A healthy thyroid is a critical component of one’s overall health, and many people are struggling with thyroid disorders such as hypothyroidism, specifically Hashimoto’s autoimmune thyroiditis. In this autoimmune condition, the immune system attacks the thyroid gland, with the resulting inflammation leading to an underactive thyroid gland or hypothyroidism. Hashimoto’s disease is the most common form of hypothyroidism and was the first condition ever to be classified as an autoimmune disease.

I’ve written extensively about thyroid health, focusing on a multitude of environmental factors that may effect thyroid function, including gluten, gut health, stress, excess iodine, and vitamin D deficiency. I’ve also discussed why dietary changes are always the first step in treating Hashimoto’s, and why replacement thyroid hormone is often necessary for a successful outcome.

There is yet another nutritional factor that may play a role in thyroid health: selenium.

Selenium deficiency is not thought to be common in healthy adults, but is more likely to be found in those with digestive health issues causing poor absorption of nutrients, such as Crohn’s or celiac disease, or those with serious inflammation due to chronic infection. (1, 2) It is thought that selenium deficiency does not specifically cause illness by itself, but that it makes the body more susceptible to illnesses caused by other nutritional, biochemical or infectious stresses, due to its role in immune function. (3) Adequate selenium nutrition supports efficient thyroid hormone synthesis and metabolism and protects the thyroid gland from damage from excessive iodine exposure. (4)

Several research studies have demonstrated the benefits of selenium supplementation in treating autoimmune thyroid conditions. One study found that selenium supplementation had a significant impact on inflammatory activity in thyroid-specific autoimmune disease, and reducing inflammation may limit damage to thyroid tissue. (6) This may be due to the increase in glutathione peroxidase and thioredoxin reductase activity, as well as the decrease in toxic concentrations of hydrogen peroxide and lipid hydroperoxides which result from thyroid hormone synthesis. (7)

Another study followed patients for 9 months, and found that selenium supplementation reduced thyroid peroxidase antibody levels in the blood, even in selenium sufficient patients. (8) While these studies show promise for the use of selenium supplementation in preventing thyroid tissue damage, further research is needed to determine the long-term clinical effects of selenium treatment on inflammatory autoimmune thyroiditis.

Additionally, selenium is also essential for the conversion of T4 to T3, as deiodinase enzymes (those enzymes that remove iodine atoms from T4 during conversion) are selenium-dependent. As I’ve explained before, T3 is the active form of thyroid hormone, and low T3 can cause hypothyroid symptoms. A double-blind intervention study found that selenium supplementation in selenium deficient subjects modulated T4 levels, theoretically by improving peripheral conversion to T3. (9) In cases of severe selenium deficiency, conversion of T4 to T3 may be impaired, leading to hypothyroid symptoms. As T3 conversion is not performed by the thyroid, the dependence on selenoproteins for this conversion demonstrates how significant selenium deficiency could lead to hypothyroid symptoms.

So the question is, should you start supplementing with selenium if you have hypothyroidism, Hashimoto’s thyroiditis, or low T3 levels?

As the answer often is, it depends. These preliminary studies show the positive effects of selenium supplementation on inflammatory activity in autoimmune thyroid conditions, but the long term effects of supplementation on thyroid health are still unknown. And we know that selenium is an essential component of the enzymes that convert T4 to T3, but whether supplementation will increase serum T3 levels is unclear.

While it seems that selenium supplementation would be an obvious solution to poor thyroid function, long term consumption of high doses of selenium can lead to complications such as gastrointestinal upsets, hair loss, white blotchy nails, garlic breath odor, fatigue, irritability, and mild nerve damage. (10) Additionally, supplementing selenium in the context of low iodine status may actually aggravate hypothyroidism. Mario Renato Iwakura discusses this particular topic extensively on Paul Jaminet’s Perfect Health Diet blog.

For now, the best option for most people may be to include selenium-rich foods in the context of a healthy Paleo diet. Great sources of selenium include: brazil nuts, crimini mushrooms, cod, shrimp, tuna, halibut, salmon, scallops, chicken, eggs, shiitake mushrooms, lamb, and turkey. For those concerned with the high level of omega-6 fats in brazil nuts, it may be worth considering the fact that it only takes one or two brazil nuts per day to improve your selenium status and boost immune function. (11)

For those who choose to supplement, I consider 200 micrograms of selenium to be a safe supplemental dose for people with thyroid issues. The brand of selenium I recommend is Life Extension Super Selenium Complex, which has four different forms of selenium, totaling 200 micrograms. It also provides vitamin E, which works synergistically with selenium as an antioxidant. This dosage is enough to be therapeutic for treating selenium deficiency, but has a lower risk of causing overdose symptoms.

Making sure your selenium intake is optimal may give your immune system and thyroid the boost it needs to help it function better. Whether through selenium-rich foods or supplements, it is especially important for those managing thyroid conditions to ensure their selenium status is adequate.

Has anyone had any experience with selenium supplementation? Was it a positive or negative experience? Let me know in the comments below.

GERD is an extremely common problem in the U.S.. 44% of Americans suffer from it at least once a month, and 20% suffer from it weekly. (1) Drug companies make $7 billion a year selling acid suppressing drugs – primarily proton pump inhibitors (PPIs) like Prilosec and Aciphex.

The popularity of these drugs is predicated on the idea that GERD is caused by stomach acid burning the esophagus. This is known as the “chemical burn” theory. It holds that GERD develops from caustic, chemical injury that starts at the surface layers of the esophagus and progresses through the tissue to the deeper layers (the lamina propia and submucosa). (2)

Early animal research seemed to support this. Studies showed large quantities of stomach acid with a pH of less than 2 does damage the esophagus. (3) However, the concentrations of acid used in these studies are much higher than those normally found in human episodes of reflux. In fact, the vast majority of human reflux episodes have a pH of more than 2 and are incapable of causing esophageal damage. (4)

What if GERD is not caused by acid burning the esophagus?

In a 2009 study Souza and colleagues connected the esophagus directly to the duodenum (the upper part of the small intestine) in a group of rats, thus permitting acid to reflux freely into the esophagus. (5) To their surprise, it took 3 weeks for damage to the esophagus to occur. Commenting on the results, senior author Stuart Spechler said:

That doesn’t make sense if GERD is really the result of an acid burn, as we were all taught in medical school. Chemical injuries develop immediately. If you spill battery acid on your hand, you don’t have to wait a month to see the damage.

If acid itself caused the damage, we’d expect to see the damage start at the superficial layers of the esophageal tissue, and then progressively deepen. Instead, this study found the opposite. 3 days after the initial acid exposure, there was no surface damage – but inflammation had already begun to develop at the deepest layer of the tissue. This inflammation didn’t rise to the surface layers until about 3 weeks after the initial acid exposure.

This suggests that GERD is an autoimmune disease.

Acid refluxing into the esophagus doesn’t damage the mucosal lining. Instead, it causes the esophagus to release inflammatory cytokines that attract inflammatory cells like interleukin-8, interleukin-6, and others. It is this inflammatory process – and not the initial exposure to stomach acid – that causes the tissue damage characteristic of GERD.

Do you have GERD – or NERD?

The theory that GERD is not caused by chemical injury is supported by the fact that 70% of westerners diagnosed with GERD have no visible tissue damage.

In fact, these people don’t have GERD at all. They have NERD, or Non-Erosive Reflux Disease. Tissue biopsy of their esophagus shows inflammation developing at the base layers of the esophagus like GERD sufferers, but no damage to the surface layers as the conventional theory would predict. It’s unclear at this point why the tissue injury progresses to the superficial layers in GERD – but not NERD – sufferers, but this study suggests that the answer may be an autoimmune mechanism.

So what does this mean for you? How do you avoid GERD and NERD in the first place?

Even if GERD is caused by an autoimmune process as this study suggests, the initial trigger seems to be acid inappropriately moving from the stomach to the esophagus. But that does not mean GERD & NERD are caused by too much stomach acid, as the common dogma holds.

In an earlier series of articles I presented evidence that acid reflux is caused not by too much stomach acid, but by not enough. I argued that low stomach acid causes bacterial overgrowth in the gut, which in turn produces gas that puts pressure on the lower esophageal sphincter, causing it to open and inappropriately allow acid into the esophagus.

I also offered a simple, 3-step protocol for treating reflux and GERD without drugs that thousands of people have now successfully used (check out the 190 comments) – including people that had been on acid suppressing drugs for 20 years or more. This is important because acid-suppressing drugs have numerous side effects and complications.

Why you should think twice about taking acid-suppressing drugs.

Acid stopping drugs promote bacterial overgrowth, weaken our resistance to infection, reduce absorption of essential nutrients, and increase the likelihood of developing IBS, other digestive disorders, and cancer. The pharmaceutical companies have always been aware of these risks. When acid-stopping drugs were first introduced, it was recommended that they not be taken for more than six weeks. Clearly this prudent advice has been discarded, as it is not uncommon today to encounter people who have been on these drugs for decades – not weeks.

