In concluding the last installment of this series, I stated that this installment would be devoted to discussions of research on dose, efficacy, and side effects in western societies. Stated more simply, I would be addressing the major controversy concerning milligram dosing of iodine; whether or not it truly causes thyroid related side effects in a significant amount of patients. However, it has occurred to me that this discussion may be a bit premature at this point. Why? It is my belief that this discussion will have the most value if it is understood how supplemental iodine, very specifically, might cause these problems. Ironically, though, in today’s world of research and information overload relating to clinical nutrition, iodine occupies a somewhat unique niche. As we all know, discussions of virtually all vitamins and minerals are incomplete unless information concerning digestion, absorption, and tissue uptake are included. Therefore, we can turn to almost any quality text or article in our personal libraries and find outstanding descriptions of digestion, absorption, tissue uptake, and metabolism of nutrients such as vitamin C or magnesium. Can the same be said about iodine? After a fairly extensive examination of several high quality textbooks and papers on micronutrients, I was very surprised to find out that the answer to this question is “No”. In fact, I found out, much to my frustration, that in contrast to the other micronutrients, basic information on what happens to iodine between the time it is ingested and before it gets inside the thyroid and is converted to thyroid hormones is quite rare. With this unfortunate reality in mind, can we ever fully understand how to effectively administer supplemental iodine to patients or why some patients have adverse reactions? To answer this question, I would like to ask another question. Can we fully understand how to effectively and safely administer supplemental vitamin C or calcium or magnesium without at least a basic knowledge of their digestion, absorption, tissue uptake, and metabolism? I would expect that the vast majority of you would emphatically answer “No” to the latter question. It is my opinion that if your answer to the latter question is “No”, so too must your answer be “No” to the former. In fact, there is no question in my mind that one of the reasons why the subject of iodine nutriture is so controversial right now is the fact that we as clinicians know so little about what happens to dietary iodine in the body before it gets into the thyroid. Just one example of this is the interesting relationship between iodine and breast health. As you read in part IV of this series, supplemental molecular iodine (I2) is much more effective in optimizing breast health than the more common form of supplemental iodine, iodide (I–). However, as you will see, common lore suggests that all dietary iodine is converted to the iodide form in the gut before it is absorbed. Obviously, both of these statements cannot be correct. So what exactly is the truth? As you will see, some very good but seldom read and quoted research resolves this seemingly unanswerable quandary very simply. Could many of the other raging iodine controversies concerning dose and safety that we are discussing almost daily now be resolved as simply if we just had a better understanding of what happens to dietary iodine before it gets inside the thyroid? I do believe so. Therefore, I would now like to explore an issue that, ironically, has been a major focus of attention with almost every micronutrient except the one that in so many ways may be receiving more attention that any other right now: iodine.
Before continuing, though, I would like to offer a sincere thank you and appreciation to Dr. Abraham. While, as you have seen, I have been highly critical of many of his statements on iodine nutriture, I applaud his efforts to emphasize the idea that we need to seriously consider the neglected research on the different forms of dietary iodine and how they are digested, absorbed, and metabolized outside of the thyroid. There is no question that I would not be presenting the vitally important discussion that follows without his writings on the subject. Furthermore, I would not be aware of much of the research that follows without his assistance. Therefore, for all that follows, I offer a sincere “Thank you” to Dr. Abraham.
IODINE DIGESTION AND ABSORPTION
As I suggested, this discussion primarily revolves around the different forms of iodine. Therefore, I would like to begin by again briefly reviewing the two different forms of iodine that were initially highlighted in the iodine and breast health newsletter. “Iodine” in this context refers to molecular iodine, often notated as “I2.” “Iodide” refers to ionic iodine, often notated as “I–.” Most supplements on the market contain iodide in the form of potassium iodide.
As I mentioned, issues relating to the digestion and absorption of iodine are rarely discussed in even the most comprehensive and current nutrition texts. An example of this can be found in what otherwise is considered to be one of the most up-to-date and comprehensive books on nutritional biochemistry and physiology, Biochemical, Physiological, & Molecular Aspects of Human Nutrition, Second Edition by Martha H Stipanuk (1). What follows is, in a chapter spanning 22 pages, the total discussion on digestion and absorption of iodine:
“Dietary iodine is reduced to iodide and absorbed efficiently along the length of the gastrointestinal tract.”
