Category Archives: Disease - Page 12

Blood Lipids and Infectious Disease, Part II

Posted by on July 12, 2011 95 comments

OK, after a diversion into hunter-gatherer lipid profiles I’m back on the original goal of this series: trying to understand why serum cholesterol is protective against infections — and considering whether or under what circumstances that knowledge should affect how we eat.

In part I (Blood Lipids and Infectious Disease, Part I, Jun 21, 2011), we learned that mortality from infectious disease is essentially zero as long as serum cholesterol remains in the physiologically normal range of 200 to 240 mg/dl, and rises precipitously as serum cholesterol falls below 180 mg/dl.

Why is that? In a previous post we found that HDL has important immune functions (HDL and Immunity, April 12, 2011). Today, we’ll look at the immune functions of lipoproteins more generally.

The Logic of Evolution and the Multiple Functions of Lipoproteins

In understanding why these particles have immune functions, it may be helpful to understand the thrust of evolution.

By the time of the Cambrian explosion 530 million years ago, organisms had similar numbers of genes to organisms today, and most of these genes must have been similar in sequence to their modern descendants. We know this because their descendant genes in nearly all modern species are “homologous” and share nucleotide sequences.

So for the last 500 million years, evolution has not been adding genes or even changing genes dramatically. It’s been tweaking a fairly stable genome. And the direction of the tweaking has been toward making the genes interact in a wider and more complex number of ways with the other genes.

The effect is to give every molecule in the body a diversity of functions. Possibly serum lipoprotein particles started out merely as transporters. But they developed new functions. The most important additional functions were roles in immunity.

Because these particles circulate in the blood, and pathogens have to transit the blood in order to cause tissue infections, blood is the natural location for the strongest defenses against pathogens. For hundreds of millions of years, every blood component will have been under selective pressure to develop immune functions.

It’s commonly said that the primary function of LDL and HDL is lipid transport. But this is too narrow a view. Since pathogens are the primary cause of disease, it may be the immune functions of LDL and HDL which account for their significance as biomarkers of health and disease.

The Immune Functions of Lipoproteins

Most of the following discussion will draw from a recent review, “Plasma lipoproteins are important components of the immune system” [1]. References from this paper will be listed in parentheses, eg (1).

Lipoproteins have been shown to:

  1. Prevent bacterial, viral, and parasitic infections.
  2. Detoxify pathogen “die-off” toxins and protect against pathogen toxin-induced tissue damage.
  3. Present pathogen “die-off” toxins to the immune system to trigger antibody formation.

Detoxification and Toxin Defense

When a pathogen dies, it typically fragments and releases compounds which are toxic to humans. Such “die-off” toxins include lipopolysaccharides (LPS) and lipooligosaccharides (LOS) from Gram-negative bacteria, lipoteichoic acid (LTA) from Gram-positive bacteria, fungal cell wall components, and so on.

During infection, the number of such circulating toxins can be vastly larger than the number of pathogens. Such toxins can do a great deal of harm, and often account for most of the ill effects of disease. Medical researchers studying the often-fatal condition of sepsis commonly induce nearly all the characteristics of sepsis in animals merely by injecting LPS.

VLDL, LDL, lipoprotein(a) and HDL can all detoxify LPS and LTA; HDL is the most potent (2, 4, 5). Injecting reconstituted HDL (rHDL) into humans relieves endotoxemia (6) and LPS-induced inflammation in cirrhosis patients (7). Both LDL and HDL detoxify E. coli LPS (35).

LDL binds and inactivates some toxins, including Staphylococcus aureus ?-toxin (8), Yersinia pestis topH6-Ag (30). (Methicillin-resistant S. aureus, or MRSA, is an increasing cause of death in hospitals, and last year claimed my next-door neighbor. See The FDA Is On The Side of the Microbes, Aug 11, 2010).

LDL probably works against many other toxins too, since rats with low LDL have higher mortality when infected, but the mortality can be lessened with injections of human LDL (9). Injections of LDL prevent lethality in Vibrio vulnificus infections of mice (34).

In mice with the LDL receptor knocked out, LDL concentrations in blood are higher and there is enhanced immunity to Klebsiella pneumoniae (27) and Salmonella typhimurium (29). If the gene for apoE, a protein found in IDL which upregulates VLDL levels, is knocked out, mice become more susceptible to infection, so it appears that apoE also has immune functions (28). Mice lacking apoE are susceptible to Listeria monocytogenes (32) and Mycobacterium tuberculosis (33).

Lipoproteins may be even more important against viruses. HDL has a broad antiviral activity (18-20), and can prevent many virus species including influenza and hepatitis C from entering cells. VLDL and LDL have specific activity against certain types of virus including togaviruses and rhabdoviruses (3). Trypanosoma brucei, the parasite that causes sleeping sickness, does not always cause disease in humans because a subspecies can be destroyed by a subfraction of HDL particles which include haptoglobin-related protein and apolipoprotein L-I (10).

The role of oxLDL

Evolution has a way of turning lemons into lemonade, and fragile molecules into sensors. In the book we discuss how the body uses fragile polyunsaturated fats as signaling molecules, exploiting their proclivity to oxidize. Something similar happens with LDL.

LDL particles are fragile and easily oxidized. The body uses them as a sensor of infections, and as signaling molecules that control the response to infections.

For instance, LPS (an endotoxin) induces neutrophils to adhere to endothelial cells, promoting vascular inflammation. LPS also oxidizes LDL, creating a compound called oxPAPC which inhibits neutrophil adhesion to endothelial cells, thereby limiting the inflammatory response (12). Minimally oxidized LDL detoxifies LPS (13).

OxLDL is taken in not by the LDL receptor, but by receptors on immune cells called macrophages. When macrophages take up oxLDL they upregulate their scavenger receptors (classes A and E) by which they phagocytose (eat) bacteria and clear endotoxins (39). It has been shown that infection causes an increase in oxidation of LDL and that the resulting oxLDL promotes phagocytosis by macrophages of the specific pathogens which oxidized the LDL (42).

This may explain why atherosclerotic lesions contain large amounts of bacterial and viral DNA. Macrophages in these lesions have been stimulated by oxLDL to scavenge bacteria and viruses from the blood.

OxLDL stimulates antibody formation, including antibodies against phosphorylcholine (PC), a compound found on a wide range of pathogens including bacteria, parasites, and fungi (45-49). Anti-PC antibodies help to prevent upper airway infections (50-53).

It is thought that oxidation of LDL is an important part of the host defense to infections. OxLDL inhibits cell entry of hepatitis C (59) and Plasmodium sporozite (60).

The role of Lp(a)

Lp(a) is essentially an LDL particle with an extra apo(a) molecule bound to the apoB100 molecule by a disulfide bridge.

Some insight into the immune functions of Lp(a) developed after considering the role of plasminogen. Many pathogens recruit human plasminogen and use it to penetrate tissue barriers, enabling them to invade tissue (70, 71, 72). For instance, group A streptococcus releases an enzyme called streptokinase that activates human plasminogen and promotes invasion (73). Lp(a) has anti-fibrinolytic activity and recruits plasminogen itself, reducing availability for pathogens. For instance, Lp(a) blocks streptokinase activity (75), inhibits Staphylococcus aureus activation of plasminogen.

Moreover, Lp(a) inhibits the inflammatory response to LPS. As there is great variation in Lp(a) levels among individuals (76), this may account for variability in inflammatory response to infections.

The Exception: Candida

HDL may promote fungal infections. A recent study found that infusion of reconstituted HDL enhances the growth of Candida (25).

LDL also seems to promote fungal infections. In LDL receptor knockout mice, which have high levels of LDL, there is decreased resistance to Candida (37, 38).

OxLDL also loses its normal anti-infective role against Candida. Worse, it inhibits production of antibodies against Candida albicans (63), thus actually hurting anti-fungal immunity.