What’s more, a recent study showed that proton-pump inhibitors (PPIs) – the most popular class of acid-suppressing drugs – induce “rebound acid reflux” in healthy people. The researchers took a group of people without any history of reflux and put them on PPIs for 8 weeks (where did they find these volunteers???) More than 40% of the healthy volunteers developed rebound acid-related symptoms like heartburn, acid regurgitation and dyspepsia once they stopped taking the drugs. (6) The authors of the study stated:

If rebound acid hypersecretion (RAHS) induces acid-related symptoms, this might lead to PPI dependency and thus have important implications.

I’d say!

If you suffer from acid reflux, make sure to read the entire series, and then follow the 3-step protocol I laid out. In a future article I’ll be covering some additional natural treatments that studies have shown to be just as effective as PPIs, with virtually no side effects or risks.

For decades now, the general American population has been neurotically avoiding cholesterol-rich foods for fear of developing heart disease, thanks to the promulgation of the unfortunate Diet-Heart hypothesis. (1)

Those of us that follow a paleo diet are well aware by now that dietary cholesterol does not significantly affect cholesterol levels in the blood or risk for heart disease, and that there is no reason to avoid whole foods with naturally high levels of cholesterol.

However, beyond just ‘not avoiding’ high cholesterol foods, there is a significant reason for us to make a special effort to include many high cholesterol foods in our diet.

The reason? The much under-appreciated B-vitamin called choline, found primarily in cholesterol-rich foods.

If you haven’t heard of choline, or don’t know much about this vital nutrient, you’re not alone. Choline has only been ‘officially’ recognized as an essential nutrient since 1998, when the Food and Nutrition Board of the Institute of Medicine established an Adequate Intake (AI) level of 425 mg per day for women and 550 mg per day for men. (2) Even though it has been deemed a nutrient vital for human health, only 10% of Americans are meeting the conservative AI levels established by the IOM.

If you eat a strict paleo diet, you may be closer to meeting your choline needs than the average American, but only if you are regularly including choline rich foods in your diet. The best whole food sources of dietary choline are egg yolks and liver, which are often avoided by many Americans due to unfounded fear of dietary fat and cholesterol. However, these high cholesterol foods are at the top the choline-rich foods list, followed (albeit distantly) by beef, cod, brussels sprouts, and broccoli. (3)

Why is choline such an important nutrient to consider in one’s diet?

Choline has a variety of functions in the body, including the synthesis of the neurotransmitter acetylcholine, cell-membrane signaling, lipid transport, and methylgroup metabolism. (4) In addition, it is an essential component of the many phospholipids that make up cell membranes, regulates several metabolic pathways, and aids detoxification in the body. During pregnancy, low choline intake is significantly associated with a higher risk of neural tube defects in the newborn.

Choline deficiency over time can have serious implications for our health. Symptoms of choline deficiency include fatigue, insomnia, poor kidney function, memory problems, and nerve-muscle imbalances. Extreme dietary deficiency of choline can result in liver dysfunction, cardiovascular disease, impaired growth, abnormalities in bone formation, lack of red blood cell formation, infertility, kidney failure, anemia, and high blood pressure. Incredibly, choline deficiency is the only nutrient deficiency shown to induce the development of spontaneous carcinoma. (5)

Chris Masterjohn has written extensively about choline deficiency and its relationship to fatty liver disease which affects as many as 100 million Americans and is often attributed to excess alcohol and sugar consumption by conventional practitioners. After a review of the literature, Masterjohn concludes that choline deficiency plays a role in virtually every type of diet-induced fatty liver model, and that adequate dietary choline is essential for proper liver function. He also suggests that high consumption of dietary fat, including saturated fats, increases the amount of choline required to prevent the accumulation of fat in the liver. (6)

This means that if you’re eating a higher fat diet, it is even more crucial that you include a variety of choline rich foods in your diet.

Another important factor to consider is that while humans are able to produce some level of endogenous choline, some people have a common gene variation that further increases the amount of choline they must consume to satisfy their body’s requirements. (7) These particular people are more susceptible to choline deficiency, and must be especially vigilant about including choline rich food in their diets.

As choline is so important, you may be wondering what the best food sources are in order to improve your intake. There are many natural, whole foods that are excellent sources of bioavailable choline, with the best sources being beef liver, poultry liver, and whole eggs. (8) These foods are not only high in choline, but are also very high in many different vitamins and minerals such as as vitamin A, arachidonic acid, DHA, and the B vitamins. (9)

We already know liver is an amazing superfood. Liver from pastured animals is a great source of trace elements such as copper, zinc and chromium, plus highly bioavailable folate and iron. (10)

Liver is also the most potent source of dietary choline that we know of.

For example, a three ounce serving of pan-fried beef liver has over 400 mg of choline in it, compared to less than 80 mg in the same amount of cooked ground beef. (11) While you don’t need to consume beef liver on a daily basis to reap the benefits of this superfood, it should be clear that including pastured liver and other organ meats as part of a nutritionally complete diet is one of the best ways to improve your health and prevent the many types of chronic disease caused by nutrient deficiencies.

If you’re not used to including lots of liver and whole eggs in your regular meal plan, give a few of the following recipes a try. It’s never too late to start incorporating more choline into your diet!

Liver recipes: get your choline!

• http://cavegirleats.com/2011/09/09/baked-liver-pate-yum-seriously-seriously
• http://balancedbites.com/2011/05/easy-recipe-chicken-liver-pate.html
• http://paleodietlifestyle.com/simple-and-delicious-liver-pate-recipes/
• http://www.foodnetwork.com/recipes/ina-garten/chopped-liver-recipe/index.html
• http://www.foodrenegade.com/egg-drop-soup/
• http://nomnompaleo.com/post/1983505174/easy-paleo-frittata
• http://www.theclothesmakethegirl.com/2011/01/17/dont-be-lily-livered-aromatic-chickenlivers/
• http://www.theclothesmakethegirl.com/2010/05/17/scotch-eggs-a-k-a-protein-pellets/
• http://www.primal-palate.com/2011/01/root-vegetable-hash-with-poached-egg.html

In this final article in the series on Low T3 Syndrome, we’ll discuss whether thyroid hormone replacement therapy is an appropriate treatment in these cases.

Unfortunately, there are few studies that have examined this question specifically, and even fewer that have explored the question of whether T4 or T3 (and which type of each) would be the best choice.

As a clinician, my primary concern is always primum non nocere, or “first, do no harm.” From this perspective it’s important to recognize that the changes seen in Low T3 Syndrome may represent a restorative physiological adaptation by the body to chronic illness. In other words, T3 levels are low because the body is attempting to conserve energy and resources to better cope with the challenges it is facing. Increasing thyroid hormone levels in this situation could conceivably have adverse effects.

For example, the changes observed in the thyroid axis in acute illness are similar to those observed in fasting, which can be interpreted as an attempt to reduce energy expenditure and protein wasting. (1) Giving fasting subjects thyroid hormone results in increased catabolism (breakdown). (2)

In cases of chronic illness, however, it is less clear what effect thyroid hormone replacement has. The few studies that have been done produced mixed results. (3)

Some studies show that treatment causes harm, others show no change, and still others show an improvement. After reviewing the literature on this, I’ve come to the following tentative conclusions:

• T4 is rarely, if ever, effective in Low T3 Syndrome and may even cause harm. This is probably due to the decreased conversion of T4 to T3 that is seen in chronic illness.
• T3 replacement has been shown to be consistently beneficial only in cardiac patients who’ve recently had surgery, heart failure or a transplant.

That said, I’ve heard anecdotal reports of improvement from people who have taken replacement T3 hormone for a condition called “Wilson’s Syndrome” (which does not exist in the scientific literature or according to any mainstream medical organizations). Wilson’s Syndrome refers to low basal body temperature and other nonspecific symptoms occurring in the presence of normal thyroid hormones.

I’ll be the first to admit that “lack of evidence is not evidence against”, and as I mentioned earlier, there’s not a lot of research on the effectiveness of T4 and T3 replacement therapy in Low T3 Syndrome. It may be that as we look into this further, we’ll discover a role for thyroid hormone replacement in these conditions.

That said, I think caution is warranted. Taking T3 when you don’t need it is potentially dangerous. It can significantly upregulate the metabolic rate and lead to cardiovascular complications in some patients. And, if the changes seen in Low T3 Syndrome are a compensatory adaptation of the body in response to chronic illness, increasing T3 levels artificially may have undesirable effects.

In the majority of cases of Low T3 Syndrome, I think it’s preferable to identify the underlying cause and treat that. As I discussed in articles #3 and #4 in this series, those causes most often include infections, autoimmunity and inflammation.

Have any of you tried thyroid replacement for Low T3 Syndrome? If so, what was your experience? Please let us know in the comments section.

Articles in this series:

• Low T3 Syndrome I: It’s Not About The Thyroid!
• Low T3 Syndrome II: Myths and Misconceptions
• Low T3 syndrome III: Inflammation Strikes Again
• Low T3 Syndrome IV: An Autoimmune Disease You’ve Never Heard Of?
• Low T3 syndrome V: Should It Be Treated With Thyroid Hormone?