More evidence of this lack of attention to this important aspect of iodine nutriture can be seen in one of the premier endocrinology textbooks, Principles and Practice of Endocrinology and Metabolism, Third Edition (2) where the following is stated:
“Virtually all of dietary iodine is reduced to iodide and absorbed in the small intestine.”
Furthermore, I would next like to point out that, based on conversations with others in the field of clinical nutrition, I would suspect that the above claim about iodine digestion and absorption has probably been stated in several other high profile nutritional texts and publications. Interestingly, reading the following statement on iodine digestion and absorption by Abraham (3) first made me suspect that this commonly repeated dictum may be in error:
“Recent textbooks of endocrinology continue the tradition of the past, reaffirming that iodine is reduced to iodide prior to absorption in the intestinal tract, referring to a study by Cohn, published in 1932, using segments of the gastrointestinal tract of dogs, washed clean of all food particles prior to the application of I in the lumen. However, Thrall and Bull observed that in both fasted and fed rats, the thyroid gland in the skin contained significantly more I when rats were fed with iodide than with iodine; whereas the stomach walls and stomach contents had a significantly more I when rats were fed with iodide than with iodine; whereas the stomach walls and stomach contents had a significantly greater level of I in iodine-fed rats than iodine-fed animals. Peripheral levels of inorganic I were different with different patterns, when rats were fed with these 2 forms of I. The authors concluded: “These data lead us to question the view that iodide and iodine are essentially interchangeable.”
While I realize this quote is a bit complicated, I hope you can see that, if the research by Thrall and Bull mentioned in the above quote is correct, the implications concerning the forms of iodine supplementation we typically provide to patients is enormous. Why? As I mentioned above, virtually all iodine supplementation on the market comes in the form of potassium iodide. This would certainly make physiologic and biochemical sense if the conventional belief that all dietary iodine is converted to iodide in the gut before absorption is correct. However, if is not; if Abraham’s statement above about the research by Thrall and Bull is correct, then we need to totally revise our approach to iodine supplementation. Therefore, I would now like to look at the research that forms the basis of this controversy in much more detail.
Iodine and the gut – the conventional point of view
Based on my guidelines for judging controversies that I highlighted earlier in this series, I have difficulty supporting the point of view that suggests all dietary iodine is converted to iodide in the gut before it is absorbed. Why? Both of the above quotes on the subject, even though they come from highly respected textbooks were not referenced. In contrast, the point of view advocated by Abraham was referenced, with, as I mentioned, a paper by Thrall and Bull. Therefore, with the assumption that this is a credible paper, the edge for me has to go with Abraham’s point of view. Thus, I would now like to examine the paper by Thrall and Bull in detail.
Iodine and the gut – the alternative point of view
First, it should be noted that a Medline search reveals that Thrall and Bull actually published three papers on the subject of the different forms of iodine and their absorption. However, I would like to begin this discussion with the earliest paper, which is the one referenced by Abraham in his quote above. In “Differences in the distribution of iodine and iodide in the Sprague-Dawley rat” (4), Thrall and Bull examined absorption and metabolism of radioactive molecular iodine (I2) and iodide (I–) in rats. As you will see in the quote below, the findings from this study differed significantly from the conventional expectation that all the I2 was converted to I– before absorption:
“The experiments presented indicate clear differences in the behavior of I– and I2 in the body. These data lead us to question the view that iodide and iodine and essentially interchangeable…”
What findings in the study led Thrall and Bull (4) to this conclusion? Please note the following:
“Four observations are key to this conclusion: (1) Fed animals initially retained a larger percentage of 125I derived from I2 in their gastric contents than with I– at 2 hr. (2) In fasted animals, the uptake of I2 and I– into the thyroid differed significantly despite the absence of differences of uptake into the blood. (3) I2 pretreatments were significantly less effective in suppressing uptake of radioiodide into the thyroid gland than I– pretreatments. (4) Total urinary levels of 125I excreted over a 72-hr period when administered as I2 and I– were basically equivalent, indicating that total absorption was essentially identical.”
