every household in the western world will have somewhere in a bathroom cupboard or drawer a bottle of aspirin or ibuprofen. Given how close to warfarin they are in popularity of usage, there’s clearly no need to even say that this anti-coagulant drug is in broad and widespread use.

Isn’t this great, though? Millions of people at risk of having blood clots that would possibly cause them a stroke or heart attack, protected by taking a little warfarin every day? Yes, I suppose in some ways, it is, if these people are actually at risk. But, unfortunately, with a drug like that, we can be pretty sure that most are taking it preventatively, as in, just in case. And this is a problem.

Warfarin works by disrupting the process that leads to the activation of coagulation factors. The blood’s ability to form clots quickly is one of its most vital functions, because without it we would just bleed to death from a flesh wound. Evolutionarily, we simply would not have made it to here without this protection mechanism that ensured that when we were wounded, the blood would immediately thicken to stop it bleeding out of our body by forming clots at the surface of the open wound as fast as possible. The special proteins responsible for regulating coagulation are vitamin K-dependent proteins (VKDPs).

It has taken a long time to understand, first of all, that there wasn’t just vitamin K, but in fact two different kinds of vitamin K. It is also true that it has taken a long time to identify the major vitamin K-dependent proteins and figure out how they work. We are talking about 40 years from the 1950s to the 1990s. So, you really shouldn’t be surprised if you haven’t read or heard about this before.

But today, a lot has been understood through in vitro and in vivo observations, trials and studies both in animal models and in humans. And even though we will inevitably continue to deepen our understanding of the subtleties of the molecular mechanisms, the species, and the interactions involved in the life of cells and proteins in how they affect the state of our blood vessels and organs, this is a sketch of the picture we have at this stage.

Vitamin K dependent proteins

There are about twenty identified VKDPs belonging to two classes: hepatic—those produced by the liver, and extra-hepatic—those produced in other tissues. Those from the first class are the most well-known and well-studied. They are the coagulation factors (II, VII, IX, and X) manufactured by the liver and activated within it before being pushed into the bloodstream and circulated throughout the body to maintain a healthy coagulation response in case it is ever needed. These are the ones targeted by warfarin. Naturally, since that drug has been around since the 1950s, the role and function of these vitamin-K dependent coagulation factors have also been known at least since that time.

The second class is less known and less studied but has—luckily for us—gained much more attention in the last two decades. It includes three very important proteins whose functions are essential in maintaining healthy blood vessels. But unlike the coagulation factors produced in the liver, these proteins are instead produced by the vascular smooth muscle cells and activated there locally in the vasculature. These vascular health factors, we call them that in analogy to but to distinguish them from the coagulation factors, were identified much more recently in the 1980s and 1990s. All are proteins that contain gamma-carboxyglutamic acid abbreviated Gla.

Some important ones for us here are osteocalcin, for which it took 30 years to be identified as an inhibitor of calcification when it was discovered in vitro to prevent the precipitation of crystals in a supersaturated calcium solution. This means that without it, calcium crystals would have inevitably formed spontaneously in the solution. Osteocalcin is also called bone Gla protein. Growth arrest specific protein 6 is involved in the regulation of cell proliferation, and seems to inhibit premature cell death. And the most important one in relation to soft tissue calcification, matrix Gla protein abbreviated MGP.

Matrix Gla protein was originally isolated from bone, but it has been found to be expressed in several other tissues including kidney, lung, heart, and—most critically—vascular smooth muscle cells or VSMCs. It is now known to be the most potent inhibitor of calcification of blood vessels, and even though the liver does produce and secrete MGP into the bloodstream, only the MGP produced in the vasculature inhibits calcification.

Besides being produced in different tissues, another important difference between the two classes of VKDPs is that the liver-produced coagulation factors are phylloquinone—or vitamin K1-dependent, whereas the vascular smooth muscle cell-produced proteins are menaquinone—or vitamin K2-dependent. In light of the fact that it is rather hard to find vitamin K1 insufficiency with a diet that contains at least some green plant foods, while the exact opposite is true for vitamin K2 of which the western diet is practically devoid, this difference is highly significant.

Both vitamin K1 and K2 are absorbed in the second and third portions of the small intestine, the jejunum and ileum, K1 is delivered to the liver, whereas K2 is transported via LDL and HDL to other organs. K1 is mainly found in the liver, whereas K2 is preferentially stored in peripheral tissues, with the highest levels in the brain, aorta, pancreas, and fat tissues. This obviously attests to the importance of these essential vitamins.

While vitamin K1 and K2 are really two different vitamins with different functions, transport mechanisms, and distribution in the tissues, and while there are several differences between the vitamin K1-dependent and the vitamin K2-dependent proteins, these have one essential thing in common. This is, as their name says, that they are vitamin K-dependent. What this means is that all these proteins share the same enzymatic chain of activation—whether it mediated by K1 or K2—that transforms them into their biologically active form, the form they need to have in order to do the things they are meant to do.

All VKDPs must be carboxylated in order to be activated. The process is complicated and not yet completely understood. We know that it is targeted to the glutamic acid (Glu) residues on the protein that must be made into gamma-carboxylglutamic acid (Gla). We also know that the process is mediated by the enzyme gamma-glutanyl carboxylase (GGC), and that vitamin K is the main co-factor that enables the enzyme to perform the activation. In the end, the process leads to the addition of a carbon dioxide molecule to the gamma-carbon of Glu, which transforms it into Gla. However, it is the reduced form of vitamin K that is required.