In the last article in this series I discussed several lines of evidence suggesting that inflammation is one of the primary causes of Low T3 Syndrome.

In this article we’re going to discuss another common, but lesser known, cause: autoimmune hypopituitarism.

Say what? I know that’s a mouthful. Let’s break it down.

The pituitary gland is located just below the hypothalamus, but outside the blood-brain barrier. It’s primary job is to monitor the levels of hormones produced by various endocrine organs (like the thyroid), and release stimulating hormones (like TSH) that direct those organs to produce their respective hormones (like T4 and T3).

The pituitary gland can be the target of inflammatory response to local infections, cancer or autoimmune reactions. When an autoimmune mechanism is involved, lymphocytic adenohypophysitis (LAH) or autoimmune hypopituitarism are the terms used to describe the condition. (I’ll refer to this condition as LAH throughout the article.)

What is autoimmune hypopituitarism?

LAH is characterized by progressive destruction of pituitary tissue, which over time produces a decline in the function of the pituitary gland. (1) When the pituitary is damaged more than one hormone is affected, especially as the disease becomes more advanced.

It was originally believed that LAH occurred exclusively in pregnant women. (2) But although prevalence is still much higher in that population, we now know it also occurs in non-pregnant women, men and children. (3)

Adrenocorticotropin (ACTH) deficiency is most common (60%), followed by thyrotropin (TSH) deficiency (47%), gonadotropin (FSH/LSH) deficiency (42%), growth hormone deficiency (42%) and prolactin deficiency (34%).

What is remarkable about this condition is how unknown it is in spite of its prevalence. It’s true prevalence is unknown, but most investigators believe it is under-reported because it is often misdiagnosed. I’ve seen some estimates that it may affect up to 0.5% of the population and up to 40% of Hashimoto’s patients.

How is autoimmune hypopituitarism diagnosed?

The reason it’s so often misdiagnosed is that it’s difficult to pin down. It is strongly associated with other autoimmune diseases, which further complicates the clinical picture. In fact, concurrent autoimmune conditions are reported in 20-50% of LAH cases. (4)

Interestingly, Yoon et al. injected hamsters with Rubella virus glycoproteins and consistently induced LAH, as evidenced by autoantibodies to pituitary cells and infiltration of the pituitary gland by lymphocytes. (5) This finding suggests there may be some connection between viral infections and LAH.

Other investigators have identified antibodies to growth hormone (GH), thyrotropin (TSH), and luteinizing hormone (LH) in cases of LAH. (6) Unfortunately, the only conclusive test for LAH is a tissue biopsy, which is obviously problematic due to the location of the pituitary gland.

Low levels of the pituitary hormones can indicate LAH, but they can also be a sign of other functional problems with feedback in the hypothalamus or a primary problem with the hypothalamus itself.

What are the signs and symptoms of LAH?

The hallmark sign of LAH is atrophy of the gonads, adrenals and thyroid gland. Endocrine tissue is similar to muscle tissue in the sense that it will atrophy if it’s not stimulated regularly (similar to how men who take testosterone have shrunken testes).

Symptoms include:

• Headache
• Impaired vision
• Nausea
• Weakness
• Loss of appetite
• Hormone imbalances
• Hyperprolactinemia

However, LAH is difficult to characterize because it can mimic so many other conditions. A problem with the pituitary gland can affect the entire endocrine system, because the pituitary sends out the stimulating hormones that direct the organs (thyroid, adrenals, ovaries, testes, etc.) to produce their respective hormones. This is, of course, how LAH can lead to low T3 levels.

It’s also interesting to note that there appears to be a connection between LAH and celiac disease. (What isn’t connected with celiac disease?) Delvecchio et al found that about 40% of newly diagnosed celiac patients had anti-pituitary antobidies in their blood and it resulted in – at a minimum – growth hormone deficiency. (7) This is an important finding that I have rarely seen discussed.

How is autoimmune hypopituitarism treated?

Not very well, in the conventional model. Some doctors use immunosuppressants like prednisone, azothioprine and methotrexate, but the risks and side effects of these drugs can often be worse than the disease itself.

The first step to take is to make sure you’re eating a diet that is free of foods that tend to provoke an autoimmune response. A Paleo-type diet is the best starting place, but you may also want to remove dairy, nightshades and eggs for at least 30 days because those foods can be problematic for people with autoimmune disease.

It’s also important to focus on nutrients that support proper T-regulatory cell function, like vitamin D and glutathione, and nutrients that support overall immune health like vitamin C, iodine and selenium.

I would also consider low-dose naltrexone (LDN), a medication that is being used to successfully treat a wide range of autoimmune diseases – including Hashimoto’s and Graves’. In most cases I don’t recommend pharmaceuticals because they tend to suppress symptoms without improving function. LDN, however, actually improves the function of the body by upregulating endogenous endorphin production and balancing the immune system.

Articles in this series:

• Low T3 Syndrome I: It’s Not About The Thyroid!
• Low T3 Syndrome II: Myths and Misconceptions
• Low T3 syndrome III: Inflammation Strikes Again
• Low T3 Syndrome IV: An Autoimmune Disease You’ve Never Heard Of?
• Low T3 syndrome V: Should It Be Treated With Thyroid Hormone?

In the last article in this series we discussed some common myths and misconceptions about Low T3 Syndrome. In this article, we’re going to look at causes and mechanisms.

As I mentioned briefly before, researchers now believe that the fall in T3 seen in acute and chronic illness is most likely due to either impaired production of T3 in the thyroid (due to a change in the hypothalamic-pituitary-thyroid axis) or to a decrease in thyroid binding proteins. Both of these changes are caused by inflammation.

The thyroid set point

There’s been a lot of discussion recently in the blogosphere about the body fat set point, which is the complex neurobiological system that regulates weight. However, there is also a set point of the hypothalamic-pituitary-thyroid (HPT) axis that regulates the production of endocrine hormones, including TSH, T4 and T3.

It seems that the low TSH associated with illness, or the failure of TSH to rise in response to low T4 and T3, is caused by alterations in the set point of the HPT axis. There’s a set of neurons in the paraventricular nucleus (PVN) of the hypothalamus that is responsible for promoting TSH synthesis in the pituitary and regulating thyroid hormone synthesis.(1)

Post-mortem samples from patients who died after prolonged illness show a decrease of thyrotropin-releasing hormone (TRH) gene expression in the PVN.(2) Moreover, administering TRH and growth-hormone (GH) secretogogues to patients with prolonged illness at least partially restores TSH, T4 and T3 levels.(3) Both of these lines of evidence suggest that a change in the HPT axis is involved in the Low T3 Syndrome.

While there are multiple causes of such changes in the HPT axis, two of the more clinically relevant ones are inflammation and either a decline in serum leptin levels or leptin resistance.

Inflammatory cytokines released in the acute phase response (the inflammatory process) suppress the production of TRH in the PVN.(4) I’ll discuss the role of inflammation in more detail below.

Fasting or diminished calorie intake due to prolonged illness leads to decreased T3 levels, and this is thought to be mediated by a decrease in circulating leptin. Leptin prevents certain neurons (NPY/AgRP) from inhibiting TRH gene expression.(5)

Although I haven’t seen any studies on this specifically, it’s entirely conceivable that leptin resistance (which characterizes obesity) could have the same T3 decreasing effect. Most people are aware that poor thyroid function contributes to weight gain, but this mechanism suggests that it may also work in reverse: leptin resistance associated with overweight and obesity may contribute to poor thyroid function.

Thyroid binding proteins

When thyroid hormone is produced and released into the circulation by the thyroid gland, it’s bound (reversibly) to thyroxine-binding globulin (TBG), transthyretin and albumin. TBG is the major binding protein in humans, and under normal circumstances, less than 0.05% of thyroid hormone is unbound (“free”) in the blood.

It’s thought that only this tiny fraction of “free” thyroid hormone is able to enter the cell and perform the biological actions of thyroid hormone. This means that the concentration of total T4 and T3 (produced by the thyroid gland) is heavily dependent on the concentration of these binding proteins, while the free hormone concentrations are largely independent of them.

In Low T3 Syndrome, the concentration of thyroid binding proteins decreases as a consequence of the “acute phase response” (a.k.a. inflammation). For example, TBG levels decrease by as much as 60 percent in the 12 hours following bypass surgery.(6) In rodents, inflammation leads to a significant decrease in transthyretin, which is the major plasma thyroid hormone binding-protein in that species.(7) The fall in these binding proteins is probably what accounts for the decrease in total (protein-bound) T4 and T3 levels in acute and chronic illness.

Inflammation strikes again

Pro-inflammatory cytokines, which are chemical messengers involved in the inflammatory response, have been shown to contribute to Low T3 Syndrome in multiple ways.