Candida is an unusual pathogen that is unusually well-adapted to living in the human body. It has learned to turn an important part of human immune defense to its own advantage.

Conclusion

High serum cholesterol protects against a host of bacterial and viral infections and some parasites, but increases risk for Candida fungal infections.

Related Posts

Other posts in this series include:

References

[1] Han R. Plasma lipoproteins are important components of the immune system. Microbiol Immunol. 2010 Apr;54(4):246-53. http://pmid.us/20377753.

Thoughts on Obesity Inspired by Stephan

Posted by on June 2, 2011 58 comments

Stephan Guyenet recently did a great podcast with Chris Kresser, discussing the relationship between food reward and obesity. At his blog Whole Health Source he has been expanding upon the podcast with a series titled “Food Reward: A Dominant Factor in Obesity.”

Stephan is a neurobiologist and an expert in the role of the brain in obesity – something I know little about – so it was delightful to have a chance to learn from him.

Today I will try to place Stephan’s ideas in a larger context. I will argue that the concept of a fat mass setpoint is best understood as a dynamic equilibrium among many organs of the body, including the brain; and that food reward is a very important factor in the obesity epidemic because it helps explain many aspects of weight gain and loss and explains why many people are so eager to eat toxic and malnourishing foods, but that it may be going too far to call it a “dominant” factor in obesity.

Metabolic Damage

In some ways I think we know about the causes of obesity than about its nature. It’s very easy to induce obesity in both animals and humans: feed a malnourishing diet providing calories in the form of a combination of wheat, fructose, and polyunsaturated fats.  The links between these toxic foods and obesity are discussed in our book and in several blog posts (see Why We Get Fat: Food Toxins, Jan 20, 2011, and Wheat and Obesity: More from the China Study, Sep 4, 2010). Malnutrition contributes to obesity by promoting metabolic syndrome and appetite (see Choline Deficiency and Plant Oil Induced Diabetes, Nov 12, 2010).

Grains, fructose sugars, and omega-6 vegetable oils provide about 60% of calories in the modern diet, up from less than 10% in the Paleolithic. The strongest rise has been in omega-6 and fructose consumption since about 1970. At the same time, there has been a shift from home cooking of fresh foods to industrially processed and preserved foods. Lack of freshness and industrial processing can significantly increase food toxicity. With these shifts, obesity rates have skyrocketed.

It seems clear that these toxic, malnourishing diets can induce “metabolic damage”: biological changes that alter the way energy is metabolized and energy expenditure is managed – changes that bring about and maintain obesity.

What Are the Sites of Metabolic Damage?

In the obese, altered biology has been detected in many organs. Examples include:

  • Liver
  • Adipose tissue
  • Brain
  • Skeletal muscle
  • Gut and gut flora
  • Endocrine organs (thyroid, adrenals, pituitary)

Metabolic damage is a complex topic in part because so many parts of the body experience it, and interactions between these organs are crucial to understanding obesity.

Any good theory of obesity will have to explain the damage that occurs in all of these organs. It will also have to explain the interactions and interdependencies among these organs.

Stephan: The Brain’s Sub-Systems Matter

Stephan has taught us an important fact: that the brain has two connected but somewhat independent organs that participate in obesity:

  • The energy homeostasis system
  • The food-reward system

The energy homeostasis system is located in the hypothalamus and listens to the hormone leptin, which is released by adipose cells. More leptin indicates more fat mass (but not everyone has the same leptin level for the same amount of fat). The energy homeostasis system adjusts activity and thermogenesis (“calories out”) to achieve its desired leptin level – which translates to a desired fat mass “setpoint.”

The food-reward system influences appetite (“calories in”). It evolved for the purpose of getting us to eat the most healthful and beneficial foods. Thus, starches and fats, staples of the Perfect Health Diet, are good at stimulating the food reward system. Eating large amounts of a single flavor is boring; variety – which minimizes the dose of any one toxin, and ensures a diversity of nutrients – is higher in reward.

So one part of the brain manages “calories in” with an eye toward being well nourished, while another part manages “calories out” with an eye toward achieving just the right amount of fat.

What could go wrong?

Misdirected Food Reward

Unfortunately, a reward system that evolved in the Paleolithic is not necessarily a good guide to navigating modern foods:

  • New foods have come into existence – agriculturally produced cereal grains, hybridized for greater toxicity; refined fructose-rich sugars; and vegetable seed oils high in omega-6 – that didn’t exist in our evolutionary past. These toxic but malnourishing foods confuse the food reward system by invoking the same signals highly nutritious Paleo foods do – starch; fat; salt – but lack nutritional value, and indeed can act as poisons.
  • Food scientists have learned how to design toxic and malnourishing foods that hyperstimulate the food reward system. They stimulate addictive behavior: when you eat one, you want another one, and another. All aspects of the food are designed to trick the food reward system into wanting more – even color.

In this modern environment of industrially processed toxic foods, following our innate food preferences may easily lead us to eat unhealthy diets. It may also lead us to eat more calories than we need, creating a “positive energy balance” that Stephan associates with inflammation.

Food Reward Paradoxes

Food reward is rather hard to make sense of. Many commenters have noted this, and Stephan had to do a post clarifying what he means by food reward:

Food reward is the process by which eating specific foods reinforces behaviors that favor the acquisition and consumption of the food in question.  You could also call rewarding food “reinforcing” or “habit-forming”, although not necessarily in an addictive sense.

A seeming paradox is this: On the one hand, the food reward system evolved to guide us toward healthy foods, as Stephan says:

Food reward is essential for survival in a natural environment, because it teaches you what to eat …

Yet in the modern environment eating high-reward foods is supposed to impair health and cause obesity.

This is of course consistent with our view of obesity – modern industrial foods are toxic and malnourishment – but the mechanisms involving the food reward system are still a bit confusing.

One confusing aspect is that Stephan has spoken of the reward value of macronutrients, with carbs and fat being generally more rewarding than protein, and a carb-fat mix being most rewarding.

This does explain certain observed facts: that “lean meat and vegetables” diets, which are high in protein and therefore low in food reward, tend to induce immediate weight loss. Many popular diet books – Atkins, the Eades Protein Power books, the Dukan Diet – recommend such diets; immediate weight loss helps the diets go viral.

Yet it is not clear that it is consistent with all the facts. In particular high food reward may be consistent with good or ill health, obesity or slenderness. Some of the healthiest weight loss diets, such as ours, are high in food reward (see Low-Protein Leanness, Melanesians, and Hara Hachi Bu, Jan 27, 2011; Perfect Health Diet: Weight Loss Version, Feb 1, 2011).

The food reward system evolved to make us healthier. So it would seem to be the modern environment, especially newly available types of high-reward but unhealthy food, that is the cause of obesity. Food reward enters into obesity only because the food reward system no longer guides us to the optimal foods.

On our view, that toxicity is what matters most, the combination of wheat and fructose with polyunsaturated fats creates obesity, while the combination of safe starches with saturated and monounsaturated fats makes one slender. Yet both may have the same proportions of carb and fat! So it is not clear why food reward is a “dominant factor in obesity” if obesity-causing and obesity-curing diets may have similar food reward.

One possible explanation is that food reward is strongly influenced by subtle changes in the intensity of flavors and flavor associations. Seth Roberts today has a post illustrating this: a reader lost almost all excess weight simply by shifting from Coke and Pepsi to iced tea flavored with a cup of sugar per gallon. Seth writes:

His drink was pleasant enough. It derived pleasure from flavor (tea), sweetness (sugar), and sourness (lemon juice).

Of course Coca-Cola is flavored, sweet, and acidic. Why does one drink cause weight loss and the other obesity?