Vitamin K, whether it is the plant-based phylloquinone (K1) or the animal-based menaquinone (K2), enters the body through the diet in its non-reduced form. Reduction involves the addition of hydrogen in molecular form, H2, to make KH2. Transformations of this kind are generally always done by enzymes, and so is this one. In this case the enzyme is vitamin K epoxide reductase (VKOR). Its action is essential because it is the reduced form KH2 that acts as the co-factor in the process of carboxylation.

The energy released by the oxidation of KH2 drives the addition of the carboxyl group unto the glutamic acid residues. But the oxidised form of vitamin K, KO, can subsequently be reduced again to KH2. Thus vitamin K is first reduced, then oxidised to help push the carboxyl group unto the glutamic residue, and then reduced once more to start the whole cycle again. This cycle is called the vitamin K epoxide reductase or VKOR cycle.

For this class of proteins, the VKDPs, activation through carboxylation means for them to acquire the structure and properties needed to bind calcium in order to transport it. You may recall from a previous chapter in the story of vitamin K2, matrix Gla protein generally transports calcium out of soft tissues in order to prevent calcification, and bone Gla protein generally transports it into bones and teeth to prevent osteopenia, osteoporosis, and tooth decay.

The big red flag

Now you understand why it is that when, in our remarkable cleverness, we understood that the main coagulation factors depended on the action of these enzymes to be activated and rendered functional, we naturally concluded that the best way to prevent clot formation would be to prevent coagulation, and that this could be achieved by blocking these enzymes from doing what they are intended to in a healthy organism. This is precisely what warfarin does.

And it does it well. Otherwise it wouldn’t have become as commonly used as it is. And we can be certain it has saved a lot of people much of the pain and possibly life-threatening conditions that a blood clot could have caused them. The problem is that the vascular health factors so critical for maintaining healthy blood vessels, depend on the same enzymes for activation as do the coagulation factors. Preventing the carboxylation of coagulation factors, prevents, in exactly the same way, the carboxylation of the vascular health factors.

This was only understood to be a major problem relatively recently. We first had to understand that there isn’t just one kind of vitamin K, but that there are two, and that they are very different in their functions. We had to understand that both vitamin K1 and vitamin K2-dependent proteins rely on the same enzymes to get activated. We had to understand the carboxylation process by which they are activated. And we had to understand that MGP, BGP, and Gas 6 are vitamin K-dependent proteins, that they are specifically vitamin K2-dependent, how they are activated, what they actually do in our veins and arteries, and what happens if they can’t do what they are designed to do.

A major red flag about anticoagulants and warfarin came up from what was seen in mice. The first part of the study was with MGP-knockout mice, (mice in which the MGP-encoding gene was deactivated). They were observed to have stunted growth from the premature calcification of the epiphysis—the part at the end of bones and at the junction with the cartilage of the joint which allows the bone to grow longer. As as soon as the epiphysis calcifies, longitudinal growth stops. But this was the least severe of the problems that were observed.

The MGP-knockout mice very quickly developed severe arterial calcification, and died highly prematurely, within 6 to 8 weeks, of strokes, heart attacks, and rupture of the aorta. Normal lab mice live 2 to 3 years and some even up to 4 years. So, in the least extreme case, a MGP-knockout mouse dying from aortic rupture at 2 months instead of living a relatively short normal life of only 2 years, would be equivalent for a human that would normally live to the age of 72 to die at the age of 6!

Here is what severe coronary calcification looks like in humans:

severe_coronary_calcification

Severe coronary calcification in a patient with end-stage renal disease. We can see that these blood vessels are basically filled with bone tissue that appears bright white. (https://www.bmj.com/content/362/bmj.k3887)

It was also observed that although the liver did produce and release MGP into the bloodstream, it had no effect on the arteries. Only the tissue-specific, locally-produced MGP within the vascular smooth muscle cells was able to inhibit calcification.

To check these conclusions, a similar study was done on normal mice that were given vitamin K1 to ensure proper liver function and healthy coagulation, and warfarin to block all extra-hepatic MGP action in tissues. The result? Stunted growth, pervasive arterial calcification, and premature death from stroke, heart attack, and aortic rupture.

The conclusions were solid: matrix Gla protein is the organism’s primary protection against soft tissue and arterial calcification; liver MGP has no protective effect on arteries, and only VSMCs-produced MGP can inhibit calcification in the arteries; both vitamin K deficiency and disruptions of the action of the enzymes that activate MGP cause extensive soft tissue calcification; and only vitamin K2, not vitamin K1, can inhibit warfarin-induced calcification.

Going further

When this was understood, more attention began to be paid to matrix Gla protein. Many other details were elucidated through further investigations. It was found that MGP is an 84-amino acid protein with five Gla residues. That all of these Gla residues are produced by gamma-carboxylation, which is mediated by the enzyme gamma-carboxylase that requires vitamin K2 as a cofactor, and that until now, the only known function of Gla residues is to bind calcium ions and crystals (calcium apatite). It was discovered that the concentration of calcium and phosphate in extracellular fluids is high enough to trigger and sustain growth of crystals, but that MGP and BGP prevent this from happening. That MGP is required by VSMCs to maintain their elastic and contractile nature. And not just that.

MGP actually inhibits the transformation of VSMCs into bone cells by antagonising the action of Bone Morphogenic Protein 2 (BMP2). It turns out that the muscle cells of the blood vessels have in them the potential to either stay smooth elastic contractile muscle cells, or turn into osteoblast-like bone building cells. BMP2 triggers that osteogenetic gene expression in the VSMCs: it tells muscle cells of the blood vessels to transform into bone-building cells.  And as if this wasn’t enough, BMP2 also induces apoptosis: it tells blood vessel muscle cells to commit suicide, which is certainly to help in the process given that once dead, they can be used as seeds for calcium crystal formation, and thus promote a faster and more efficient calcification.