Interleukin-6 (IL-6) is positively correlated with reverse T3 (an inactive form of T3) and negatively correlated with free T3.(8) In other words, the more IL-6 that is circulating in your blood, the less active thyroid hormone you’ll have available to your cells and tissues.

Administration of tumor necrosis factor alpha (TNF-alpha) to healthy individuals produces changes in thyroid hormones characteristic of Low T3 Syndrome.(9)

Administration of interferon alfa (IFN) to normal volunteers results in a decrease in T3 and TSH and a rise in reverse T3.(10)

Other studies have shown that lipopolysaccharide (LPS), a bacterial endotoxin, can downregulate TSH, T4 and T3 levels.(11) This explains the link between chronic bacterial infections and the Low T3 Syndrome, and it’s yet another connection between gut health and the thyroid (since many people with poor gut health have gut infections).

The takeaway of this article is that the primary mechanisms of Low T3 Syndrome are mediated by inflammation. That inflammation could be caused by an infection, autoimmune disease, obesity, diabetes or other chronic illness. Just about any disease you can think of is characterized by inflammation, so the list here is quite long.

In the next article I’ll discuss how – and if – Low T3 Syndrome should be treated.

Articles in this series:

• Low T3 Syndrome I: It’s Not About The Thyroid!
• Low T3 Syndrome II: Myths and Misconceptions
• Low T3 syndrome III: Inflammation Strikes Again
• Low T3 Syndrome IV: An Autoimmune Disease You’ve Never Heard Of?
• Low T3 syndrome V: Should It Be Treated With Thyroid Hormone?

In Low T3 Syndrome I, I introduced the Low T3 Syndrome (a.k.a. Euthyroid Sick Syndrome, Non-Thyroidal Illness Syndrome), provided some background on thyroid physiology and metabolism, and emphasized the fact that Low T3 Syndrome is not caused by a problem in the thyroid gland itself.

In this article we’re going to discuss common myths and misconceptions about Low T3 Syndrome and problems diagnosing it in a clinical setting.

This is important because there’s a lot of chatter around the internet these days about this condition. I’m getting a lot of questions about it and I see a lot of people diagnosing themselves with Euthyroid Sick Syndrome on the basis of what I feel is pretty sketchy evidence.

Early theories on Low T3 Syndrome

The typically accepted view in the scientific literature until quite recently was that the conversion of T4 to T3 is impaired in illness because of a decrease in the activity of D1 & D2 thyroid deoidinases (enzymes responsible for activation of thyroid hormone) in the liver, kidney, skeletal muscles and other peripheral tissues. (1)

The trigger for these changes was thought to be an increase in cortisol and pro-inflammatory cytokines, both of which typically occur in chronic illness.

Recently, however, this theory has been challenged. Researchers now argue that the changes seen in D1, D2 & D3 (deodinase) expression may be the consequence – not the cause – of changes in T4 and T3 levels. (2)

This is supported by studies on D1, D2 and D3 knockout mice subjected to treatment with lipopolysaccharide (LPS), an pro-inflammatory endotoxin. These mice, which don’t have any thyroid deiodinase activity, experienced the same decrease in T4 and T3 as wild-type mice. (3)

Also, when wild-type mice are injected with LPS, the fall in T4 and T3 precedes the decline in deiodinase activity (4), and in humans it has been shown that decreased D2 activity doesn’t contribute to Low T3 Syndrome in either prolonged or acute illness. In fact, D2 expression increases two- to three-fold in chronic illness states. (5)

However, evidence now suggests that the fall in T3 found in acute illness is more likely to be caused by impaired production of T3 in the thyroid gland (in turn caused by decreased hypothalamic production of TRH and pituitary production of TSH), and the reduction in thyroid horomone-binding proteins in the serum. (6) We’ll discuss these mechanisms in more detail in the next article.

Problems with testing and diagnosis

One of the biggest problems with getting a better understanding of Low T3 Syndrome is that the methodologies for testing thyroid hormones in the general population are often inappropriate or outdated.

First, it’s often the case that only total T4 and T3 are tested, rather than free T4 and free T3. While total T4 and T3 give us important information about what the thyroid gland itself is producing, free T4 and T3 tell us how much thyroid hormone is actually available at the cellular level to exert its metabolic effects.

But even when free T4 and T3 are tested, the results are often inaccurate because of the methods used. Although it is often claimed that free T4 is low in patients with Low T3 Syndrome, when the proper methodology is used, free T4 is rarely low – and is often normal or even high. (7)

In fact, is studies using reliable assays for free T4, around 50% of patients had low total T4 but only 2% had low free T4! (8)

The situation is even more problematic, in some ways, with the measurement of free T3 – especially because the free T3 level is fundamental to the diagnosis of Low T3 Syndrome.

It is unequivocal in the literature that total T3 falls during illness, and that the degree of the fall is directly proportional to the severity of the illness. And most routine methods used to measure free T3 commercially and even in research settings tend to show that it drops right along with total T3.

However, results from two studies that have used an improved method for free T3 analysis have found that illness results only in a modest fall in free T3. In fact, free T3 levels were only 10% lower in sick patients than in healthy controls. (9)

Another study using this method found that while 70-80% of sick patients had low total T3, only 27% of them had low free T3. (10)

Why does this matter? Two reasons:

• First, a lot of people diagnosed with Low T3 Syndrome may not actually have low free thyroid hormones. This is a concern because some people are supplementing with T4 and/or T3 under the false impression that their hormones are low.
• Second, it implies that the significant changes seen in total T4 and T3 in Low T3 Syndrome are largely due to changes in the serum binding capacity for thyroid hormones.

We’ll discuss each of these points in more detail in the posts to follow.

Articles in this series:

• Low T3 Syndrome I: It’s Not About The Thyroid!
• Low T3 Syndrome II: Myths and Misconceptions
• Low T3 syndrome III: Inflammation Strikes Again
• Low T3 Syndrome IV: An Autoimmune Disease You’ve Never Heard Of?
• Low T3 syndrome V: Should It Be Treated With Thyroid Hormone?

The more damaged you are, the more carbohydrate restriction is likely to benefit you long term.
- Peter @Hyperlipid

I don’t think there are too many people out there familiar with the mechanisms of diabetes and insulin resistance that would disagree with that statement.

But just because a low-carb diet causes fat loss in this population, that doesn’t mean that carbs caused the fat gain or damaged metabolism in the first place.

I wrote about this in a previous article, There is No Single Cause of (or Treatment or) Obesity, but based on some of the comments and discussion I’ve been seeing online recently, I think it bears repeating: in order to properly frame this debate, it’s essential to separate the causes and treatment of obesity. If we don’t do this, we might as well not even have a debate at all because we won’t be talking about the same thing.

We know without a doubt that statins lower cholesterol. But does that mean high cholesterol is caused by a statin deficiency? If you break your arm, your doctor will probably put a cast on to help it heal. Does that mean we should all wear casts on our arms to make sure they don’t break?

Metabolically damaged vs. healthy: apples & oranges

Another important distinction that should be made – but often isn’t – is the difference between how people that are metabolically healthy and metabolically damaged respond to food. Of course excess carbohydrates are more likely to cause problems in someone with leptin and insulin resistance and impaired glucose tolerance. But it doesn’t follow that the same will be true in someone without metabolic problems.

People without gall bladders don’t digest fat very well. Does that mean fat causes indigestion? I have patients with iron overload due to a genetic condition called hemachromatosis. They need to limit their red meat intake because of this. Does this mean we should all avoid red meat to prevent iron overload?

We’re not robot clones. We have different genes, lifestyles, gut flora, immune fitness and exposures to toxins, stress and infections, as well as different emotional and psychological relationships with food. All of these factors play a role in weight regulation.

This explains why two people can react to the same diet in entirely different ways. And it also explains why it’s so ridiculous to extrapolate something that you experience personally to everyone else. (If I read another comment from someone saying that a low-carb diet worked for them, so the insulin-carb theory must be correct, I’m going to lose it. And it takes a lot to make me lose it!)

My unified theory of obesity

For what it’s worth, here’s my “unified theory” on what causes obesity.

Modern lifestyle + genetic predisposition = obesity.

It really is that simple.

Modern lifestyle includes processed, refined and highly rewarding and palatable foods, excess fructose, unprepared grains (especially flour), industrial seed oils, environmental toxins, sedentary behavior, stress, infections and dysregulated gut flora.

But the modern lifestyle doesn’t cause obesity in all people. I’m sure we all know someone who eats a horrible diet, doesn’t exercise, is under tons of stress and lives a shockingly unhealthy lifestyle – but doesn’t gain a single pound.

That’s where genetics come in.

Human evolution didn’t stop in the Paleolithic

A commonly held belief in the Paleo-sphere (I held it myself, until fairly recently) is that our genes haven’t changed much since the Paleolithic era. But recent evidence suggests a much more rapid pace of genetic change in humans than was previously estimated.

The birth of agriculture introduced significant selection pressure, and thus mutation, because humans were not well-adapted to this new way of life. And the evolutionary response to agricultural diet differs because different peoples adopted agriculture at different times and in different places.