Seth’s correspondent had drank the iced tea daily for 3 years. If rewarding food is food that people keep returning to, then it seems the iced tea was as rewarding as the Coca-Cola. On the other hand, if the only way we have to judge that iced tea is low in food reward is that it leads to weight loss, or that Coca-Cola is high in food reward is that it leads to weight gain, then the theory becomes circular. Is there some independent way of judging food reward?

Toward a Food-Reward Theory of Obesity

To expand this into a theory of obesity, one has to address both the “calories in” and “calories out” sides of the equation; and also the “body composition” issue – if you have more calories in than out, where do they go? To fat or muscle?

Food reward obviously influences “calories in.” But to be “a dominant factor in obesity” the food reward system has to influence “calories out” as well. How does it do this?

Stephan believes that there is “reciprocal regulation” between the food reward system and the brain’s energy homeostasis system, so that when highly rewarding food is available the food reward system persuades the hypothalamus to accept a higher fat mass.

I’m not aware that Stephan has indicated whether he thinks the food reward system can have any influence on body composition.

So the food-reward theory of obesity seems to be only a partial explanation of obesity. Yet there is evidence for it.

Evidence: Weight Plateaus

The greatest merit of the theory is that it explains why weight tends to reach plateaus and stay at specific weights as long as the diet remains unchanged.

I’ve previously shown this plot from Seth Roberts:

Note how every time he adopted a new diet or lifestyle, weight changed rapidly at first and then settled at a plateau. On low-carb, Alex lost 50 pounds in his first year and then spent most of 2003 at 200 pounds with little change. On the Shangri-La diet he lost 30 pounds in six months and then spent a year at a plateau of 190 pounds. A vegan diet moved him to a plateau at 230 pounds, where he seems to have spent about 8 months.

This is exactly what the food-reward theory predicts. A diet stimulates the food-reward system and leads to setting of the fat mass setpoint. Different food rewards, different setpoints. Manipulating food reward, as in Shangri-La Diet or low-carb high-protein dieting, lowers the setpoint.

But here are two things to consider:

(1)   There is no evidence that the setpoint that is ultimately reached is the optimal weight. Often the plateau weight is still abnormally high, even on low-carb Paleo or Shangri-La Diets.

(2)   There is no evidence that reaching a “normal” weight through a low food reward diet is the same as achieving health.

I think we have to ask the question: what is our goal?  Is it weight loss, or is it returning to optimal health?  If the latter, does a diet that achieves weight loss by manipulating food reward improve health?

This issue came up in the podcast and Stephan’s answer was that a low food reward diet reduces calorie intake leading to negative or neutral energy balance. In many studies, positive energy balance is associated with increasing inflammation while calorie restriction is associated with improved biomarkers and reduced inflammation. So low food reward diets may well be health improving.

I think this quite likely, but here are two possible objections:

(1)   Low food reward dieting has transient and reversible benefits. The period of positive or negative energy balance is transient on all diets; eventually weight settles at a plateau and neutral energy balance is once again attained. So if energy balance is all that matters, the health benefits of a low food reward diet will also be transient. If the low food reward diet is not maintained for life, then eventually a switch to a higher food reward diet will introduce a period of health damage that may exactly compensate for the benefits won during the transition to the low food reward plateau.

(2)   Low food reward dieting is suboptimal for health. If food reward evolved to lead us to the healthiest diet in the evolutionary milieu, isn’t the best health to be achieved by eating for HIGH food reward and living in the evolutionary style eating evolutionary foods?

The first issue tells us that for real health benefits, the low food reward diet has to be a lifelong practice, or else there has to be an independent effect of fat mass on health, with elevated fat mass impairing health regardless of energy balance.

The second issue is particularly interesting in light of the fact that some aspects of Stephan’s diet, which he describes in his podcast with Chris Kresser, seem designed to reduce the food reward of his diet. For instance, he minimizes spices or salt, and avoids between-meal snacks.

Salt is a source of food reward. It also may improve health, as it seemed to do in the recent study published in the Journal of the American Medical Association in which people eating 6 g/day (highest third of salt consumption) were only one-fifth as likely to die of heart disease as people eating less than 2.5 g/day (lowest third).

So should we target low food reward, or high food reward but with evolutionary foods in an evolutionary lifestyle?

Our weight loss advice (See Perfect Health Diet: Weight Loss Version, Feb 1, 2011) is essentially the latter. We favor a mixed carb and fat diet with savory sauces and broths that includes high food-reward items like salt. We disagree with the “lean meat and vegetables” approach to weight loss dieting, although we acknowledge that it usually brings on rapid initial weight loss.

I should say that Stephan’s diet, described in the podcast, is very close to ours. It could be described as a high-carb version of the Perfect Health Diet, with diversity of carbs increased by using detoxification procedures like soaking, sprouting, and fermenting to increase the number of “safe starches.” In describing his diet, he mentioned eating rice but not other cereal grains.

So it seems the differences between Stephan’s diet and ours are rather subtle. But one could argue that the differences between the sugared iced tea and Coca-Cola which Seth’s correspondent drank are also subtle. In the food reward theory of obesity, little changes in flavor can make a big difference in weight.

Does Food Reward Explain Obesity – Or Weight?

I think it’s important to distinguish between the disease of obesity – the health disorder characterized by metabolic damage – and the condition of being fat. Consider:

  • An obese person whose metabolic damage was suddenly and completely cured would be healthy but still fat, because it would take some time to lose weight. But the weight would fall off rapidly.
  • One could be slender and yet still have the disease of obesity, if metabolic damage persisted. If the site of metabolic damage is elsewhere than adipose cells, then liposuction might make a person slender but it wouldn’t cure obesity. The weight would return. This is in fact what happens.

Looking back at Alex Chernavsky’s weight chart, it’s clear that low-carb and Shangri-La diets reduced his weight. It’s not obvious that any diet cured his obesity.

Likewise, we’re all familiar with young people who eat massive quantities of junk food and remain slender. The high food reward diets, even toxic and malnourishing diets, seem not to cause weight gain until some kind of metabolic damage occurs.

It seems that metabolic damage – the disease of obesity – is a prerequisite for food reward to matter.

Stabby found an interesting paper that addresses this. They write:

Only some of the leptin-resistance models (leptin antagonist blockade and aged obese rats) exhibit heightened weight and adiposity gain on a chow diet, while all models discussed demonstrate obesity in the presence of an HF diet. Thus, the leptin resistance appears to be reinforcing “reward eating” beyond caloric energy requirements….

Leptin receptors … act through the JAK-STAT signaling pathway and decrease food consumption upon leptin action. The fact that a chronic reduction in leptin receptor activity in the VTA by siRNA knockdown enhances sensitivity to highly palatable food underscores an important role of leptin receptor function in the regulation of reward feeding behavior (24).

In other words, leptin resistance may have to exist before high-reward foods induce “reward feeding behavior,” or excessive consumption of calories. Likely it has to exist also before the fat mass setpoint is altered from normal.

If obesity (the disease) must exist before food reward becomes a factor in obesity, then it hardly seems likely that food reward is a dominant factor in obesity the disease. It is rather a dominant factor in how much an obese person weighs. That is a different thing.

Fat Mass Setpoint as a Dynamic Equilibrium

Early in this post I listed a half dozen sites of metabolic damage; the brain was only one. I believe that the fat mass setpoint is not controlled by any one metabolic organ, but rather that it is a dynamic equilibrium that is influenced by the whole body.

In other words: metabolic damage anywhere will affect the fat mass setpoint. The brain is not unique in its metabolic role. There are a myriad of ways to alter the fat mass setpoint, and they don’t all involve food, the food reward system, or even the brain.

Is the Brain the Pre-Eminent Site of Metabolic Damage?

Food reward looks to be important because changing the food reward of the diet changes the fat mass setpoint. Reduce food reward and weight drops; raise food reward and weight (usually) increases. This occurs in humans as well as lab animals, as Alex Chernavsky’s chart shows.

But all this really shows us is that food reward is a lever that we can use to adjust weight. It doesn’t tell us that it is the only or most important lever.