What induces expression of BMP2 in cells? Probably several things that we haven’t yet identified. But for now we know that BMP2 is stimulated by oxidative stress, chronic inflammation, and high blood sugar levels. The good news is that MGP protects against all of these effects by antagonising BMP2. So if there is enough MGP and enough vitamin K2, if there are no disruptions to the action of the vitamin K dependent enzymes by anticoagulants like warfarin, and if oxidative stress, inflammation, and blood sugar are kept low, then there is protection against calcification of the arteries and other soft tissues like the liver, kidneys, and heart.

Recap

Here we have it. We have now understood the role of vitamin K dependent proteins in vascular calcification. And although it was a little long and maybe somewhat arduous, all the details are clear. It is complicated. I won’t deny that. But I have strived to make it all as accessible as I could without diluting the mechanisms of action and relationship between the different players. Let’s recap to make sure you are left with the essential elements in mind.

Vitamin K dependent proteins can either be vitamin K1 or vitamin K2 dependent. The dependence comes from the fact that vitamin K is required to activate the protein. This activation is the carboxylation in which a carbon dioxide is added to the glutamic acid residues along the protein. Carboxylation is mediated by carboxylase (GGC) that requires the reduced form of vitamin K in order to oxidise it and get the energy to push the carbon dioxide molecule onto the glutamic acid residue. Vitamin K is reduced by reductase (VKOR) which can do it over and over again in what is called the VKOR cycle.

Vitamin K1 dependent proteins are mostly liver based coagulation factors. Vitamin K2 dependent proteins are mostly outside the liver and generally involved in inhibiting soft tissue calcification. The most important calcification-inhibiting VKDP is matrix Gla (MGP), which performs a wide range of tasks to maintain elastic, flexible, calcium-free blood vessel walls.

Calcification is triggered by the death of vascular smooth muscle cells. These dead muscle cells act at seeds for calcium apatite crystals to form. VSMCs can be induced to become osteoblast bone-building like cells that then go on to stimulate the growth of bone tissue within the artery walls. This process is stimulated by bone morphogenic protein 2 (BMP2), which is expressed under conditions of oxidative stress, inflammation, and hyperglycaemia.

To prevent and reverse calcification the most important is to provide a good supply of vitamin K2 through diet and supplementation. Because it is essential in the activation of Gla proteins but only through its role in the VKOR cycle, the amount of K2 is the rate limiting factor. Hence more is better than less, and excess will simply remain unused but will not cause harm.

Naturally, matrix Gla protein needs to be available. Cells of tissues where calcification occurs (kidney, liver, heart, and blood vessels) secrete MGP. An interesting evolutionary self-protection adaptation mechanism. And here’s another: the amount of MGP that is produced by a cell depends on at least two factors that have been identified. One is the amount of calcium; the other is the amount of vitamin D3. In both cases, the more there is, the more MGP is produced.

So, vitamin D3 has the role of making calcium available but at the same time stimulates the production of MGP in order for the calcium to be available to the bones and not to the soft tissues. But for this, it relies on vitamin K2. This is why vitamin D3 without vitamin K2 leads to calcification: because MGP and BGP remain inactive and incapable of binding to the calcium ions to move them into bones and out of tissues. On the other hand, plenty of vitamin K2 would indeed activate the available MGP, but without enough vitamin D3 there might not be enough MGP to confer proper protection against calcification. This is a perfect example of the complementarity of action and function in essential micronutrients. There are certainly many more, but this one is particularly remarkable.

Final thoughts

I want to close on a final consideration. It is so easy and seems so natural for us to think in terms of this and that, good and bad, for and against, that our tendency is to look at everything in these terms. This is also true when we look at biochemical processes like the ones we have described and explored here. We naturally lean towards looking at the calcification inhibiting mechanisms as protective, and those that promote calcification and apoptosis as destructive.

But the reality is that cells, proteins, and enzymes don’t behave in these terms, they don’t think in these terms simply because they don’t think. They react biochemically to what they are exposed to, to the molecules and chemical messengers they encounter, to the quality of the liquids in which they bathe, to the characteristics of the environment in which they live, microsecond after microsecond, without any forethought or concern for the microsecond that will follow. The only guiding principle that can be used to lead us to understand why things happen the way they do is evolutionary adaptation to survive.

Having recognised this, we immediately see that the mechanisms that promote apoptosis of VSMCs, their subsequent transformation to osteoblast-like cells, and the growth of bone tissue within the artery walls that we refer to as arterial calcification, can only be a protection mechanism. A mechanism to protect the tissues and cells from the damaging effects of exposure to free radicals, inflammatory molecules, and glucose. Because, as we have seen, the process is reversible, it would be perfectly natural to undergo periods of calcification followed by periods during which the bone tissue is broken down and removed from our arteries and other soft tissues and organs when the circumstances allow it. Actually, we should say when the circumstances dictate it, because no matter what happens, it is always the circumstances—the environment—that dictate what is to happen.

What we can do, with the knowledge of what we have understood, is make choices about what we eat and drink, when and how much we eat, and how we live, sleep, and exercise. Choices that will shape or reshape, define or redefine the makeup of this internal environment of the body to always move us in the direction of optimal biochemistry, optimal physiology, optimal metabolism, and optimal health.

Everything that we explore together is always about just this. But sometimes the corrective action requires effort, sometimes even a lot of effort. In this case, however, it is as simple as can be, because it only requires us to supplement with vitamin K2 and possibly also D3. Of course, the last thing we want is a lifestyle that promotes the expression of BMP2 and the growth of bone tissue within our arteries. But supplementing with K2 and D3 together will in general bring only benefits. I know it was a very long-winded way to get to this, but now you understand why. That was—and is—the whole point of this blog, after all. I hope you enjoyed reading.

