Monday, July 1, 2013

Should people with adrenal fatigue be tested for iodine deficiency and bromide toxicity?

Adrenal fatigue and iodine deficiency share a lot more in common than the fact that most physicians don't believe they exist or that they are not a significant problem in the United States.  These conditions share treatments, symptoms, and a host of other interesting commonalities.  In this blog article I will discuss these commonalities as well as provide evidence that people with adrenal fatigue should be tested for iodine deficiency and bromide toxicity.

Adrenal Fatigue

Adrenal fatigue is a syndrome where the adrenal glands produce insufficient levels of the adrenal hormones cortisol and aldosterone or an altered circadian rhythm of cortisol release.  Adrenal fatigue is thought to be the product of excessive stress, poor stress management, and nutritional deficiency.  In addition to these factors that are thought to be at the root of adrenal fatigue, the reliance on energy drinks and caffeine to provide energy are also thought to be relevant.

Iodine deficiency and bromide toxicity

Iodine deficiency and bromide toxicity go hand in hand.  Iodine and bromide are known as halides, a group of elements that can substitute for one another in specific tissues in the body.  Fluoride, chloride, iodide and bromide are the primary halides with astatide being a less commonly seen halide in biology.  Iodide and chloride have biological value to humans while fluoride and bromide do not and can potentially be toxic.  In a person with sufficient iodine/iodide there tends to be no issue, but when a person is not getting sufficient levels of this nutrient or the other halide chloride, bromide can accumulate in the body tissues that store them, including the thyroid and stomach.

Bromide is thought to be a neurotoxin and it's use as a sedative provides support for this notion as overdose of sodium bromide can lead to neurological issues.  The use of bromide in prescription and OTC medicines was ceased in the 1970s because bromide's half-life(12 days in humans) made it difficult to dose.  Bromide is ubiquitous in modern society.  It is found in some citrus drinks and bread and bakery products but it is primarily an environmental toxin.  Bromide is used as a flame retardent in mattresses, carpets, and upholstered furniture and can also be found in plastics, car upholstery, pool and hot tub chemicals, pesticides, and certain medications including atrovent.  Since bromide toxicity is unlikely to occur in someone sufficient in iodine that isn't taking large doses of bromide-based medications, we will consider the two more or less the same for this discussion.  While it is possible that someone could be deficient in iodine and not have bromide toxicity, it is unlikely given our current environment.

Bromide competes with iodide in the thyroid and the goitrogenic effect of bromide is enhanced under conditions of iodine deficiency(1, 2).  Under iodine deficient conditions, up to 40% of the iodide in the thyroid can be replaced by bromide.  With sufficient iodide supply, a constant iodide to bromide ratio is established in the thyroid(2).  Very high bromide intake shortens the half-life of iodine in the thyroid of both iodine sufficient and iodine deficient rats to about 1/3rd of the value in controls and increases whole body loss of iodine via the kidneys(2).  This is a problem because bromide's serum half-life in humans is 12 days compared to iodine's which is approximately 10 hours in iodine sufficient people and significantly lower in those with iodine deficiency(3).  This is the primary reason it takes high doses and long periods of time to improve an iodine deficiency and bromide toxicity.  In addition, bromide's half-life is increased significantly in salt deficient diets and can be shortened with increased salt consumption(2).

The interesting thing about iodine deficiency and bromide toxicity is that increasing iodine intake increases bromide excretion in the urine.  This is more than likely initiated first by iodine replacing bromide on receptors of cells in target tissues.  This will lead to an increase in serum bromide until the kidneys filter bromide out of the blood and into the urine.  This is an important process and one I believe to be the primary link between iodine deficiency/bromide toxicity and adrenal fatigue as bromide has a long half-life in serum and the kidneys can only filter out so much bromide at a time.  Once kicked off of receptors and in to the blood, bromide can mess with electrolyte balance and cause a host of other problems.  On the surface, it doesn't appear that these conditions are related in anyway.  When you take a look at some of the common symptoms between the two, a potential relationship begins to emerge.  Below is a list of the common symptoms of adrenal fatigue and iodine deficiency/bromide toxicity:

Common symptoms include:
Electrolyte imbalance
Hormonal imbalance
Frequent urination
Brain fog
Skin problems/dermatitis
Dream changes
Sleep problems

As you can see, that is quite a laundry list of symptoms.  It is important to realize that a person who experiences either adrenal fatigue or iodine deficiency/bromide toxicity may not have all of those symptoms and may have separate symptoms that are not listed.  These are just the common symptoms that tend to be reported in people with adrenal fatigue and/or iodine deficiency/bromide toxicity.  In addition to these symptoms, both adrenal fatigue and bromide toxicity have similar treatments as well.  These treatments include high doses of salt, vitamin C, and magnesium.  As you can see, a relationship begins to emerge just by looking at common symptoms and treatments.  Let's take a look at some of the science to identify how these seemingly unrelated conditions can have such a strong relationship.