Food reward is a very easy lever for scientists to manipulate. It’s easy to replace rodent chow with Cheetos and see what happens. It’s a bit harder to adjust the state of the liver, the adipose tissue, the thyroid, or skeletal muscle.

When those other sites of metabolic damage are manipulated, does the fat mass setpoint change as dramatically as it does when food reward is manipulated?

I think it does. Consider this classic study by Maria Rupnick and colleagues. Giving or withholding angiogenesis inhibitors causes mice to cycle between obese and normal weight:

In some ways this weight cycling is more dramatic than any of the food reward studies, because weight in leptin-impaired (ob/ob) mice goes all the way back to normal with angiogenesis inhibition. And it is thought that the angiogenesis is occurring purely in adipose tissue, not in the brain – so it would seem that this is a clean manipulation of adipose tissue only. Perhaps adipose tissue angiogenesis is a “dominant factor in obesity.”

Many other manipulations of adipose tissue change the equilibrium weight (the “fat mass setpoint”). For instance:

  • The level of activation of PPAR-gamma affects the amount of leptin released per unit fat mass. PPAR-gamma deficiency leads to hypersecretion of leptin from adipocytes; mice become very slender and adipocytes very small because the brain thinks the body is fat. These mice never develop insulin resistance. PPAR-gamma can be influenced by diet.
  • The number of eosinophils – a type of white blood cells – controls whether adipose tissue macrophages are in a pro-inflammatory or anti-inflammatory state. This in turn controls whether adipose cells are insulin resistant or insulin sensitive, with implications for obesity and diabetes. This is one possible pathway by which gut flora may affect obesity, since the types of gut flora influence eosinophil counts.

It’s starting to look like metabolic damage in the adipose tissue alone may be sufficient to induce obesity.

We’ve previously discussed the fact that choline deficiency induces obesity, primarily (it is thought) through effects in the liver. It is likely that alternating high-choline and zero-choline diets would induce fluctuations similar to those in Maria Rupnick’s angiogenic mice. Choline deficiency induced obesity suggests that metabolic damage to the liver alone may be sufficient to induce obesity.

It may be that every organ with a role in metabolic regulation can be manipulated in some way to induce obesity. It looks like the fat mass setpoint is a dynamic equilibrium which depends on the state of every one of the organs involved in metabolic regulation.

If every site of metabolic damage matters and is influential on weight, then it would seem an exaggeration to describe food reward as a dominant factor in obesity. It is an important factor, but not obviously more important than any of the other systems or organs involved in metabolic regulation.

Conclusion

I am grateful to Stephan for sharing his knowledge of the food reward system and the neurobiology of obesity. I immensely enjoyed listening to his podcast and reading his blog posts, and look forward even more to future posts so I can chase references.

But nothing he said has caused me to change my views of obesity or of the best weight loss diet:

  • I think the focus should be on recovering health by curing metabolic damage.
  • I think our evolved preference for tasty foods including starches, fat, salt, and other “high reward” flavors indicates they are healthy, and therefore that a diet rich in such foods is most likely to cure metabolic damage.
  • I think it is essential to stay away from toxic, malnourishing foods made from wheat, fructose sugars, omega-6 oils, and bioactive compounds like MSG; and instead to eat foods that accord with our evolutionary history.

In one sense I think Stephan is right to call food reward a dominant factor in the obesity epidemic. If industrial food designers weren’t trying to make toxic foods rewarding, we might not have an obesity epidemic. People consume large quantities of toxic malnourishing foods because industrial food designers have learned how to conceal their poor taste and make them hyperstimulate our food reward system.

But looking at biology, I have a hard time believing that the food reward system in the brain is a dominant site of metabolic damage. The liver, adipose tissue, and hypothalamus seem likelier candidates to me. So if your goal is not merely to manipulate weight, but to cure the disease of obesity, then I think it is necessary to look not at food reward, but at food toxicity, nutrition, chronic infections, and gut flora. Those are the levers the obese should look to for a cure.

Iodine and Hashimoto’s Thyroiditis, Part 2

Posted by on May 26, 2011 344 comments

Mario Renato Iwakura’s guest series on the place of iodine and selenium supplementation in treatment of hypothyroidism continues. This is part 2. Thank you Mario! – Paul

UPDATE November 2023: Since this article was written, PHD recommendations for iodine have become firm. We recommend consistent daily supplementation in the range of 150 to 225 micrograms (not milligrams) per day, plus frequent seafood consumption. The supplementation (a) ensures a healthful supply of iodine and (b) accustoms the thyroid to the presence of iodine which minimizes the risk of thyroid injury from intake of a large amount of iodine at once, possibly at a time of selenium deficiency, for example from an all-you-can-eat crab buffet. Supplementation of >1 mg high doses of iodine carries a high risk of thyroid injury, making some parts of the thyroid hypothyroid and possibly also creating nodules with hyperthyroid activity. … Although our recommendations are not in line with Mario’s, nevertheless Mario’s article is fascinating, and a few people have reported benefit from high-dose iodine. Please read his article and judge for yourself! Best, Paul

In Part I (Iodine and Hashimoto’s Thyroiditis, Part I, May 24, 2011) we looked at evidence from animal studies that iodine is dangerous to the thyroid only when selenium is deficient or in excess, and that optimizing selenium status allows the thyroid to tolerate a wide range of iodine intakes. In fact, there were some hints (such as an improved CD4+/CD8+ T cell ratio) that high iodine, if coupled with optimal selenium, might actually diminish autoimmunity.

If that holds in humans too, we should expect that populations with healthy selenium intakes should see a low incidence of thyroid disease and no effect from iodine intake on the incidence of Hashimoto’s thyroiditis. Is that the case?

Korean Study

Dr. K [1] quotes a Korean study [3] of Hashimoto’s patients. Half restricted iodine intake to less than 100 mcg/day, the other half ate their normal seaweed and iodine. Of the 23 patients who restricted iodine, 18 (78%) became euthyroid in the sense of having TSH below 4.43 mIU/L, while only 10 (46%) of the 22 that did not restrict iodine became euthyroid. There was no measurement of symptoms at all, and no report of thyroid antibody titers after iodine restriction, so we don’t know if the iodine restriction relieved the underlying autoimmune disorder.

The selection of subjects for the two groups was odd. Group 1, the iodine restricted patients, had an extremely wide range of starting TSH, averaging 38 mIU/L but with a standard deviation of 82 mIU/L. Since all subjects began with TSH above 5 mIU/L, it’s clear that many of the Group 1 members had TSH near 5 and others had TSH well over 100 mIU/L. In comparison, Group 2, the controls, averaged a TSH of 11 mIU/L with a standard deviation of 11 mIU/L – less than 1/7 the standard deviation of Group 1. Few Group 2 members had a TSH above 30.

Table 2 presents the results. Mean TSH in Group 1 was reduced a little, but it did not even come close to normal. Since 78.3% of Group 1 had TSH below 4.43 mIU/L after 3 months, the other 21.7% had to have averaged a TSH above 102.2 mIU/L at the conclusion of the study. The standard deviation of Group 1 TSH at the end of 3 months of iodine restriciton was 71 mIU/L.

Meanwhile, Group 2 members still had a much lower standard deviation at the end of the study: 19 mIU/L.

A conclusion of this study was that “the initial serum TSH concentration was significantly lower in the recovered patients than in the non-recovered patients, which suggests that the possibility of recovvery is increasingly rare as the initial hypothyroidism becomes more severe.” Since Group 1 originally had a much larger fraction of members with very low TSH than Group 2 (plus a few with extremely high TSH to raise the average TSH), and the definition of recovery was a reduction of TSH to 4.43, perhaps it is not surprising that a higher fraction of Group 1 recovered.