Agriculture began in the Middle East 10,000 years ago, but it was never adopted by Aboriginal Australians. Might we expect the descendants of people from these two regions to have different responses when exposed to agricultural diets?

Absolutely. Researchers in Iceland have discovered a gene that regulates blood sugar tolerance. (I discussed the role of genetics in obesity and diabetes in a previous article, Are You At Risk For Diabetes and Obesity?) And we know that Aboriginal Australians have a 4 times greater risk of developing adult-onset diabetes than Australians of European descent.

Lactase persistence is another example. During Paleolithic times, humans stopped producing lactase (the enzyme required to digest lactose, the sugar in milk) shortly after weaning. There was no need for it, since Paleo people didn’t raise cattle or drink milk. Skeletal remains from northern Europeans 8,000 – 9,000 years ago confirm that there was no lactose tolerance at that time.

However, skeletal remains from northern Europeans living in the Bronze Age 3,000 years ago show roughly 25% of adults produced lactase. And today, in certain Scandanavian countries, more than 95% of adults are now lactose tolerant. ¹

All of these genetic changes happened within the last 8,000 years, after the advent of agriculture.

The hand you were dealt: life isn’t always fair

What this means is that some of us are likely better adapted to the modern lifestyle, while others are more susceptible to being harmed by it. Those are very likely the ones that become obese when exposed to a western diet.

But as far as I can tell, they didn’t get obese by eating natural, whole-food carbohydrates. I’ve yet to see a population that got fat eating sweet potatoes, fruit and white rice – without any exposure to modern food. If anyone knows of such a population, please let me know.

Does it even matter what causes obesity? I just want to lose weight!

Some might argue that this discussion is irrelevant, since once someone become obese it’s clear their metabolism is damaged. There are two main problems with that argument.

First, not all obese people have deranged metabolisms. Research over the past several years has defined a subset of “metabolically healthy obese” (MHO) people with normal fasting glucose, triglycerides, insulin sensitivity and other markers. I wrote about this in my article Not All Fat People Get Diabetes, and Not All Diabetics Are Fat.

Second, separating the cause and treatment of obesity is necessary to prevent confusion. Something I see all the time in my practice and in the blogosphere is normal or even underweight people following zero- or very-low-carb diets. Why? Because they’ve absorbed the notion that “carbs are bad” from the “carbs-insulin-fat gain” theory, and they avoid them in a misguided attempt to promote health. While this may work for some people, it doesn’t for many others. I know because they end up coming to me with complaints like low energy, hair loss, bad breath, constipation and more.

Food reward vs. the carbohydrate hypothesis: setting the ground rules

I’d like to see a discussion of obesity that acknowledges the difference between cause and effect, considers the varying impact of food on the metabolically healthy and unhealthy, and recognizes the role of genetics in weight regulation.

Unfortunately, these important distinctions seem to be missing from the current debate – which, in my mind, makes it far less compelling.

Hypothyroidism involves high levels of thyroid stimulating hormone (TSH) and low levels of the thyroid hormones T4 and T3.

However, in my clinical practice I frequently see people with low levels of T3 with normal T4 and either low or normal TSH. This condition has been reported on in the medical literature for years but it is rarely acknowledged or discussed in conventional medical settings. Most doctors (even endocrinologists) do not seem to know what causes it, or what to do about it. (I know this because I always ask my patients with this syndrome what their doctors said about it, and my patients’ response is almost always some variation of “not much”).

This particular pattern goes by three different names in the medical literature: Euthyroid Sick Syndrome (ESS), Non-thyroidal Illness Syndrome (NTIS), and Low T3 Syndrome.

NTIS has become the term of choice in the literature. However, I’m going to use Low T3 Syndrome in these articles because it’s more descriptive and accessible to the layperson.

What’s most important to understand about this condition is that, although it does involve low levels of T3 (the most active form of thyroid hormone), it is not caused by a problem with the thyroid gland. This is a crucial distinction and it’s what distinguishes Low T3 Syndrome from “garden-variety” hypothyroidism.

In this series we’re going to discuss 1) what causes Low T3 Syndrome, 2) it’s clinical significance, and 3) if it should be treated, and if so, how.

But first we need to lay the foundation with a little basic thyroid physiology.

Basic thyroid physiology

In order to understand Low T3 Syndrome, you’ll need a basic understanding of thyroid physiology. Regulation of thyroid metabolism can be broken down into the following five steps:

1. The hypothalamus (a pea-sized gland in the brain) monitors the levels of thyroid hormone in the body and produces thyrotropin releasing hormone (TRH).
2. TRH acts on the anterior pituitary (directly below the hypothalamus, but outside of the blood-brain barrier) to produce thyrotropin, a.k.a. thyroid stimulating hormone (TSH).
3. TSH acts on the thyroid gland, which produces thyroxine (T4) and triiodothyronine (T3), the primary circulating thyroid hormones. The thyroid produces T4 in significantly greater quantities (in a ratio of 17:1) than T3, which is approximately 5x more biologically active than T4.
4. T4 is converted into the more active T3 by the deiodinase system (D1, D2, D3) in multiple tissues and organs, but especially in the liver, gut, skeletal muscle, brain and the thyroid gland itself. D3 converts T3 into an inactive form of thyroid hormone in the liver.
5. Transport proteins produced by the liver – thyroid binding globulin (TBG), transthretin and albumin – carry T4 and T3 to the tissues, where they are cleaved from their protein-carriers to become free T4 and free T3 and bind to thyroid hormone receptors (THRs) and exert their metabolic effect.

Mechanisms of Low T3 Syndrome

As you can see, the production, distribution and activation of thyroid hormone is complex and involves several other organs and tissues other than the thyroid gland itself.

Hypothyroidism is a defect in step #3, because it typically involves a dysfunction of the thyroid gland itself – most often caused by autoimmune disease (Hashimoto’s, Ord’s, Graves’) and/or iodine deficiency.

However, in Low T3 Syndrome, the problem generally occurs in steps #1, #2, #4 and #5. None of those steps are directly related to the function of the thyroid gland itself.

More specifically, Low T3 Syndrome can include the following mechanisms:

• Modifications to the hypothalamic-pituitary axis
• Altered binding of thyroid hormone to carrier proteins
• Modified entry of thyroid hormone into tissue
• Changes in thyroid hormone metabolism due to modified expression of the deiodinases
• Changes in thyroid hormone receptor (THR) expression or function

Low T3 Syndrome in acute and chronic illness

Most of the studies on Low T3 Syndrome have been done on people suffering from acute, life-threatening illness. In the intensive care unit, the prevalence of abnormal thyroid function tests is remarkably high. More than 70% of patients show low T3 and around 50% have low T4.

Many of these studies have indicated a direct relationship between Low T3 Syndrome the severity and both short- and long-term outcome of disease. The lower the T3 level in critically ill patients, the worse the outcome tends to be.

However, studies examining thyroid hormone replacement in these situations have shown mixed results. In most cases – with the exception of cardiovascular disease – taking thyroid hormone did not improve outcomes. We’ll discuss this in more detail later.

Recently, more attention has been given to Low T3 Syndrome in non-critical, chronic illness. Specifically, the question on everyone’s mind (including mine) is whether thyroid hormone replacement is useful in this situation, or if – as some have suggested – it could even be harmful.

In emotional, psychological or physiological stress, the body will convert excess T4 to reverse T3 (rT3) as a means of conserving energy for healing and repair. It is at least possible, therefore, that replacing thyroid hormone in these cases may not be beneficial.

On the other hand, in those suffering from long-term chronic illness, Low T3 Syndrome may be more reflective of pathology than adaptation, and this group may benefit from T4 or T3 supplementation.

We’ll explore all of these questions in more detail in the articles to follow, and I’ll also share some of my observations from my clinical practice. Stay tuned!

Articles in this series:

• Low T3 Syndrome I: It’s Not About The Thyroid!
• Low T3 Syndrome II: Myths and Misconceptions
• Low T3 syndrome III: Inflammation Strikes Again
• Low T3 Syndrome IV: An Autoimmune Disease You’ve Never Heard Of?
• Low T3 syndrome V: Should It Be Treated With Thyroid Hormone?

One of the most hotly debated subjects over the past few years has been the cause of the obesity epidemic, and along with that, the best strategy for weight loss.

Some folks (Atkins, Taubes, Eades, etc.) believe that carbohydrates are to blame. Others (Ornish, Campbell, Esselstyn, Fuhrman, etc.) believe that fat is the problem. More recently, researchers like Seth Roberts and Stephan Guyenet and clinicians like Dr. Sharma have raised awareness of another hypothesis, called the food reward theory, which holds that the consumption of highly palatable foods leads to overeating and weight gain. And Paul Jaminet and others have argued that micronutrient deficiencies, toxins and infections may play a significant role in the obesity epidemic.

Here’s what I think: the most accurate answer to “why do people get fat?” and “what’s the most effective weight loss strategy?” is: “it depends.”