 

The information in this article comes primarily from the following papers: Molecular Mechanisms Mediating Vascular Calcification by Proudfoot and Shanahan (2006); Vitamin K-dependent Proteins, Warfarin, and Vascular Calcification by Danziger (2008); The Role of Vitamin K in Soft Tissue Calcification by Theuwissen, Smit, and Vermeer (2012).

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Insulin and Triglycerides

Every time I review someone’s blood test results, and then discuss with them what they mean and what they should do to improve their numbers, there’s something I almost always have to explain. And this was the relationship between fasting insulin and triglyceride levels.

Take a look at this plot:

trigs_vs_insulin_gb

Plot showing ten pairs of measurements of insulin and triglycerides, made from the same blood samples. They were collected between 2011 and 2017, and all are from my own blood tests.

It shows measurements of insulin concentration on the horizontal axis in mili units per millilitre (mIU/ml), and triglyceride levels on the vertical axis in milligrammes per decilitre (mg/dl). This is a correlation plot in which independent measurements of one variable are plotted against independent measurements of another in an attempt to see if there is a relationship between them.

Is there an order in the way the dots are organized? They are clearly not randomly distributed as a circular cloud of dots—it would mean that there is no relationship. Instead, we see what looks like a linear relationship in which lower values of insulin correspond to lower values of triglycerides, and higher values of insulin correspond to higher values of triglycerides. It’s not a straight line, but it’s definitely a clear linear relationship, and the value of the correlation coefficient, which quantifies how tight the relationship actually is, of just under 0.9 is pretty close to 1. In other words, it’s a pretty tight linear relationship.

Triglyceride is a fancy word for fat or lipid, because fat molecules are composed of three fatty acids held together by a glycerol structure. This is what triglyceride refers to. The amount of fat in the blood is affected by the amount of fat we eat, and the amount of body fat we have. Naturally, after a fatty meal, triglyceride levels will increase as the fat goes from the digestive system into the blood, they will reach a maximum, and then start to go down. The longer we wait before we eat again, the lower they will go. But there’s a few complications.

The first is that depending on the amount of insulin, one of whose jobs it is to transport nutrients into cells, whatever is circulating in the blood—and this includes glucose, of course, but also protein and fat—will in general be stored away faster if insulin is higher, and slower if insulin is lower. This means that if you eat fat together with sugar or starch, the whole lot will be packed away, and mostly as fat, minus the little bit of glucose your muscles and liver have room to store up as glycogen.

The second is that depending on the state of insulin sensitivity—the fundamental parameter that determines how well or poorly cells can use fat for fuel—triglycerides will in general be used up faster if we are more insulin sensitive and slower if we are more insulin resistant. This means that in the morning, twelve to fourteen hours after having had the exact same meal, the more insulin sensitive person will have lower triglyceride levels than the more insulin resistant.

And in fact, no matter if we have a measure of fasting insulin or not, and no matter how little we know about the person’s overall health, fasting triglyceride concentration is probably the best general marker of insulin sensitivity. Nevertheless, because their levels fluctuate quite a lot over the course of each day as a function of what we eat and drink, it is true for triglyceride levels as it is true for many other blood tests that are affected by the kind and amount of food and drink we’ve had over the last days, and most importantly by the amount of sweet or starchy carbohydrates.

Now, take a look at this second plot:

trigs_vs_insulin_final

Plot showing, in addition to the 10 points shown in the first plot (in red), another 20 pairs of measurements of insulin and triglycerides, also all from the same blood samples, but from seven other persons.

It shows the same 10 data points shown in the first plot from my own results, but with another 20 pairs of measurements taken from other people that I’ve coached and helped with the interpretation of their results. You can see that the relationship is better defined because of the additional points that now together cover a wider range of values on both axes.

However, you can also see that, the relationship is not as tight. In particular, there are a few points that are quite far off the main trend—mostly those at the top of the plot with high triglyceride and low insulin values. We see how these off-trend points affect the tightness of the relationship seen in the initial data set when we compare the values of the correlation coefficients. These off-trend points lead us to the third complication I wanted to bring up.

But first, please take a minute to consider the matter: What could lead to having low insulin and at the same time high triglycerides? What could be the cause of the difference between my numbers, which did contain some very low insulin levels, but all of which were paired with equally low triglyceride values, and this other person’s numbers? What causes insulin to go down? What happens when insulin is low? What could cause triglycerides to go up while insulin is low?

Insulin, no matter how high it is, will start to go down when we stop eating. The longer we fast, the lower it will go. Each person’s baseline will be a little different depending mainly on their metabolic health and their body fat stores. The more efficient the metabolism is at using fat for fuel—the more insulin sensitive, the lower insulin will go. But also the lower the body fat stores are, the lower insulin will go. On the flip side, the more insulin resistant and the fatter we are, the longer it will take for insulin to drop and the higher it will stay at baseline.

This is pretty shitty. I mean, as we develop insulin resistance, average insulin levels will become higher and higher. As a result we’ll store calories into our growing fat cells more and more easily, and will therefore become fatter and fatter, faster and faster. But fat cells also secrete insulin! So, the more fat cells there are, the higher the insulin levels will be, and the harder it will be to lower our basal insulin. To burn fat, we need to lower insulin levels. The fatter we are, the higher the insulin levels will tend to be. And the fatter we are, the harder it will be to lower insulin levels.