Further calling into question the conclusion that lower iodine intake is beneficial is another observation. Looking at Table 1, we see that Group 2 (controls) had, at baseline, much higher iodine intake and higher urinary iodine excretion. Despite this, goiter size, TSH, antimicrosomal (MSAb) and antithyroglobulin (TGAb) antibodies were all lower!

A Japanese Study

A similar study with similar results was done in Japan [4].

In Asia, high iodine intake is due to high consumption of seaweed. Seaweed is high in naturally produced bromine compounds [5][6][7], arsenic [9][12][13], and mercury [9], and can accumulate radioactive iodine [8][9][10][11]. All these substances are known to interfere with thyroid function.

Bromide levels in urine in Asia are very high and are associated with seaweed consumption [6][7]. Values of 5 to 8.1 mg/l have been observed among Japanese, and 8 to 12 mg/l among Koreans.

It is quite possible that any benefits from “iodine restriction,” i.e. seaweed restriction, were due to reduced intake of bromine, arsenic, mercury, and radioactive iodine.

A China Study

Dr. Kharrazian [2] cites a study done in China [14] comparing three different areas: one with iodine deficiency (Panshan), another where iodine is more than adequate (Zhangwu) and a third where iodine is excessive (Huanghua). More than adequate and excessive iodine was associated with increased risk for subclinical and overt hypothyroidism.

But, another study [15], done in the same regions, showed that, coincidentally, Huanghua, the region with excessive iodine, and Zhangwu, the region with more than adequate iodine, had lower median serum selenium concentrations than Panshan, where iodine was deficient. Blood selenium concentrations were 83.2, 89.1 and 91.4 microg/L, respectively. So iodine consumption was inversely related to selenium consumption. Was it lower iodine, or higher selenium, that was beneficial?

TPOAb antibody levels were inversely associated with selenium levels. Patients with the highest TPOAb antibodies (>600 UI/ml) had lower selenium levels than patients with moderate and lower TPOAb antibodies (respectively 83.6, 95.6 and 92.9 UI/ml). [15]

Studies from Brazil, Sri Lanka, Turkey, and Greece

Dr K also cites a rise in Hashimoto’s incidence in Brazil, Sri Lanka, Turkey and Greece after salt iodinization began. Are these countries deficient in selenium? Well, lets see:

Brazil: The study was done in São Paulo, a city with a large Brazilian-Japanese population. Brazilian-Japanese have significant lower levels of Se than Japanese living in Japan [16].

Greece: Selenium status is one of the lowest of the Europe [17].

Turkey: Selenium status of Turkish children is found to be unusually low, only 65 ng/ml in boys and 71 ng/ml in girls [18]. Turkey is characterized by widespread iodine deficiency and marginal selenium deficiency [19].

Sri Lanka: Significant parts of the Sri Lankan female population may be selenium deficient [20].

One study, done in Egypt, measured iodine excretation in urine and its relation with thyroid peroxidase antibody (TPOAb) [21]. Although the abstract said that a significant correlation was found, this is far from reality, as we can see from Fig. 2.

Another study from Brazil [2] measured urinary iodine excretation and serum TPOAb and TgAb antibodies from 39 subjects with Hashimoto’s, none of whom were receiving treatment at the time of the study. Both antibody titers had no obvious correlation with urinary iodine.


Two discordant epidemiological studies

From the Netherlands, we have a prospective observational study looking at whether the female relatives of 790 autoimmune thyroid disease patients would progress to overt hypothyroidism or hyperthyroidism [22].

Although the relationship was not considered statistically significant, they found that women with high iodine intake (assessed through questionnaires) were 20% less likely to develop thyroid disorders.

Another study from western Australia (a region that has previously been shown to be iodine replete) measured urinary iodine concentration (UIC) of 98 women at 6 months postpartum and checked their thyroid status both postpartum and 12 years later [23]. UIC at 6 months postpartum predicted both postpartum thyroid dysfunction and hypothyroidism  12 years later:

The researchers concluded:

The odds ratio (OR) of hypothyroid PPTD with each unit of decreasing log iodine was 2.54, (95%CI: 1.47, 4.35), and with UIC < 50 lg/l, OR 4.22, (95%CI: 1.54, 11.55). In the long term, decreased log UIC significantly predicted hypothyroidism at 12-year follow-up (p = 0.002) … The association was independent of antibody status.

In short, the more iodine being excreted (and thus, presumably, the more in the diet and in the body), the less likely were hypothyroid disorders – not only at the time, but also 12 years later.

Dangers of selenium supplementation in iodine deficiency.

Selenium supplementation when iodine and selenium deficiencies are both present  can be dangerous, as the experience in northern Zaire, one of the most severely iodine and selenium deficient population in the world, shows [25].

Schoolchildren and cretins were supplemented for 2 months with a physiological dose of selenium (50 mcg Se per day as selenomethionine). Serum selenium was was very low at the beggining of the study and was similar in schoolchildren and in cretins (343 +- 190 nmil/L in schoolchildren, n=23, and 296 +- 116 nmol/L in cretins, n=9). After 2 months of selenium supplementation, the massive decrease in serum T4 in virtually every subject can be seen in fig. 4 below:

In schoolchildren, serum free thyroxin (fT4) decreased from 11.8 +- 6.7 nmol/L to 8.4 +- 4.1 nmol/L (P<0.01); serum reverse triiodothyronine (rT3) decreased from 12.4 +- 11.5 nmol/L to 9.0 +- 7.2 nmol/L; mean serum T3 and mean TSH remained stable. In cretins, serum fT4 remained the same or decreased to an undetectable level in all nine cretins; mean serum T3 decreased from 0.98 +- 0.72 nmol/L to 0.72 +- 0.29 nmol/L, and two cretins who were initially in a normal range of serum  T3 (1.32-2.9 nmol/L) presented T3 values outside the lower limit of normal after selenium supplementation; mean serum TSH increased significantly from 262 mU/L to 363 mU/L (p<0.001).

Another previous similar trial, this time done in 52 schoolchildren, reached the same results: a marked reduction in serum T4 [26][27]. This previous trial “was shown to modify the serum thyroid hormones parameters in clinically euthyroid subjects and to induce a dramatic fall of the already impaired thyroid function in clinically hypothyroid subjects” [27].

What stands out is the difference in the results between euthyroid schoolchildren and cretins/hypothyroids. Two months of selenium supplementation was probably not enough time to affect significantly the thyroid of the euthyroid schoolchildren (althougt already impacted T4 and fT4). But, in cretins and hypothyroids, where the thyroid was already more deficient, the impact was evident.

Conclusion and What I Do

Iodine and selenium are two extremely important minerals for human health, and are righly emphasized as such in the Perfect Health Diet book and blog. I believe they are fundamental to thyroid health and very important to Hashimoto’s patients.

A survey of the literature suggests that Hashimoto’s is largely unaffected by iodine intake. However, the literature may be distorted by three circumstances under which iodine increases may harm, and iodine restriction help, Hashimoto’s patients:

  1. Selenium deficiency causes an intolerance of high iodine.
  2. Iodine intake via seaweed is accompanied by thyrotoxic metals and halides.
  3. Sudden increases in iodine can induce a reactive hypothyroidism.

All three of these negatives can be avoided by supplementing selenium along with iodine, using potassium iodide rather than seaweed as the source of iodine, and increasing iodine intake gradually.

It’s plausible that if iodine were supplemented in this way, then Hashimoto’s patients would experience benefits with little risk of harm. Anecdotally, a number have reported benefits from supplemental iodine.

Other evidence emphasizes the need for balance between iodine and selenium. Just as iodine without selenium can cause hypothyroidism, so too can selenium without iodine. Both are needed for good health.

A few months after I was diagnosed with Hashimoto’s I started 50 mg/day iodine plus 200 mcg/day selenium. If I were starting today, I would follow Paul’s recommendation to start with selenium and a low dose of iodine, and increase the iodine dose slowly. I would not take any kelp, because of potential thyrotoxic contaminants.