Separating cause from mechanism and effect

One of the biggest mistakes often made in this debate is the confounding of cause, mechanism and effect. A classic example is the assumption that if reducing carbohydrate or fat intake leads to weight loss, then the original weight gain must have been caused by excess carbohydrate or fat consumption.

While it’s tempting to make such an assumption, the logic is faulty. It’s kind of like saying “Advil cures headaches. Therefore, headaches must be caused by Advil deficiency.”

Let’s look at some definitions.

Cause: something that brings about an effect or a result

Mechanism: the fundamental processes involved in or responsible for an action, reaction, or other natural phenomenon

Effect: an outward sign

Obesity is an effect. Insulin resistance, leptin resistance, lipotoxicity, disruption of the mesolimbic dopamine reward pathway and inflammation of the hypothalamus are presumed mechanisms. Excess consumption of carbohydrates, fat, highly palatable food and food toxins (wheat, seed oils, liquid fructose, etc.), exposure to environmental toxins (chemicals), stress, infections, etc. are presumed causes.

Say we do a study on obese people and we observe that they eat a lot of carbohydrates and are insulin and leptin resistance. It’s easy to assume that the chain of causality worked like this: normal weight person eats high-carbohydrate diet, becomes insulin and leptin resistant, and then becomes obese.

But again, this is faulty logic. There’s no proof that A (high carbohydrate intake) was what led to B (insulin and leptin resistance) was what led to C (obesity).

In fact, we could disprove that theory simply by observing another individual or group that eats a very high carbohydrate diet, but does not develop insulin or leptin resistance and obesity. Guess what? Such individuals and groups most certainly exist. There goes that theory.

Likewise, we could also disprove this theory by observing people that are insulin and leptin resistant, but don’t become obese. Such people do exist, and I’ve written about them in my series on diabesity here.

A more rigorous approach

How have we developed our theories on obesity and weight regulation? It seems to me they come from a blend of personal experience, belief and facts. And I think it’s time to become more rigorous about keeping them separate. Here’s an example of what I mean:

Personal experience: I lose weight on an low-carb diet, therefore low-carb diets must be best for weight loss.

Belief: carbohydrates are responsible for the obesity epidemic, via their effects on insulin.

Fact: many cultures around the world eat high-carbohydrate diets and are exceptionally lean.

Those who’ve lost a lot of weight on a low-carb diet have a tendency to become convinced that their wife, friends, family, plumber and everyone else will also lose weight following the same diet.

From this personal experience, a belief is formed. And once we believe in something, we have a remarkable ability to filter out any evidence that might contradict that belief.

This is especially true if our reputation or financial livelihood is tied to said belief. As Upton Sinclair famously said:

It’s difficult to get a man to understand something when his salary is dependent upon him not understanding it.

When a belief like “carbs cause obesity” is shared between enough individuals, it becomes a meme. Once that happens, it is accepted by most as fact – regardless of whether it has any scientific basis. Hence we had the idea for decades that eating fat makes you fat, and now the more recent idea that eating carbs makes you fat.

There’s no single cause (or treatment) of obesity

Perhaps one of the reasons it’s so easy to confuse cause, mechanism and effect and personal experience, belief and fact is that obesity is an incredibly complex disease. Just how complex is it?

Click on the Obesity Systems Influence Diagram below to find out.

Click image for larger version

Wow. That should give you a rough idea of how many variables are potentially involved in weight regulation. Now you know why it has been such a challenge to come up with a single, unified theory of obesity.

That said, of all of the hypotheses advanced to explain the mechanisms behind obesity, I think the food reward theory is the most inclusive.

However, as even its proponents would agree, it doesn’t tell the whole story because there are people and groups that eat large amounts of highly palatable foods that do not become obese.

My opinion is that the modern lifestyle (i.e. food and environmental toxins, stress, poor gut health, infections, micronutrient deficiencies, sleep deprivation, etc.) interfere with hypothalamic hormonal regulation, dopamine signaling, leptin and insulin sensitivity at the cellular level, glucose metabolism and a range of other mechanisms that lead to obesity.

This is consistent with the observation that obesity is extremely rare or nonexistent in traditional cultures that do not consume modern foods and do not live a “modern” lifestyle.

But even this theory is incomplete, because there are people fully exposed to the modern lifestyle that do not become overweight or obese. This suggests that genetics, and perhaps other undiscovered factors, also play a role.

We’re not robots

Humans are not robots. We’re living, breathing, dynamic organisms influenced by varying genetics and environmental conditions.

Anthropological evidence combined with modern research has helped us to reveal the basic template of a species-appropriate diet. However, it has also shown us that humans can thrive on a wide variety of macronutrient ratios and foods within that basic template.

This is not a belief. It’s a fact, supported by the evidence as a whole. Ignoring the evidence doesn’t make it go away. Believing passionately in something doesn’t make it true. Experiencing something personally doesn’t make it fact for everybody else.

19th century philosopher Charles Peirce said:

The state of belief is a calm and satisfactory state which we do not wish to avoid, or to change to a belief in anything else.

And Tolstoy said:

I know that most men, including those at ease with problems of the greatest complexity, can seldom accept even the simplest and most obvious truth if it be such as would oblige them to admit the falsity of conclusions which they have delighted in explaining to colleagues, which they have proudly taught to others, and which they have woven, thread by thread, into the fabric of their lives.

Recognizing this basic human trait, philosopher of science Karl Popper advised every researcher to earnestly try to discredit their own hypotheses.

That is no easy task, and it asks a lot of us. Yet intellectual rigor, emotional maturity and personal integrity are characterized by the capacity to question our own beliefs, no matter how deeply cherished they are or how much is at stake.

I sometimes wonder why we’re all so sure of ourselves. It helps me to remember that at every point in history scientists (and the general public) were convinced they had the right answers. At one time the world was flat, the earth was the center of the solar system and disease was caused by foul humors and could be cured by bloodletting.

Nowadays we look back on those fallacies with a smirk. But are we so arrogant to assume that our great-grandchildren won’t do the same?

The truth is, there’s far more we don’t know than we do know.

This week we’re happy to have Stephan Guyenet from Whole Health Source back to discuss the body fat set point and food reward theories of obesity and weight regulation.

Questions covered include:

• How does the food reward system work? Why did it evolve?
• Why do certain flavors we don’t initially like become appealing over time?
• How does industrially processed food affect the food reward system?
• What’s the most effective diet used to make rats obese in a research setting? What does this tell us about human diet and weight regulation?
• Do we know why highly rewarding food increases the set point in some people but not in others?
• How does the food reward theory explain the effectiveness of popular fat loss diets?
• Does the food reward theory tell us anything about why traditional cultures are generally lean?
• What does this all mean from a practical perspective? How can these theories be applied to regulate weight and improve metabolism?

Click here to read all of Stephan’s recent posts on the food reward concept.

I believe regular movement and exercise is essential to health. As Stephan Guyenet pointed out in a recent blog post, our paleolithic ancestors had a different word for exercise: “life“. They naturally spent a lot of time outdoors in the sun, walking, hunting, gathering, and performing various other physically-oriented tasks. They had no concept of this as “exercise” or “working out”. It was just life.

But while exercise contributes to health in several different ways, it’s not very effective for weight loss. Or, more specifically, I should say that low-intensity, “cardio” – which is how most people exercise – is not effective for weight loss.

Why cardio doesn’t work

How could this be? There are three main reasons:

• caloric burn during exercise is generally small;
• people who exercise more also tend to eat more (which negates the weight regulating effect of exercise); and,
• increasing specific periods of exercise may cause people to become more sedentary otherwise.

In an example of the first reason, a study following women over a one-year period found that in order to lose one kilogram (2.2 pounds) of fat, they had to exercise for an average of 77 hours. That’s a lot of time on the treadmill just to lose 2 pounds!

In an example of the second reason, a study found that people who exercise tend to eat more afterwards, and that they tend to crave high-calorie foods. The title of this study says it all: “Acute compensatory eating following exercise is associated with implicit hedonic wanting for food.” I love it when researchers have a sense of humor.

In an example of the third reason, one study assigned 34 overweight and obese women to an exercise program for 8 weeks. Fat loss at the end of the study was an average of 0.0kg. Not very impressive. But the researchers noticed that some women did lose weight, while others actually gained. What was the difference? In the women that didn’t lose weight, the increase in specific periods of exercise corresponded with a decrease in overall energy expenditure. Translation: they were more likely to be couch potatoes when they weren’t exercising, which negated the calorie-burning effect of their workouts.

If you’re still not convinced, the Cochrane group did a review of 43 individual studies on exercise for weight loss. Study length ranged from 3 to 12 months, and exercise sessions lasted on average 45 minutes with a frequency of 3-5 times per week. The results? On average, the additional weight loss from exercise averaged about 1 kg (2.2 pounds). Meh. Assuming they worked out for 45 minutes 4x/wk over 6 months, that means they had to exercise 69 hours to lose that 1 kg.