Adrenal fatigue, iodine deficiency, bromide toxicity, and electrolyte imbalance

In his book Adrenal fatigue: The 21st century stress syndrome, Dr. James Wilson points out that many of the symptoms of adrenal fatigue are related to an electrolyte imbalance(4).  This is primarily due to low levels of the mineralocorticoid aldosterone.  When sodium levels in the body become too low, aldosterone is secreted by the adrenal glands and acts on the kidneys to reabsorb sodium and water and excrete potassium in the urine.  Aldosterone can be stimulated in multiple ways including via adrenocorticotropin hormone, the renin-angiotensin system, or simply by high potassium levels.  Since adrenocorticotropin hormone is also responsible for secretion of cortisol, it appears to be the link between cortisol and aldosterone in adrenal fatigue.  However, the link between aldosterone and the renin-angiotensin system appears to be the link between iodine deficiency/bromide toxicity and adrenal fatigue.

The renin-angiotensin system helps regulate blood pressure via fluid and electrolyte balance.  When blood pressure is low, the kidneys secrete renin which converts angiotensinogen in to angiotensin I.  Angiotensin I is then converted to angiotensin II which acts on blood pressure by constricting blood vessels as well as signalling the adrenal glands to secrete aldosterone.  Aldosterone then signals the kidneys to recycle sodium and water in to the blood to bring blood pressure back up.  In situations where aldosterone is low, sodium is wasted and blood pressure drops further.  Needless to say, low levels of renin will have the same effect since renin helps to stimulate aldosterone release.  In adrenal fatigue, aldosterone levels are typically low which causes salt wasting in the urine which then leads to an imbalance in the ratio of sodium to potassium.  In adrenal fatigue, licorice root is given to allow cortisol to attach to mineralocorticoid receptors and mimic the effects of aldosterone on the kidneys by recycling sodium and dumping potassium via the urine.

Increasing sodium consumption will help with any symptoms associated with a low sodium to potassium ratio; however, administration of sodium chloride in the form of salt decreases renin activity.  It seems logical that this is mediated by an effect of high sodium levels causing decreased plasma renin activity(PRA) in response to an increased sodium to potassium ratio.  This does not appear to be the case, however.  In humans, PRA is suppressed by sodium chloride but not sodium bicarbonate(5).  The effect of salt intake on PRA appears to hold true for bromide as well.  PRA decreased by nearly 50% with the administration of sodium chloride and sodium bromide but not with sodium bicarbonate or nitrate.  In addition, lysine monohydrochloride but not lysine glutamate had a similar effect, indicating a renal effect of bromide and chloride on renin activity rather than of sodium(6).  Whether this holds true for all of the halides has not been elucidated.  Regardless, high serum levels of bromide appear to have a very strong effect on sodium wasting via a reduction in PRA.

The intake of salt in the form of sodium chloride is a very powerful therapy in both adrenal fatigue and bromide toxicity.  In the treatment of adrenal fatigue, salt is used to relieve the symptoms caused by electrolyte imbalance as well as to nourish the adrenals.  In bromide toxicity, salt is used to increase the excretion of bromide.  One of the primary ways of removing bromide from the body is with the use of sodium chloride.  Increased sodium chloride intake increases bromide loss via the urine in dogs and humans and improves bromide induced dermatitis in humans(7).  Increased intake of sodium chloride in rats considerably reduces the half-life of bromide.  In 2 studies by the same authors, administering sodium in the form of 5 different salts, including sodium chloride and bicarbonate, had the same effect on the rate of bromide excretion which was proportional to sodium excretion in all 5 cases under the same sodium intake.  The authors concluded that the excretion of bromide is dependent on sodium intake rather than chloride(8, 9, 4). In addition, the proportion of bromide and sodium excretion are constant at a given sodium intake and increase with the amount of sodium ingested.

This does not mean that chloride does not also have an effect on bromide excretion.  In addition to being a halide and competing with bromide on receptors in target tissues, the sum of chloride and bromide in extracellular fluid remains constant at 110mmol/l(2).  Increasing one will cause a concomitant drop in the other as it is excreted via the urine.  In addition, bromide half-life in rats varied with chloride intake from 2.5 days with high chloride intake to 25 days under low chloride intake(10).  There doesn't appear to be a synergistic effect of sodium and chloride on bromide excretion nor does it make sense to use a different form of sodium such as sodium bicarbonate in terms of increasing bromide excretion.  However, there may be benefit to using sodium bicarbonate for bromide excretion to avoid the negative effect of reducing PRA.  As you will see shortly, PRA has a very strong impact on sleep quality.