Currently I’m doing the following to try to reverse my Hashimoto’s:

  1. PHD diet and follow PHD book and blog advices to enhance immunity against infections, since infections seems to be implicated in Hashimoto’s pathology [28][29][30]. I give special attention to what Chris Masterjohn calls “traditional superfoods”: liver and other organs, bones and marrow, butter and cod liver oil, egg yolks and coconut, because these foods are high in minerals, like iodine, zinc, selenium, copper, chromium, manganese and vanadium, all of which seems to play a role in thyroid health [31];
  2. High dose iodine (50mg of Lugol’s) plus 200 mcg selenium daily. These I supplement because of their vital importance to thyroid and immune function;
  3. 3 mg LDN (low dose naltrexone) every other day to further increase immunity. LDN resources are listed below [32][33][34][35][36];
  4. Avoiding mercury and other endocrine disruptors. When I removed 9 amalgams (mercury), my TPO antibodies increased for 3 months and took another 6 months to return to previous values. I also avoid fish that have high and medium concentrations of mercury. Cod consumption increased my TPO antibodies;
  5. 1g of vitamin C daily. Since it seems to confer some protection against heavy metal thyroid disfunction [37], improve thyroid medication absorption [38] and there is some evidence that it could improve a defective cellular transport for iodine [39];
  6. Donating blood 2 to 3 times per year. In men, high levels of iron seems to impact thyroid function [40].

Final Thanks

I would like to make a special thanks to Paul Jaminet for giving me the opportunity to write this essay, for gathering many, many papers for me, and for having the patience to revise both posts and suggest many changes that made the text clearer; and to Emily Deans who kindly sent me one key study that Paul could not get.

References:

[1] Dr Datis Kharrazian. Iodine and Autoimmune Thyroid — References.  http://drknews.com/some-studies-on-iodine-and-autoimmune-thyroid-disease/.

[2] Marino MA et al. Urinary iodine in patients with auto-immune thyroid disorders in Santo André, SP, is comparable to normal controls and has been steady for the last 10 years. Arq Bras Endocrinol Metabol. 2009 Feb;53(1):55-63. http://pmid.us/19347186.

[3] Yoon SJ et al. The effect of iodine restriction on thyroid function in patients with hypothyroidism due to Hashimoto’s thyroiditis. Yonsei Med J. 2003 Apr 30;44(2):227-35. http://pmid.us/12728462.

[4] Kasagi K et al. Effect of iodine restriction on thyroid function in patients with primary hypothyroidism. Thyroid. 2003 Jun;13(6):561-7. http://pmid.us/12930600.

[5] Gribble GW. The natural production of organobromine compounds. Environ Sci Pollut Res Int. 2000 Mar;7(1):37-47. http://pmid.us/19153837.

[6] Zhang ZW et al. Urinary bromide levels probably dependent to intake of foods such as sea algae. Arch Environ Contam Toxicol. 2001 May;40(4):579-84. http://pmid.us/11525503.

[7] Kawai T, Zhang ZW et al. Comparison of urinary bromide levels among people in East Asia, and the effects of dietary intakes of cereals and marine products. Toxicol Lett. 2002 Aug 5;134(1-3):285-93. http://pmid.us/12191890.

[8] Leblanc C et al. Iodine transfers in the coastal marine environment: the key role of brown algae and of their vanadium-dependent haloperoxidase. Biochimie. 2006 Nov;88(11):1773-85. http://pmid.us/17007992.

[9] van Netten C et al. Elemental and radioactive analysis of commercially available seaweed. Sci Total Environ. 2000 Jun 8;255(1-3):169-75. http://pmid.us/10898404.

[10] Hou X et al. Iodine-129 in human thyroids and seaweed in China. Sci Total Environ. 2000 Feb 10;246(2-3):285-91. http://pmid.us/10696729.

[11] Toh Y et al. Isotopic ratio of 129I/127I in seaweed measured by neutron activation analysis with gamma-gamma coincidence. Health Phys. 2002 Jul;83(1):110-3. http://pmid.us/12075675.

[12] Miyashita S, Kaise T. Biological effects and metabolism of arsenic compounds present in seafood products. Shokuhin Eiseigaku Zasshi. 2010;51(3):71-91. http://pmid.us/20595788.

[13] Cleland B et al. Arsenic exposure within the Korean community (United States) based on dietary behavior and arsenic levels in hair, urine, air, and water. Environ Health Perspect. 2009 Apr;117(4):632-8. Epub 2008 Dec 8. http://pmid.us/19440504.

[14] Chong W, Shit Xg, Teng WP, et al. Multifactor analysis of relationship between the biological exposure to iodine and hypothyroidism. Zhongua Yi Za Zhi. 2004 Jul 17:84(14):1171-4. http://pmid.us/15387978.

[15] Tong YJ et al. An epidemiological study on the relationship between selenium and thyroid function in areas with different iodine intake. Zhonghua Yi Xue Za Zhi. 2003 Dec 10;83(23):2036-9. http://pmid.us/14703411.

[16] Karita K et al. Comparison of selenium status between Japanese living in Tokyo and Japanese brazilians in São Paulo, Brazil. Asia Pac J Clin Nutr. 2001;10(3):197-9. http://pmid.us/11708308.

[17] Thorling EB et al. Selenium status in Europe–human data. A multicenter study. Ann Clin Res. 1986;18(1):3-7. http://pmid.us/3717869.

[18] Mengüba? K et al. Selenium status of healthy Turkish children. Biol Trace Elem Res. 1996 Aug;54(2):163-72. http://pmid.us/8886316.

[19] Hincal F. Trace elements in growth: iodine and selenium status of Turkish children. J Trace Elem Med Biol. 2007;21 Suppl 1:40-3. http://pmid.us/18039495.

[20] Fordyce FM et al. Selenium and iodine in soil, rice and drinking water in relation to endemic goitre in Sri Lanka. Sci Total Environ. 2000 Dec 18;263(1-3):127-41. http://pmid.us/11194147.

[21] Alsayed A et al. Excess urinary iodine is associated with autoimmune subclinical hypothyroidism among Egyptian women. Endocr J. 2008 Jul;55(3):601-5. Epub 2008 May 15. http://pmid.us/18480555.

[22] Strieder TG et al. Prediction of progression to overt hypothyroidism or hyperthyroidism in female relatives of patients with autoimmune thyroid disease using the Thyroid Events Amsterdam (THEA) score. Arch Intern Med. 2008 Aug 11;168(15):1657-63. http://pmid.us/18695079.

[23] Stuckey BG et al. Low urinary iodine postpartum is associated with hypothyroid postpartum thyroid dysfunction and predicts long-term hypothyroidism. Clin Endocrinol (Oxf). 2011 May;74(5):631-5. doi: 10.1111/j.1365-2265.2011.03978.x. http://pmid.us/21470286.

[24] American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hyperthyroidism and Hypothyroidism. https://www.aace.com/sites/default/files/hypo_hyper.pdf.

[25] Vanderpas JB et al. Selenium deficiency mitigates hypothyroxinemia in iodine-deficient subjects. Am J Clin Nutr. 1993 Feb;57(2 Suppl):271S-275S. http://pmid.us/8427203.

[26] Contempré B et al. Effect of selenium supplementation on thyroid hormone metabolism in an iodine and selenium deficient population. Clin Endocrinol (Oxf). 1992 Jun;36(6):579-83. http://pmid.us/1424183.

[27] Contempré B et al. Effect of selenium supplementation in hypothyroid subjects of an iodine and selenium deficient area: the possible danger of indiscriminate supplementation of iodine-deficient subjects with selenium. J Clin Endocrinol Metab. 1991 Jul;73(1):213-5. http://pmid.us/2045471.