The purpose of this rather long introduction is simply to point out that low-intensity, “cardio” exercise is spectacularly ineffective for weight loss. But that doesn’t meal all types of exercise aren’t effective.

High-intensity intermittent training (HIIT)

HIIT is a type of exercise performed in short bursts (intervals) at high-intensity. Several studies have been done comparing HIIT to low-intensity, steady-state (“chronic cardio”, as Mark Sisson calls it) exercise, and HIIT has been shown to be superior in nearly every meaningful marker.

In this study, one group was assigned to “chronic cardio”, while the other was assigned to intervals of 8-second sprints. After 15 weeks, the researchers concluded:

Both exercise groups demonstrated a significant improvement (P less than 0.05) in cardiovascular fitness. However, only the HIIE group had a significant reduction in total body mass (TBM), fat mass (FM), trunk fat and fasting plasma insulin levels.

A pair of studies done at McMaster University found that “6-minutes of pure, hard exercise once a week could be just as effective as an hour of daily moderate activity“, according to the June 6, 2005 CNN article reporting on the study.

The study itself was published in the Journal of Applied Physiology, and it revealed that HIIT resulted in unique changes in skeletal muscle and endurance capacity that were previously believed to require hours of exercise each week.

A follow-up study confirmed the results. Despite the fact that the more conventional endurance exercise group spent 97.5 percent more time engaged in exercise, both groups of subjects improved to the same degree. The group that exercised 97.5 percent more received no additional benefit whatsoever from doing so. Considering the wear-and-tear and increased risk of injury associated with that much more exercise, there’s absolutely no point to doing “chronic cardio” when you can receive the same benefits with a fraction of the time and risk by doing HIIT.

The Cochrane study I linked to earlier in the article also found that high-intensity exercise was superior to “chronic cardio”. In particular, the researchers found that high-intensity exercise led to a greater decrease in fasting blood glucose levels than low-intensity exercise.

Why high-intensity exercise is better

In his excellent book on high-intensity strength training, Body By Science, Dr. Doug McGuff explains that high-intensity training is superior to chronic cardio because it produces a greater stimulus and thus more effectively empties the muscles and liver of glucose. This stimulus can last several days with HIIT, as opposed to just a few hours with low-intensity training.

HIIT also activates hormone-sensitive lipase (HSL), which mobilizes fatty acids for energy use. This means that during HIIT, both glucose and fatty acids will be burned, leading to greater fat loss and restoration of insulin sensitivity.

High-intensity strength training: best of all?

Both high-intensity running or bicycling sprints and high-intensity strength training are effective. But I believe high-intensity strength training is probably a better choice for most, simply because the wear-and-tear and risk of injury is lower – especially if the strength-training is performed using weight machines as described in Body By Science.

This is, in fact, the method of training I’ve been doing since April of this year. I admit I was somewhat skeptical about it all before I read Body By Science. But the research and the physiology was convincing, so I decided to give it a try.

The results have been incredible. My workout varies in length between 5 and 9 minutes a week. That’s right, I said minutes. With only a few exceptions, I’ve increased the amount of weight I can lift, the time I can lift it, or both, with each successive workout. My strength has increased and my physique is, if anything, better than it was when I was lifting 3x/week for much longer periods.

Aside from the Body By Science (BBS) weight workout which I perform once a week, I stay active on a daily basis. I ride my bike or walk to work or to do errands, and rarely drive my car. I go on walks in the woods or on the beach. I surf when time permits. But I don’t do anything else for “exercise”. This routine not only feels great, it fits very well with my lifestyle and it is completely sustainable. It doesn’t feel like an effort at all.

If you’re interested in this kind of training, I’d recommend picking up a copy of Body By Science and checking out their excellent blog. You can post your weekly workout results and get help and suggestions from the very knowledgeable community there – including both authors of the book, Doug McGuff & John Little, and other experienced trainers and enthusiasts.

Another option that may be more accessible for some is Fred Hahn’s The Slow Burn Fitness Revolution. Fred also has a website and blog worth checking out.

Final note to slackers: the popular excuse of “I don’t have time to exercise” is no longer valid. You’ve got 6 minutes a week to do this. I know you do.

In the last article we discovered that the blood sugar targets established by the American Diabetes Association are far too high, and do not protect people from developing heart disease, diabetes or other complications. And we looked at what the scientific literature indicates are safer targets for fasting blood sugar, hemoglobin A1c and either OGTT or post-meal blood sugar.

In this article I’m going to introduce a simple technique that, when used properly, is one of the most effective ways to maintain healthy blood sugar and prevent cardiovascular and metabolic disease – without unnecessary drugs.

I love this technique because it’s:

• Cheap. You can buy the equipment you need for $16 online.
• Convenient. You can perform the tests in the comfort of your home, in your car, or wherever else you might be.
• Personalized. Instead of following some formula for how much carbohydrate you can safely eat, this method will tell you exactly what your carbohydrate tolerance is, and which carbs are “safe” and “unsafe” for you.
• Safe. Unlike the oral glucose tolerance test (OGTT), which can produce dangerous and horribly uncomfortable spikes in blood sugar, this strategy simply involves testing your blood sugar after your normal meals.

The strategy I’m referring to is using a glucometer to test your post-meal blood sugars. It’s simple, accessible and completely bypasses the medical establishment and pharmaceutical companies by putting the power of knowledge in your hands.

It’s one of the most powerful diagnostic tools available, and I use it with nearly all of my patients. Here’s how to do it.

Step one: buy a glucometer and test strips

A glucometer is a device that measures blood sugar. You’ve probably seen them before – they’re commonly used by diabetics. You prick your finger with a sterilized lancet, and then you apply the drop of blood to a “test strip” that has been inserted into the glucometer, and it measures your blood sugar.

There are literally hundreds of glucometers out there, and their accuracy, quality and price varies considerably. The one I recommend to my patients is called the Relion Ultima, which can be purchased with 20 test strips for $16.00 online at Walmart.com. (Note: as a rule I don’t like to support Walmart, but I haven’t been able to find this unit anywhere else at a similar price.) Even better, the test strips, which you’ll need on an ongoing basis to monitor your blood sugar, are relatively cheap for the Relion Ultima. You can get a 100 of them for $39 at Walmart online ($0.39/strip).

I’m sure there are many other choices that work well, but this is the unit I have the most experience with, and in general it is very reliable. Another good choice is the TrueTrack meter drugstores sell under their own brand name (i.e. Walgreens, Sav-on, etc.). Other models to consider are the One Touch Ultra or one of the Accu-Chek meters. The problem with these, however, is that the test strips tend to be more expensive than the Relion Ultima.

Step two: test your blood sugar

1. Test your blood sugar first thing in the morning after fasting for at least 12 hours. Drink a little bit of water just after rising, but don’t eat anything or exercise before the test. This is your fasting blood sugar level.
2. Test your blood sugar again just before lunch.
3. Eat your typical lunch. Do not eat anything for the next three hours.
Test your blood sugar one hour after lunch.
4. Test your blood sugar two hours after lunch.
5. Test your blood sugar three hours after lunch.

Record the results, along with what you ate for lunch. Do this for two days. This will tell you how the foods you normally eat affect your blood sugar levels.

On the third day, you’re going to do it a little differently. On step 3, instead of eating your typical lunch, you’re going to eat 60 – 70 grams of fast acting carbohydrate. A large (8 oz) boiled potato or a cup of cooked white rice will do. For the purposes of this test only, avoid eating any fat with your rice or potato because it will slow down the absorption of glucose.

Then follow steps 4-6 as described above, and record your results.

Step three: interpret your results

If you recall from the last article, healthy targets for blood sugar according to the scientific literature are as follows:

*To convert these numbers to mmol/L, use this online calculator.

Hemoglobin A1c doesn’t apply here because you can’t test it using a glucometer. We’re concerned with the fasting blood sugar reading, and more importantly, the 1- and 2-hour post-meal readings.

The goal is to make sure your blood sugar never rises higher than 140 mg/dL an hour after a meal, drops below 120 mg/dL two hours after a meal, and returns to baseline (i.e. what it was before you ate) by three hours after a meal.

There are a few caveats to this kind of testing. First, even reliable glucometers have about a 10% margin of error. You need to take that into account when you interpret your results. A reading of 100 mg/dL could be anything between 90 mg/dL and 110 mg/dL if you had it tested in a lab. This is okay, because what we’re doing here is trying to identify patterns – not nit-pick over specific readings.

Second, if you normally eat low-carb (less than 75g/d), your post-meal readings on the third day following the simple carbohydrate (rice or potato) challenge will be abnormally high. I explained why this occurs in the last article, but in short when you are adapted to burning fat your tolerance for carbohydrates declines. That’s why your doctor would tell you to eat at least 150g/d of carbs for three days before an OGTT if you were having that test done in a lab.

If you’ve been eating low-carb for at least a couple of months before doing the carbohydrate challenge on day three of the test, you can subtract 10 mg/dL from your 1- and 2-hour readings. This will give you a rough estimate of what your results would be like had you eaten more carbohydrates in the days and weeks leading up to the test. It’s not precise, but it is probably accurate enough for this kind of testing.