It’s a bit of a catch, but in the end, it’s not such a big deal because basically everyone who is overweight and who starts to fast and restrict carbohydrates melts their fat stores away very well. It works incrementally: insulin goes down a little, insulin resistance is reduced a little, fat-burning starts; insulin goes down a little lower, insulin resistance is further reduced, fat-burning increases; and on it goes, until we have lost all those extra kilos of fat that we were carrying on our body, be it 5, 15, 20, 35, 60 or even 100 kg of fat! It’s just a matter of time.

Now, after this little tangent on insulin and fat stores, we can come back to those anomalous points in the plot, the most conspicuous of which is the one just below 120 mg/dl of triglycerides but only 3 mUI/ml of insulin. Have you come up with an explanation? Here is mine:

That point is from one of my wife’s blood tests. It is unusual because it was done after 24 hours of fasting. My 24-hour fasting blood test done a number of weeks before, and my numbers were 41 for trigs at 2.3 for insulin. The difference between her and I was that I was already very lean, whereas she wasn’t. Therefore, as she fasted, her insulin levels dropped very low, and then the body started releasing its fat stores into the bloodstream in high gear. This is why her triglyceride levels were this high while her insulin was that low. It’s almost certainly the same for the other two points up there with trigs at 110 and 90 with insulin around 4 and 2.5 (the latter one of which is also my wife’s).

Since we did many of our blood tests around the same time, there are 9 data points from her on the plot. Several are in the centre of the main trend at insulin values between 6 and 7, but I’d like draw your attention to her lowest insulin value that was measured at 1.8, and at which time her trigs were at 57, and her lowest triglyceride level of 48, at which time her insulin was at 2.2. This shows that on average her values are a little further along the trend than mine are because of the small difference in body fat, but that she has good insulin sensitivity, and a well-functioning metabolism that can efficiently use fat for fuel.

The other off-trend point, but in the other direction on the right hand side, with insulin just above 10 and trigs around 65, is from my mother’s first blood test which I ordered and included insulin and trigs, before I got her off carbs. She was 82 at the time, eating a regular kind of diet, but not a very nutritious or varied diet with plenty of bread and cheese, because she had serious problems moving around and taking care of herself while still living alone. And so, it’s just the result of being older, having plenty of carbs, but not being highly insulin resistant nor highly overweight. Her baseline insulin levels were just generally higher because of her age and diet, but her trigs weren’t excessively high.

However, after just four days of intermittent fasting on a very low carb regime with most calories coming coconut oil spiked green juices and coconut milk smoothies, her insulin went from 10.3 to 4.7, and she lost 5 kilos, which, of course, were mostly from the release of water that the body was retaining to counter the effects of the chronic inflammation that immediately went down with the very-low carb regime and fasting.

Later, having sustained this strict green healing protocol for about 6 weeks, her numbers were at 2.9 for insulin and 56 for trigs. And by then she had lost another 5 kg, but this was now mostly fat. She had, at that point, recovered full insulin sensitivity, had lost most of her body fat stores, and overhauled her metabolism. She was 83 at that time, which shows that this sort of resetting of the metabolism can work at any age.

On this note, let’s conclude with these take-home messages:

First, the next time you get a blood test, request that insulin and triglycerides be measured, because it’s the only way to know what your fasting insulin actually is, and because it is very telling of your level of insulin resistance or sensitivity, overall metabolic health, as well as your average rate of ageing as we’ve seen in a previous post on insulin and the genetics of longevity.

Second, when you get the results back, you will be able to tell from your triglycerides concentration, in light of your insulin level, either how well the body is using fat for fuel—in the case you are already lean, or how fast you are burning your fat stores—in the case you still have excess body fat to burn through.

And third, resetting metabolic health can be done at any time and at any age, and is yet another thing that shows us how incredible our body is—the more we learn generally or individually, the more amazing it reveals itself to be.

 

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Rejecting the lipid hypothesis with a cholesterol of 278 mg/dl and a smile

When it comes to evaluating how likely you are to have a heart attack, the most accurate diagnostic—the gold standard—is the calcium score. The reason why it’s the most accurate is because it’s calculated from an actual 3D image of the heart and the blood vessels around it. A computerised tomography (CT) scan is done, and from it the amount of plaque buildup in all the places where it appears because of the high density of the calcium it contains is measured and summed to give the total calcium score.

3d_image_of_my_heart

3D volume rendering of my heart seen from the top.

Even though it has been estimated that approximately half of heart attacks are caused by non-calcified lesions, this is the closest thing we have to a direct measurement of the amount of plaque in the network of arteries around the heart. From doing this to thousands of people, we know that plaque usually begins to accumulate after the age of 35. Why isn’t the calcium score test done systematically on everyone above 40 in order to assess their immediate risk, but also to track their individual cardiovascular evolution, showing, with a reliable reference each year, how quickly or slowly arterial plaque is growing? Because it’s too expensive. Therefore, it’s only prescribed to people who are deemed to be at high risk based on other so-called “risk factors”. You know the list: overweight, sedentary, smoking, stressed, etc. But the clincher in this list of risk factors, the one factor that has pretty much eclipsed all the other ones, at least for the past few decades, is high cholesterol.

The focus on cholesterol was, over time, shifted to LDL, the “bad” cholesterol, and later on the ratio between it and HDL, the “good” cholesterol, terms introduced by the pharmaceutical industry to convince us that there is a battle between a good guy and a villain that must be stopped, which they can help with by providing us cholesterol lowering statins, even if with each passing year, the evidence exonerating cholesterol and lipoproteins from any wrong-doing in the genesis and progression of cardiovascular disease has been accumulating. Still, for people and for doctors, it’s really hard to overcome the several decades of conditioning we’ve suffered holding cholesterol as the main culprit for heart disease.