[28] Benvenga S et al. Homologies of the thyroid sodium-iodide symporter with bacterial and viral proteins. J Endocrinol Invest. 1999 Jul-Aug;22(7):535-40. http://pmid.us/10475151.

[29] Wasserman EE et al. Infection and thyroid autoimmunity: A seroepidemiologic study of TPOaAb. Autoimmunity. 2009 Aug;42(5):439-46. http://pmid.us/19811261.

[30] Tozzoli R et al. Infections and autoimmune thyroid diseases: parallel detection of antibodies against pathogens with proteomic technology. Autoimmun Rev. 2008 Dec;8(2):112-5. http://pmid.us/18700170.

[31] Neve J. Clinical implications of trace elements in endocrinology. Biol Trace Elem Res. 1992 Jan-Mar;32:173-85. http://pmid.us/1375054.

[32] David Gluck, MD. Low Dose Naltrexone information site. http://www.lowdosenaltrexone.org/.

[33] LDN Yahoo Group. http://groups.yahoo.com/group/lowdosenaltrexone/.

[34] LDN World Database. Where LDN users share their experience with various diseases. http://www.ldndatabase.com/.

[35] Those Who Suffer Much Know Much. A colection of LDN users testimonies. http://www.ldnresearchtrustfiles.co.uk/docs/2010.pdf.

[36] Elaine A. More. The Promise Of Low Dose Naltrexone Therapy: Potential Benefits in Cancer, Autoimmune, Neurological and Infectious Disorder. http://www.amazon.com/Promise-Low-Dose-Naltrexone-Therapy/dp/0786437154.

[37] Gupta P, Kar A. Role of ascorbic acid in cadmium-induced thyroid dysfunction and lipid peroxidation. J Appl Toxicol. 1998 Sep-Oct;18(5):317-20. http://pmid.us/9804431.

[38] Absorption of thyroid drug levothyroxine improves with vitamin C. The Endocrine Society. News Room. http://www.endo-society.org/media/ENDO-08/research/Absorption-of-thyroid-drug.cfm.

[39] Abraham, G.E., Brownstein, D.. Evidence that the administration of Vitamin C improves a defective cellular transport mechanism for iodine: A case report. The Original Internist, 12(3):125-130, 2005. http://www.optimox.com/pics/Iodine/IOD-11/IOD_11.htm.

[40] Edwards CQ et al. Thyroid disease in hemochromatosis. Increased incidence in homozygous men. Arch Intern Med. 1983 Oct;143(10):1890-3. http://pmid.us/6625774.

Iodine and Hashimoto’s Thyroiditis, Part I

Posted by on May 24, 2011 239 comments

Mario Renato Iwakura is a Brazilian engineer and Hashimoto’s thyroiditis patient who is intimately familiar with the hypothyroidism literature. Mario has graciously agreed to do a guest series on the place of iodine and selenium supplementation in treatment of hypothyroid disorders. I’m very excited to have Mario’s thoughts, as he’s extremely smart and passionately engaged with the science. — Paul

Most doctors believe that iodine supplementation will aggravate autoimmune (Hashimoto’s) thyroiditis. This view is supported by observations that the incidence of Hashimoto’s hypothyroidism tends to increase in populations that increase their iodine intake. (The incidence of hyperthyroidism, on the other hand, increases as iodine intake decreases.). However not all epidemiological studies support this association [1][2][3][4].

Dr. Datis Kharrazian (“Dr. K”), whose 2010 book “Why Do I Still Have Thyroid Symptoms?”[5] is popular among Hashimoto’s patients, vehemently opposes the use of iodine in Hashimoto’s [5][6][7]. Chris Kresser of The Healthy Skeptic [8] has argued this point of view in his post “Iodine for hypothyroidism: like gasoline on a fire?”. And there’s little doubt that some patients have experienced bad consequences from high-dose iodine.

On the other side, doctors such as Dr. Guy E. Abraham [9], Dr. David Brownstein [10], Jorge D. Flechas [11] and Dr. David Derry [12] have claimed success prescribing high doses of iodine for Hashimoto’s and for breast and thyroid cancers.

Can these experiences by reconciled? What we will try to do is demonstrate that iodine acts synergistically with selenium, and that it is imbalances between the two that damage the thyroid.

First, Some Background

Thyroid peroxidase or thyroperoxidase (TPO) is an enzyme expressed mainly in the thyroid that liberates iodine for addition onto tyrosine residues on thyroglobulin (TG) for the production of the thyroid hormones thyroxine (T4) or triiodothyronine (T3).

The human body normally has low levels of auto-antibodies against both TG and TPO, which serve some physiological function. Autoimmune thyroiditis features high levels of these auto-antibodies, leading to immune attacks on the thyroid.

High levels of  thyroid auto-antibodies are positively associated with hypothyroidism symptoms [13][14]. TPO antibodies and TSH levels are strongly associated with progression of subclinical hypothyroidism to overt hypothyroidism [3], as can be see in Table 3 below:

Selenium Can Cure An Iodine Excess

Dr. K said in his book and site that “iodine stimulates the production and activity of the thyroid peroxidase (TPO) enzyme” [5][7]. Since TPO is a target of autoimmune attack in Hashimoto’s patients, this might worsen the disease [5][6][7]. In his book he also states that excessive iodine will shut down TPO activity [5], but he neither cites a reference nor states what level of iodine intake will cause this to happen.

In fact, excess iodine combined with selenium insufficiency will reduce (not increase, not shut down) TPO activity [15]. Let’s look at a study that had seven groups: normal iodine and lab-chow selenium only (NI), excess iodine and lab-chow selenium only (EI), and five groups with excess iodine and steadily increasing levels of selenium added to water (IS1 to IS5). TPO activity was reduced by excess iodine (EI), but returned to control levels (NI) with moderate selenium (IS1 and IS2). With excess iodine and excessive selenium (IS3 to IS5), TPO activity was also decreased, as we can see from table 2 below.

Some other studies have also demonstrated this reduced TPO activity at high iodine intakes [23][24].

This study [15] also showed a picture (fig. 1) of thyroid follicles from rats receiving normal iodine diet (NI), excessive iodine (EI) and excessive iodine plus 0.2 mg/L selenium (IS2). Thyroid follicles from the excessive iodine group (EI) are enlarged, a characteristic of goiter. But, there is virtually no difference between the first and last picture! If selenium and iodine are increased together, no goiter occurred.

Note that the IS2 level of selenium, which protects against iodine toxicity, corresponds in a person who drinks 1-2 liters per day to a selenium dose of 200 to 400 mcg per day – which happens to be the Perfect Health Diet “plateau range” for selenium.

Selenium Can Cure Autoimmunity

Another paper, also from China, looked at the effects of selenium in an animal model of iodine induced autoimmune thyroiditis [16].

There were three groups of mice, a healthy control group, and groups with iodine induced autoimmune thyroiditis without (AIT) and with (AIT+Se) selenium. The AIT+Se group was given high iodine (AIT only) for 8 weeks to induce the disease, and then, for 8 weeks more, they were given iodine plus selenium. After 8 weeks of selenium supplementation their thyroid follicles were almost fully recovered, as we can see below, even though high-dose iodine had continued:

The AIT group has enlarged cells characteristic of goiter and dead tissue; the AIT-Se group thyroid section resembles a normal thyroid. Thyroid weight doubled in the AIT group, proof of goiter, but returned to normal after selenium supplementation.

Before selenium was given to the AIT+Se group, serum TgAb antibodies were elevated, but they returned to normal after selenium supplementation:

An interesting aspect of this study was the changing population of immune cells. A specialized subpopulation of T cells, negative regulatory T cells or Tregs, helps establish and maintain self-tolerance by suppressing response to self-antigens and suppressing excessive immune responses deleterious to the host. Deficits in Treg cell numbers or function lead to autoimmune diseases [17].