Step four: take action (if necessary)

So what if your numbers are higher than the guidelines above? Well, that means you have impaired glucose tolerance. The higher your numbers are, the further along you are on that spectrum. If you are going above 180 mg/dL after one hour, I’d recommend getting some help – especially if you’re already on a carb-restricted diet. It’s possible to bring numbers that high down with dietary changes alone, but other possible causes of such high blood sugar (beta cell destruction, autoimmunity, etc.) should be ruled out.

If your numbers are only moderately elevated, it’s time to make some dietary changes. In particular, eating fewer carbs and more fat. Most people get enough protein and don’t need to adjust that.

And the beauty of the glucometer testing is that you don’t need to rely on someone else’s idea of how much (or what type of) carbohydrate you can eat. The glucometer will tell you. If you eat a bowl of strawberries and it spikes your blood sugar to 160 mg/dL an hour later, sorry to say, no strawberries for you. (Though you should try eating them with full-fat cream before you give up!) Likewise, if you’ve been told you can’t eat sweet potatoes because they have too much carbohydrate, but you eat one with butter and your blood sugar stays below 140 mg/dL after an hour, they’re probably safe for you. Of course if you’re trying to lose weight, you may need to avoid them anyways.

You can continue to periodically test your blood sugar this way to see how you’re progressing. You’ll probably notice that many other factors – like stress, lack of sleep and certain medications – affect your blood sugar. In any case, the glucometer is one of your most powerful tools for preventing degenerative disease and promoting optimal function.

Resources

If you haven’t already, check out Jenny Ruhl’s excellent Blood Sugar 101 site. Jenny won’t tell you this herself, but she’s an authority on blood sugar and probably knows more about it than 99.9% of health care practitioners (she’s an author). In particular, check out the “Painless Blood Sugar Testing”, “Frequently Asked Questions” and “How to Lower Your Blood Sugar” sections. I’d link to them directly, but her site uses frames and doesn’t allow it.

In the last article I explained the three primary markers we use to track blood sugar: fasting blood glucose (FBG), oral glucose tolerance test (OGTT) and hemoglobin A1c (A1c). We also looked at what the medical establishment considers as “normal” for these markers. The table below summarizes those values.

In this article, we’re going to look at just how “normal” those normal levels are – according to the scientific literature. We’ll also consider which of these three markers is most important in preventing diabetes and cardiovascular disease.

Fasting blood sugar

According to continuous glucose monitoring studies of healthy people, a normal fasting blood sugar is 83 mg/dL or less. Many normal people have fasting blood sugar in the mid-to-high 70s.

While most doctors will tell you that anything under 100 mg/dL is normal, it’s not. In this study, people with FBG levels above 95 had more than 3x the risk of developing future diabetes than people with FBG levels below 90. This study showed progressively increasing risk of heart disease in men with FBG levels above 85 mg/dL, as compared to those with FBG levels of 81 mg/dL or lower.

What’s even more important to understand about FBG is that it’s the least sensitive marker for predicting future diabetes and heart disease. Several studies show that a “normal” FBG level in the mid-90s predicts diabetes diagnosed a decade later.

Far more important than a single fasting blood glucose reading is the number of hours a day our blood sugar spends elevated over the level known to cause complications, which is roughly 140 mg/dl (7.7 mmol/L). I’ll discuss this in more detail in the OGGT section.

One caveat here is that very low-carb diets will produce elevated fasting blood glucose levels. Why? Because low-carb diets induce insulin resistance. Restricting carbohydrates produces a natural drop in insulin levels, which in turn activates hormone sensitive lipase. Fat tissue is then broken down, and non-esterified fatty acids (a.k.a. “free fatty acids” or NEFA) are released into the bloodstream. These NEFA are taken up by the muscles, which use them as fuel. And since the muscle’s needs for fuel has been met, it decreases sensitivity to insulin. You can read more about this at Hyperlipid.

So, if you eat a low-carb diet and have borderline high FBG (i.e. 90-105), it may not be cause for concern. Your post-meal blood sugars and A1c levels are more important.

Hemoglobin A1c

In spite of what the American Diabetes Association (ADA) tells us, a truly normal A1c is between 4.6% and 5.3%

And while A1c is a good way to measure blood sugar in large population studies, it’s not as accurate for individuals. An A1c of 5.1% maps to an average blood sugar of about 100 mg/dL. But some people’s A1c results are always a little higher than their FBG and OGTT numbers would predict, and other people’s are always a little lower.

This is probably due to the fact that several factors can influence red blood cells. Remember, A1c is a measure of how much hemoglobin in red blood cells is bonded (glycated) to glucose. Anything that affects red blood cells and hemoglobin – such as anemia, dehydration and genetic disorders – will skew A1c results.

A number of studies show that A1c levels below the diabetic range are associated with cardiovascular disease. This study showed that A1c levels lower than 5% had the lowest rates of cardiovascular disease (CVD) and that a 1% increase (to 6%) significantly increased CVD risk. Another study showed an even tighter correlation between A1c and CVD, indicating a linear increase in CVD as A1c rose above 4.6% – a level that corresponds to a fasting blood glucose of just 86 mg/dL. Finally, this study showed that the risk of heart disease in people without diabetes doubles for every percentage point increase above 4.6%.

Studies also consistently show that A1c levels considered “normal” by the ADA fail to predict future diabetes. This study found that using the ADA criteria of an A1c of 6% as normal missed 70% of individuals with diabetes, 71-84% with dysglycemia, and 82-94% with pre-diabetes. How’s that for accuracy?

What we’ve learned so far, then, is that the fasting blood glucose and A1c levels recommended by the ADA are not reliable cut-offs for predicting or preventing future diabetes and heart disease. This is problematic, to say the least, because the A1c and FBG are the only glucose tests the vast majority of people get from their doctors.

OGTT / post-meal blood sugars

If you recall, the oral glucose tolerance test (OGTT) measures how our blood sugar responds to drinking a challenge solution of 75 grams of glucose. I don’t recommend this test, because A) it’s not realistic (no one every drinks 75 grams of pure glucose), and B) it can produce horrible side effects for people with poor glucose control.

However, there’s another more realistic and convenient way to achieve a similar measurement, and that is simply using a glucometer to test your blood sugar one and two hours after you eat a meal. This is called post-prandial (post-meal) blood sugar testing. As we go through this section, the numbers I use apply to both OGTT and post-meal testing.

As the table at the beginning of this article indicates, the ADA considers OGTT of between 140 – 199 two hours after the challenge to be pre-diabetic, and levels above 200 to be diabetic.

But once again, continuous glucose monitoring studies suggest that the ADA levels are far too high. Most people’s blood sugar drops below 120 mg/dL two hours after a meal, and many healthy people drop below 100 mg/dL or return to baseline.

This study showed that even after a high-carb meal, normal people’s blood sugar rises to about 125 mg/dL for a brief period, with the peak blood sugar being measured at 45 minutes after eating, and then drops back under 100 mg/dL by the two hour mark.

Another continuous glucose monitoring study confirmed these results. Sensor glucose concentrations were between 71 – 120 mg/dL for 91% of the day. Sensor values were less than or equal to 60 or 140 mg/dL for only 0.2% and 0.4% of the day, respectively.

Even the American Association of Clinical Endocrinologists is now recommending that post-meal blood sugars never be allowed to rise above 140 mg/dL. Unfortunately, less informed groups like the ADA haven’t caught up with the science.

The consequences of this are severe. Nerve damage occurs as blood sugar rises above 140 mg/dL. Prolonged exposure to blood sugars above 140 mg/dL causes irreversible beta cell loss (the beta cells produce insulin). 1 in 2 “pre-diabetics” get retinopathy, a serious diabetic complication. Cancer rates increase as post-meal blood sugars rise above 160 mg/dL. This study showed stroke risk increased by 25% for every 18 mg/dL rise in post-meal blood sugars. Finally, 1-hour OGTT readings above 155 mg/dL correlate strongly with increased CVD risk.

What does it all mean?

Let’s take a look again at what the ADA thinks is “normal” blood sugar:

But as we’ve seen in this article, these levels are only normal if you think increased risk of diabetes, heart disease, cancer and other serious complications is normal. Just because these conditions are common, doesn’t mean they’re normal.

If you’re interested in health and longevity – instead of just slowing the onset of serious disease by a few years – you’d be well advised to shoot for these targets instead:

*If you’re following a low-carb diet, fasting blood sugars in the 90s and even low 100s may not be a problem, provided your A1c and post-meal blood sugars are within the normal range.

Another key takeaway from this article is that fasting blood glucose and A1 are not very reliable for predicting diabetes or CVD risk. Post-meal blood sugars are by far the most accurate marker for this purpose. And the good news is that this can be done cheaply, safely and conveniently at home, without a doctor’s order and without subjecting yourself to the brutality of an OGTT.

I’ll describe exactly how to do this in the next article.