Fortunately, this knowledge and information have been shared and available for as long as the first experiments that set us on this damning direction in thinking and mindset. For my part, I first read a clear expose on the function of cholesterol and lipoproteins from Ron Rosedale over 10 years ago. Then I read it from Uffe Ravnskov, then from Anthony Colpo, then from Malcolm Kendrick who has and to this day continues to investigate the topic and share his findings on his blog, and then from Gary Taubes. All of this has taught me that cholesterol, HDL, and LDL, are not only not dangerous, but that they are essential and crucial for optimal health. This, I shared with you in But what about cholesterol? and shaped my diet to maintain healthy levels: I restricted carbohydrates and polyunsaturated oils, and have gotten most of my calories from minimally processed saturated fats from grass fed animals fats, coconut oil, butter, and olive oil. In this endeavour to maintain strong cholesterol and lipoprotein levels, as you can see below, I have succeeded.

The following plot shows all the measurements of total cholesterol I have ever gotten made from blood tests over the past decade. What you can see is that in late 2007—a time before which I ate mostly complex carbohydrates and polyunsaturated seed oils while avoiding animal and saturated fats—my total cholesterol was below 150 mg/dl. Since then, it has been generally around or above 200 mg/dl with a slight upward trend over the years.

ts_total

My own total cholesterol levels in mg/dl measured from late 2007 to mid 2018.

If we look at the concentration of low and high density lipoproteins LDL and HDL, we also see consistently high levels, with LDL typically 10-30 mg/dl higher than HDL levels. Unsurprisingly, the same general shape and trend are is seen in these measurements as are seen in those of the total cholesterol.

ts_hdl_ldl

My own LDL and HDL levels in mg/dl measured from late 2007 to mid 2018.

Many of you have been reading this blog for a while, and I trust that you have therefore also known for a while that cholesterol is good for you, and that we should strive to have robust levels of HDL, LDL, and total cholesterol. Whether you have managed to overcome the conditioning we have all been subject to over our lifetimes about the purported but never-substantiated dangers of cholesterol and saturated fats, I cannot know. But I hope that I have at least helped a little in that respect.

In any case, I have for several years, every since I first read about the calcium score, wanted to get this test done, and see where I actually stood on the arterial calcification scale. I’ve never had fears or apprehension about it because even when I first read about it, I felt that I had a pretty good idea of the process by which cardiovascular disease evolved, and was following a regime that I knew would minimise the likelihood of atherosclerosis. But still, there is a big difference between having confidence that something is the case, and actually knowing that it is by seeing observational, quantitative, measured evidence for it. Finally, this spring, I was able to get a calcium score done.

I was very lucky to be referred to a young (45), well-informed, and open-minded cardiologist who also does research and has led trials on a group of several thousands of people who work at the Santander Bank campus near Madrid. He also happens to be the head of the cardiology imaging unit of the Clinical Hospital San Carlos in Madrid, a post he has held for more than 6 years now. So, he’s not just any cardiologist: he’s one of the best, and most importantly, one of the very best in cardiology imaging, which was exactly the purpose of consulting with him in the first place. I could not have been in better hands.

On our first appointment, after the initial conversation and questions regarding medical and health history, his assistant helped do an ECG, which looked “perfectly normal”, he said. Then he did the ultrasound with Doppler imaging that allows to see the heart pumping and the blood flowing with a colour coding of red and blue for the blood flowing away and towards the probe. To the trained eye of the imaging cardiologist, the Doppler ultrasound shows how the heart moves, how the cross-sections of the arteries pulsate with the heart beats, how the valves open and close, how flexible the tissues are, and how impeded or unimpeded the flow is. After a thorough examination, from one side and then from the other, he said everything looked very good.

At the end of the appointment he wrote a prescription for the CT scan to be able to get my calcium score, and another for a set of blood tests to which he willingly allowed me to request any additional one I wanted to have done. Before leaving the clinic, the assistant was able to arrange to have the blood test and the scan on the same day one week later: the blood test would be done in house first thing in the morning, and the scan would be done afterwards at the best medical imaging facility in the city.

The day before the scan, I read up on the test, how it’s done, how the measurements are made, and what the score means. I found out that, first, that the measuring of the amount of plaque buildup was done by eye, meaning that the experience and know-how of the cardiologist doing it was quite important. Second, I found out that the scale was not normalised like a scale from 1 to 10 or 0 to 100; that it was from 0 to whatever, which could be 400, 1000 or 4000. Although I was surprised and a little disappointed at first—we all love to get a score that can be immediately compared to everyone else’s, and gives us a sense of where we stand with respect to the rest of the population—I quickly realised that this made good sense given that it is not a relative but instead an absolute measure of plaque buildup in the arteries: naturally, this can go from no plaque to a little bit, to a lot, and to a ton of plaque. One could imagine estimating a maximum amount—say the amount needed to completely fill up the arteries—and use that as the normalising factor representative of 100%, and expressing every other result with respect to this. For now, this hasn’t been done, and the guidelines for interpreting your calcium score suggest values as follows:

  • 0 — No identifiable plaque. Risk: Very low, generally less than 5 percent.
  • 1 – 10 — Minimal identifiable plaque. Risk: Very unlikely, less than 10 percent.
  • 11 – 100 — Definite, at least mild atherosclerotic plaque. Risk: Mild or minimal coronary narrowing likely.
  • 101 – 400 — Definite, at least moderate atherosclerotic plaque. Risk: Mild coronary artery disease highly likely, significant narrowings possible.
  • 401 or Higher — Extensive atherosclerotic plaque. Risk: High likelihood of at least one significant coronary narrowing.