In this study, CD4+CD25+Foxp3+ Treg Cells were reduced by high iodine, but returned much of the way toward normal after 8 weeks of selenium even though high iodine intake continued. The implication is that selenium-iodine balance may be needed to maintain proper Treg cell populations, and that selenium supplementation may restore normal regulation of autoimmunity.

The researchers concluded:

“In the present study, we observed that Se supplementation increased the frequency  of CD4+CD25+Foxp3+ T cells and enhanced expression of Foxp3 in vivo. These changes were accompanied by suppressed TgAb titers and reduced thyroiditis. Thus the benefit of Se treatment may be due to the increase of CD4+CD25+ regulatory T cells.”

Under What Circumstances Does Excess Iodine Induce Autoimmunity?

In the previous study high doses of iodine were used to induce autoimmune thyroiditis. Let’s look more closely into the circumstances in which that happens.

It’s often said that excessive iodine in Hashimoto’s triggers an immune response characterized by proliferation of T lymphocytes, a disrupted Th1/Th2 axis, and altered CD4/CD8 levels. Pathogenesis of autoimmune disease is believed to begin with the activation of T cell autoaggression (turning them into “allergized T cells”).

Our next study, also from China, showed that excess iodine can indeed cause such an autoimmune pathology, but only if there is a deficiency in selenium [18].

Mice in 5 groups were orally administrated different combinations of iodine and selenium for 30 days. Four groups had no selenium but varying amounts of iodine in their water:  0 μg/L (group I), 1500 μg/L (group II), 3000 μg/L (group III), and 6000 μg/L (group IV). The fifth group had 6000 μg/L iodine plus 0.3 mg/L selenium (group V).

In Group IV, high-dose iodine at 6000 μg/L caused a proliferation of lymphocytes. But this was completely abolished by the addition of selenium to water in Group V:

Normally there are relatively stable population of T cells and their subgroups in tissue till immune function is in disorder. As we can see from Fig. 1, increasing iodine increased T lymphocytic reproductive activity, and was clearly high in group IV. But group V, which also received selenium, had the same values as the control group (I).

Subjects with Hashimoto’s also have a lower ratio of CD4+ to CD8+ lymphocytes than controls [19][20]. From fig. 2, we can see that iodine supplementation in groups II and III actually increased the CD4+ to CD8+ ratio, until the onset of autoimmune symptoms at very high doses in Group IV when the ratio decreased. However, group V, which had the highest iodine intake but with selenium as well, had the highest CD4+ to CD8+ ratio of all groups.  This suggests that high-dose iodine and selenium together may actually diminish the autoimmune syndrome compared to the low levels in the controls.

Another marker of autoimmune thyroiditis is the relative strength of the Th1 and Th2 responses, as indicated by the markers interferon-gamma and interleukin-4 (Th2). Th1(IFN-γ)/Th2(IL-4) ratios are increased in Hashimoto patients [21][22], and related with severity of Hashimoto’s disease [22].

As we can see from Fig. 3, the group with the highest iodine intake but no selenium (IV) was the only group that had clearly higher Th1/Th2 ratio. High iodine plus selenium in group V had similar Th1/Th2 ratios than control group (I).

The researchers concluded:

“The results revealed that there was no significant difference in the immunotoxicity between interventional group (group V) and control group (group I), indicating that adequate selenium has a favorable interventional effect on excessive iodine intake.”

Conclusion

Excess iodine intake can cause an autoimmune thyroiditis that bears all the characteristics of Hashimoto’s. However, in animal studies this occurs only if selenium is deficient or in excess. Similarly, in animal studies very high iodine intake can exacerbate a pre-existing autoimmune thyroiditis, but only if selenium is deficient or in excess.

With optimal selenium status, thyroid follicles are healthy, goiter is eliminated, and autoimmune markers like Th1/Th2 ratio and CD4+/CD8+ ratio are normalized over a wide range of iodine intake. It seems that optimizing selenium intake provides powerful protection against autoimmune thyroid disease, and provides tolerance of a wide range of iodine intakes.

In the next post in this series (Iodine and Hashimoto’s Thyroiditis, Part 2, May 26, 2011), we’ll transition from animals to humans. Does epidemiological evidence suggest that these animal findings are transferable to humans?

References:

[1] F. Aghini-Lombardi et al. The spectrum of thyroid disorders in an iodine-deficient community: the Pescopagano Survey. J. Clin. Endocrinol. Metab. 84, 561–566 (1999). http://pmid.us/10022416.

[2] Marino MA et al. Urinary iodine in patients with auto-immune thyroid disorders in Santo André, SP, is comparable to normal controls and has been steady for the last 10 years. Arq Bras Endocrinol Metabol. 2009 Feb;53(1):55-63. http://pmid.us/19347186.

[3] Strieder TG et al. Prediction of progression to overt hypothyroidism or hyperthyroidism in female relatives of patients with autoimmune thyroid disease using the Thyroid Events Amsterdam (THEA) score. Arch Intern Med. 2008 Aug 11;168(15):1657-63. http://pmid.us/18695079.

[4] Stuckey BG et al. Low urinary iodine postpartum is associated with hypothyroid postpartum thyroid dysfunction and predicts long-term hypothyroidism. Clin Endocrinol (Oxf). 2011 May;74(5):631-5. doi: 10.1111/j.1365-2265.2011.03978.x. http://pmid.us/21470286.

[5] Dr. Datis  Kharrazian. Why Do I Still Have Thyroid Symptoms? When My Lab Tests Are Normal: A Revolutionary Breakthrough In Understanding Hashimoto’s Disease and Hypothyroidism.

[6] Dr. Datis  Kharrazian. Iodine and Autoimmune Thyroid — References. http://drknews.com/some-studies-on-iodine-and-autoimmune-thyroid-disease/.

[7] Dr. Datis  Kharrazian. Iodine and Hashimoto’s. http://drknews.com/iodine-and-hashimotos/.

[8] Chris Kresser. Iodine for hypothyroidism: like gasoline on a fire?. http://thehealthyskeptic.org/iodine-for-hypothyroidism-like-gasoline-on-a-fire.

[9] Dr. Guy E. Abraham. http://www.optimox.com/.

[10] Dr. Brownstein. Iodine, Why You Need It. https://www.drbrownstein.com/homePage.php.

[11] Dr. Jorge D. Flechas. http://cypress.he.net/~bigmacnc/drflechas/index.htm.

[12] Dr. David Derry. Breast Cancer and Iodine : How to Prevent and How to Survive Breast Cancer.

[13] Ott J et al. Hashimoto’s thyroiditis affects symptom load and quality of life unrelated to hypothyroidism: a prospective case-control study in women undergoing thyroidectomy for benign goiter. Thyroid. 2011 Feb;21(2):161-7. Epub 2010 Dec 27. http://pmid.us/21186954.

[14] Díez JJ, Iglesias P. Relationship between thyrotropin and body mass index in euthyroid subjects. Exp Clin Endocrinol Diabetes. 2011 Mar;119(3):144-50. Epub 2010 Nov 17. http://pmid.us/21086247.

[15] Xu J et al. Supplemental Selenium Alleviates the Toxic Effects of Excessive Iodine on Thyroid. Biol Trace Elem Res. 2010 Jun 2. http://pmid.us/20517655.

[16] Xue H et al. Selenium upregulates CD4(+)CD25(+) regulatory T cells in iodine-induced autoimmune thyroiditis model of NOD.H-2(h4) mice. Endocr J. 2010 Jul 30;57(7):595-601. Epub 2010 Apr 27. http://pmid.us/20453397.

[17] Sakaguchi S et al. Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006 Aug;212:8-27. http://pmid.us/16903903.

[18] Chen X et al. Effect of excessive iodine on immune function of lymphocytes and intervention with selenium. J Huazhong Univ Sci Technolog Med Sci. 2007 Aug;27(4):422-5. http://pmid.us/17828501.

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