Of course, the second and third observations relate more to metabolism which I will start to address in the upcoming section on metabolism. However, as I hope you can see, observations one and four make it abundantly clear that, contrary to conventional teaching in leading nutrition and endocrinology texts, not all dietary iodine is converted to iodide (I–) in the gut before absorption.
In 1992, Thrall et al (5) conducted a similar study using the two different forms of iodine (I2 and I–). However, this time results were monitored by determining the uptake of each form of iodine in different blood components. Similar to the first paper, different patterns of distribution were seen with the two forms of iodine. This led the authors to conclude:
“These data indicate a differential distribution of radioactivity depending on whether it is administered as iodide or iodine. This is inconsistent with the commonly held view that iodine (I2) is reduced to iodide (I–) before it is absorbed systemically from the gastrointestinal tract.”
Based on these studies plus the lack of studies to support the conventional point of view, I feel we must conclude that the form of iodine being administered must be considered along with dose anytime iodine supplementation is contemplated.
As I have been suggesting in this series, probably the biggest controversy in the debate over milligram dosing of iodine relates to what happens metabolically after the iodine is absorbed, particularly in relation to thyroid function. Unfortunately, most references on the subject of iodine and the thyroid primarily discuss this connection only in relationship to thyroid hormone production. As you will see, understanding the relationship between iodine and thyroid beyond hormone production may be equally as important, particularly in terms of resolving the current iodine controversies. In addition, now that it is apparent that different forms of dietary iodine will be absorbed intact, we need to also consider whether these different forms can have a different impact on the thyroid. Therefore, this section will be devoted to the rarely examined issue of iodine and its relationship to the thyroid beyond thyroid hormone production.
In looking at this relationship between iodine and the thyroid, I would like to begin by examining it from a “big picture” perspective. How is the thyroid supposed to respond when encountering different amounts of iodine? In Principles and Practice of Endocrinology and Metabolism, Third Edition, Nuovo and Wartofsky (6) state:
“The normal thyroid adapts easily to iodide excess or deficiency. Hyperthyroidism or hypothyroidism resulting from abnormal amounts of dietary iodine is unusual.”
Why is it necessary for the thyroid to be so adaptable to different amounts of dietary iodine? Very simply, the reason is that amounts of dietary iodine can vary tremendously based on locale, time of year, and personal preference concerning foods. Nuovo and Wartofsky (6) briefly comment on this variability in the US:
“In the United States, dietary iodide intake is estimated to average 350 to 650 Âµg per day, although it may exceed 1 mg per day in some areas.”
Before continuing, please note that Nuovo and Wartofsky (6) are using the term “iodide” as opposed to “iodine.” Why? As stated previously, the textbook containing the authors’ review and commentary takes the position that all dietary iodine is reduced to iodide before absorption. As you now know, this is not true.
So if the thyroid is so adaptable to different amounts of iodine, why all the controversy over dosage? Nuovo and Wartofsky (6) state:
“Although the normal thyroid gland usually adapts readily to extremes of iodine intake, some persons are vulnerable to the induction of goiter, hypothyroidism, or hyperthyroidism with exposure to excess iodine.”
Therefore, given that virtually all of us see sick people who have come to see us because they are not functioning normally, it should not come as a surprise that a certain percentage of abnormal, sick people have adverse reactions to milligram dosing of iodine. Thus, the key question in the dosing controversy, in reality, may not be just an issue of amount. Rather the question revolves around the idea of the right dose based on the needs of different abnormally functioning individuals. In what ways does the thyroid function abnormally so as to make people more reactive to variable amounts of iodine? One possible answer to this question is that the thyrocyte (A thyroid cell) loses its ability to tightly control the transport of iodine in and out of the cell. What controls transport of iodine in and out of the thyrocyte? There are two factors. One is called the “sodium iodide symporter” (NIS). The other is called “pendrin” (PEN).