I got the blood test results back before the calcium score: everything looked good. Because most of my blood markers have been stable for years, especially the metabolic markers related to glucose and fat metabolism, the ones I am most interested in are those I need to monitor: things like B12, folate, homocysteine, and D, all of which need to be controlled and their levels adjusted with supplements; those that show my hormonal status, especially for the thyroid and sex hormones; and finally the markers of systemic inflammation which should always be as low as possible. The cholesterol panel is the one that for me has the least importance. But we are here considering cholesterol and lipoproteins in relation to cardiovascular risk assessed by means of the calcium score. So, these were the measured values: total cholesterol was 278 mg/dl, HDL was 122 mg/dl, LDL was 145 mg/dl, VLDL was 11 mg/dl (ref: <40), lipoprotein(a) was 4.40 mg/dl (ref: <30), and the ratios of total/HDL and LDL/HDL labelled atherogenesis indices were 2.28 (ref: <4.5) and 1.19 (ref: <3.55), values which are all deemed very good, of course.

A few days later I got my calcium score back. What do you think it was? You know I’m currently 45 and that calcification begins to grow after the age of 30-35, and has definitely progressed by the age of 40. You also know that—from what we are told by most doctors and health authorities—that plaque buildup and calcification is an inevitable part of ageing, that no matter what we do or eat or not eat, even if we might be able do things to slow it down, plaque accumulates and calcification progresses in only one direction: upward and onward. With this in mind, what would you guess my calcium score was?

My calcium score—based on 3D imaging of the heart and the region around it, and calculated by the one of best imaging cardiologist in Spain—was 0. It wasn’t 10 or 20. It wasn’t even 1, or 2, or 3. It was zero.

In our scientific training we learn that theories can never be proven—that they can only be disproven, and that hypotheses can never of accepted—that they can only be rejected. We also learn that to disprove or reject a theory or hypothesis, what is needed is a single contradicting piece of evidence, a single contradicting observation. The lipid hypothesis—that elevated blood cholesterol leads to atherosclerosis of the arteries, and that therefore decreasing blood cholesterol concentration significantly reduces cardiovascular risk—has been ingrained into our psyche more solidly than almost anything else that we collectively believe. But faced with this evidence, even if it is from one person only, of having maintained “elevated” fasting cholesterol levels consistently for a decade while in spite of this having gotten a perfect calcium score at the age of 45, the hypothesis must surely be rejected.

Even if we didn’t have any other evidence at all, according to the scientific principle that one contradicting piece of evidence is sufficient to reject a hypothesis, this single instance of my history of high total cholesterol together with a calcium score of zero is enough to reject the hypothesis that having elevated blood cholesterol levels over a long time leads to atherosclerosis and therefore to cardiovascular disease.

And we can be sure I’m not the only one. In fact, I’m willing to bet anything that most people in the low carb community who have been low carbers for as long as I have will have high cholesterol levels and low calcium scores. But still, to change the mindset of several generations of doctors, journalists, and people everywhere—hundreds of millions of educated people conditioned from decades of misinformation—will take years, probably decades. That’s how we are as social animals: stubborn in our beliefs.

In any case, I hope you, at least are, if you weren’t already, are now convinced that having high cholesterol does not cause atherosclerosis. Are you now curious to find out what your calcium score is? If you do get it done, please share.

For my part, I feel even more confident than I did. Even if I assured you more than five years ago in the spring of 2013 in At the heart of heart disease that you could be entirely free from cardiovascular disease by following some basic guidelines I listed regarding our eating, drinking, and living habits, there is nothing like observational evidence. And now we have it.

 

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Case study: B12 deficiency, rapid weight loss, protein in the urine, osteoarthritis, elevated vitamin D

Just last week, a friend of mine wrote me this:

My mom has not been well.  Not eating well, massive head ache, lost a lot of weight.  Blood test results yesterday showed that she’s B12 deficient;  urine, however, has too much protein.  Any idea why?

I suppose, since he asked me, it most likely meant her MD didn’t offer an explanation for the test results.  One this is sure, neither she nor he knew what to do.  My feeling is that he asked just in case I knew anything that could help. And I did. So, I did.

Let’s go through the analysis together:

case_study_analysis

Is it normal to have protein in the urine?  What is supposed to be excreted in the urine?  What organ regulates what goes and what doesn’t go into the urine?  Under what circumstances would protein end up in the urine?

From a biological standpoint protein is precious.  From an evolutionary standpoint protein is hard to come by and hence relatively rare.  Therefore, the body has evolved to use and keep as much protein as it can.  The urine is intended to excrete uric acid, which is the main acid produced by metabolic processes.  Urine is excreted through the urethra, it is stored in the bladder, and it is produced by the kidneys, which filter the acids out of the blood.  The kidneys try to prevent large molecules like amino acids and glucose from going through into the urine.  The solids in the blood are separated from the water, the acid is filtered out of it, and depending on the state of hydration, more or less water is used to make urine or returned back to the blood.  The only circumstances under which protein would end up in the urine are 1) that the kidneys are not working properly, and unable to filter the protein out of the blood, 2) that there is a serious excess of protein in the blood, or 3) that there is both kidney dysfunction and excess amino acids in the blood.  We’ve explored kidney function in great detail before in The kidney: evolutionary marvel, and this understanding comes from there.

This means we already know that his mom either has kidney disease, that there is too much protein in the blood, or both.  But he wrote that she had lost a lot of weight.  Losing weight can be due to fat loss, muscle loss, or both.  Usually, very rapid weight loss in the elderly is not voluntary, and almost always means rapid loss of fat and muscle.  Therefore, for sure, the protein in the urine was the result of a the fast weight loss with rapid breakdown of muscle tissue.