Decreased PRA is associated with increased wakefulness and a decrease in sleep efficiency index.  PRA activity is higher during non-REM sleep, but PRA had no relationship with cortisol levels(11).  Multiple studies have established a strong link between PRA and sleep stage.  Specifically, PRA drops as someone enters REM sleep and increases during non-REM sleep(12, 13, 14, 15), with entering REM sleep leading to a near complete cessation of renin release(13).  In addition, peak levels of renin occurred during the transition from deep sleep to light sleep and the initiation of rises in PRA occurred in the transition from REM to stage 2.  All sleep disturbances and irregularities were reflected in deviations from the normal PRA curve.  Finally, both provoked and spontaneous awakenings blunted the rise of PRA found in deep sleep(14). Given the fact that sleep disturbances are both a strong contributor to and a primary symptom of adrenal fatigue, these relationships provide strong evidence that adrenal fatigue and iodine deficiency/bromide toxicity are related by changes in sleep quality.

Another interesting relationship worth exploring is that of magnesium with PRA.  High plasma magnesium levels have a strongly positive relationship with the release of renin by the kidney of dogs(16) as well as rats(17, 18) and humans(19).  However, this relationship seems to be flipped in people with hypertenson(19, 20) and may be a result of a decreased pool of intracellular magnesium due to abnormal intracellular magnesium metabolism(21).  Interestingly enough, while magnesium has an effect on renin release, it appears to decrease aldosterone release in rats(17) and humans(19).  In addition, magnesium deficient rats have higher levels of aldosterone secretion than magnesium sufficient rats(17).  One thing most users of supplemental magnesium notice, particularly those with adrenal fatigue, is an improvement in sleep quality.  Magnesium is also used in the treatment of iodine deficiency and bromide toxicity, further strengthening their relationship to adrenal fatigue.


All of the evidence described above points to a strong relationship between adrenal fatigue, iodine deficiency, and bromide toxicity.  It is difficult to draw hard conclusions with this evidence since a lot of it is not done in humans, but there is certainly enough evidence to support the notion that people with adrenal fatigue should be tested for iodine deficiency and bromide toxicity.  While there is strong evidence that they are related, we do not know whether one causes the other or they share a separate variable; whether they are related in a large number of cases or only a few; and how iodine deficiency and bromide toxicity relate to low or altered cortisol levels.  In addition to the effects of bromide on sodium loss, iodine is found in significant concentrations in the adrenals and there is the potential for there to be a direct effect of iodine deficiency on adrenal function, but this has not been studied.  A few other questions emerge as well.  One question worth answering is if bromide and sodium excretion levels are constant at a given sodium intake, does this mean being in a low sodium state increases the likelihood of bromide accumulation in the blood and, in a state of iodine deficiency, in the cells as well?  Could the natriuresis of fasting associated with low carb diets exacerbate this effect with inadequate sodium intake?  Are the negative effects of very low carb diets on sleep and thyroid function caused by iodine deficiency and/or bromide toxicity and can this be avoided with adequate iodine and salt intake?

There are other avenues worth exploring with the relationship between adrenal fatigue, iodine deficiency, and bromide toxicity.  Digestive problems are associated with both adrenal fatigue and bromide toxicity.  Since bromide concentrates in the gastric mucosa, is secreted into the stomach, and is known to replace chloride in other tissues, there is the potential that hydrobromic acid could be produced rather than hydrochloric acid and interfere with digestion.(1).  In addition, given that the sodium calcium exchanger is highly expressed in the smooth muscle cells of the intestinal wall, could a drop in sodium levels caused by increased exposure to bromide slow peristalsis and impact digestion by increasing the amount of time food spends in the digestive tract?  Is a reduction in the sodium to potassium ratio a contributor to poor digestion in adrenal fatigue?  As you can see, there are many unanswered questions in this relationship.  At this point it seems prudent to begin testing people with adrenal fatigue for iodine deficiency and bromide toxicity in integrative/functional medicine clinics to help provide some of the answers clinical research is unlikely to answer.

For more information on adrenal fatigue, consult Adrenal fatigue: The 21st century stress syndrome by Dr. James Wilson.

For more information on iodine deficiency, consult Iodine: Why you need it, why you can't live without it by Dr. David Brownstein.

For more information on properly supplementing with iodine consult this blog.