But why?  Why would she all of a sudden start losing weight so fast?  What could have happened or triggered this?

Well, he also wrote that she was found to be B12 deficient.  And if this was recognized by the conventional MD who ordered the tests, you can be sure B12 levels were very low: surely below 200 pg/ml.

Do we become B12 deficient all of a sudden?  Or do B12 levels decrease slowly and gradually over the years?  Can we even become B12 deficient all of a sudden?  Why do we become B12 deficient in the first place?  And why is B12 important and relevant in this case?

It is possible to become B12 deficient all of a sudden.  This happens when our levels are marginally acceptable to start, and we receive a large dose of an anesthetic, before a surgery, for example.  Anaesthetic drugs deplete B12; and the larger the dose, the more severe the depletion.  But this is certainly not the majority of cases.

Most of the time, B12 levels decrease slowly and gradually over the years,  either from inadequate intake, or from compromised digestion.  In the younger population, it is usually from inadequate intake—as is the case for vegans and vegetarians.  In older adults, it is usually from compromised digestion—as is the case from the middle aged to the elderly, generally from a damaged gut and stomach cells that do not produce enough hydrochloric acid needed to break down the protein we eat.

As some of you will remember, we’ve also explored the importance and functions of vitamin B12 in B12: your life depends on it and more recently in Case Study: Homocysteine, B12, and folate.  Vitamin B12 is most important for its role in the nervous system: for healthy nerves and proper brain function.  But it is also an important anabolic nutrient essential in building and preserving muscle tissue.  Bodybuilders everywhere have been taking B12 supplements for at least 4 decades, exactly because it’s a potent natural anabolic.

Therefore, here is where our analysis leads us:

The most probable explanation is that his mother has been growing more and more deficient over the years, a B12 deficiency developed over several decades that just recently reached critically low levels. This triggered rapid weight loss that caused both the loss of body fat stores and the breakdown of muscle tissue.  The fat loss released streams of toxins that have been accumulating in the fat cells over years and years, and which caused the massive head aches from which she was complaining.  The muscle loss, the rapid breakdown of muscle tissue due to the extreme B12 deficiency, caused the kidneys to be overwhelmed and become unable to keep all these amino acids in circulation, and the protein therefore spilled into the urine.

My recommendation: B12 shots of 1 mg once a week for 10 weeks, and then of 5 mg once a month for the rest of her life.

 

The story doesn’t end here.  It turns out that she has osteoarthritis and she’s in pain.  Some time ago some friends of hers recommended taking vitamin D supplements, and so she did.  When she got her blood test done, her 25-OH-D was through the roof at 127 ng/ml.  If you’ve read our last post on vitamin K2 you will know that this is possibly the worst thing that someone with arthritis can do: high levels of D without correspondingly high levels of K2 will accelerate soft tissue calcification.  And since osteoarthritis is a disease of calcification, it will make everything much worse than it already is.  Naturally, I immediately recommend she stop taking vitamin D and start taking large doses of vitamin K2 as soon as possible, before something more serious like a stroke or a heart attack happens.

He sent me the blood tests, which I examined to get a better picture.  Interestingly, few markers were out of the reference ranges.  This is probably why nobody said anything other than to point out the obvious abnormalities: low B12, high D, and protein in the urine.

But in addition, what could be seen was that both urea and creatinine were near the top of their range, which is expected from rapid weight (muscle) loss, and the eGFR (the estimated glomerular filtration rate) was at the low end of the reference range, which is expected from compromised kidney function given the protein in the urine.  C-reactive protein was high but not super high.  This signals system inflammation, and is naturally excepted for someone with arthritis, as we also have seen together in the past (https://healthfully.net/category/arthritis/).  Lastly, calcium was also high, but nevertheless within the reference range, something we would expected for someone with high D and not enough K2.

 

I asked if she was taking medications, and she was.  Several different drugs among which were a statin drug to lower cholesterol, a malaria drug used to treat symptoms of arthritis, and a couple of high blood pressure drugs one that is a diuretic and forces the kidneys to excrete more water, and the other that is an angiotensin antagonist that blocks the hormone which tells the kidneys to retain water when hydration is inadequate.  I replayed my view that drugs typically always attempt to block some pathway, and prevent the body from doing something that it naturally does to protect itself.  And in this case, she should wean herself off all of these over a few weeks.

I also explained that one of the most serious side effects of statin drugs is that they cause muscle wasting, promoting muscle tissue breakdown.  Statins do this in everyone, but in the elderly who already have accelerated muscle breakdown, it can be very serious.

My final recommendations, beside coming off the various drugs gradually to avoid a shock to the body, were as simple as possible for an old woman to follow: high dose B12 shots, high dose K2 pills, and high dose Mg as L-threonate, plenty of water and salt each day, a low carb diet rich in animal fats and green veggies, and sodium bicarbonate in water first thing in the morning on an empty stomach.  We’ll see what happens.

 

Blood tests can be used very effectively as a window onto the inner environment of the body.  MDs tend to only pay attention to the markers outside the reference range that appear in bold on the print outs.  But the reference range is derived from the blood tests of the whole population, and the population is far from being optimally healthy, that’s for sure.  What we need are not reference ranges derived from a sickly population, but an understanding of how the body works, what its organs and systems are trying to do, and with that understanding, of what our blood markers should be … ideally. What they should be in the best possible case.

That’s what we have to aim for.  And that’s what we have to learn to do, because we certainly can’t rely on your average MD to help us in this.  If you are an MD, and you are reading this, you already know that you are not your average MD, and I’m pretty confident you also know that your patients are lucky to have you.

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