The sodium iodide symporter (NIS)
As you will see from this commentary by Smyth and Dwyer (7), the sodium iodide symporter (NIS) is one of the best mechanisms we have to protect the thyroid from the negative effects that can occur due to variations in iodine intake:
“The movement of a variety of species from the iodine-rich environment of the sea to the relatively iodine-deficient land has necessitated the development of mechanisms which will trap more efficiently inorganic iodide (I–) necessary for the formation of thyroid hormones. In man as in other mammals iodide uptake by the thyroid is mediated via a TSH-dependent transmembrane protein, the sodium iodide symporter (NIS), so-called because it co-transports Na+ with I– into the thyroid against the concentration gradient.”
Where is the NIS and how does it work? The authors continue:
“The NIS is located in the basolateral membrane of thyroid follicular cells, and accumulated I– is organified to molecular iodine (I2) through the action of the enzyme thyroid peroxidase (TPO) in the presence of H2O2, which takes place mainly at the apical membrane of the follicular cell.”
In turn, what happens to the organified iodine? Smyth and Dwyer (7) state:
“Organified iodine iodinates the thyroid protein thyroglobulin, which when stored in the lumen of thyroid follicles represents a storage site for the hormones thyroxine (T4) and triiodothyronine (T3). Possession of NIS enables the thyroid to concentrate I– 20-40 fold.”
Thus, as you can see, proper functioning of the NIS is critical in regulating overall exposure of thyroid cells to iodine. This overall importance is summarized very well by Carrasco (8):
“The Na+/I– symporter mediates the first and key step in the process of supplying I– to the gland for thyroid hormone biosynthesis, that is, active transport of I– against its electrochemical gradient across the basolateral plasma membrane into the cytoplasm of the follicular cells.”
Like the NIS, pendrin functions as one of the two gatekeepers of the thyroid in terms of regulating passage of iodine in and out of the thyrocyte. More specifically, Smyth and Dwyer (7) state the following about pendrin:
“NIS exerts its effect as an iodide symporter at the basolateral membrane of the thyroid follicular cell while another transporter, pendrin, acts at its apical end. Like NIS, pendrin is also a transmembrane protein which transports both chloride and iodide. Pendrin is believed to act in the thyroid, perhaps in conjunction with other transporters, in facilitating efflux of iodide from the thyroid follicular cell into the lumen of the thyroid follicle.”
From a functional standpoint, what is the relevance of pendrin? The authors state:
“As the main role of pendrin is in promoting I– transport from the thyroid follicular cell into the follicular lumen, its functional activity is necessary for thyroid hormonogenesis and in this role it functions in concert with NIS.”
Together, as noted by the authors, NIS and pendrin control the uptake and retention of iodine in the thyroid.
To me the significance of understanding NIS and pendrin cannot be overstated in terms of providing some degree of resolution to the iodine dose/side effects controversy. For, while it is important to examine research and clinical reports that claim milligram dosing of iodine either does or does not cause thyroid related side effects in some individuals, this type of review of conflicting literature really does not answer the most important question we want answered: “Will the patient in front of me that I am treating have an adverse reaction to milligram dosing of iodine?” However, if we can understand why a patient might or might not react negatively, then I feel we truly have information of real clinical value. In turn, it seems to me that if we understand what controls the uptake and retention of iodine in the thyroid, we could very well have tremendous insight as to whether patients will experience thyroid related side effects to milligram levels of supplemental iodine.
Does research exist that would validate my hypothesis that disturbances in iodine transport into the thyroid might be responsible for some of the side effects reported with milligram dosing of iodine? Absolutely!! Interestingly, while I was able to find little research on pendrin, I was able to find several papers on NIS and clinical thyroid function. Therefore, I would like to now examine NIS function in relationship to the two broad groupings of side effects that have been reported in relationship with milligram iodine supplementation, those that suggest hyperthyroid function and those that suggest hypothyroid function.
Graves’ disease and NIS malfunction
Does research exist that suggests a relationship between hyperthyroid issues such as Graves’ disease and dysfunction of the NIS? In the paper “Increased expression of the Na+/I– symporter in cultured human thyroid cells exposed to thyrotrophin and in Graves’ thyroid tissue” by Saito et al (9), the following is stated:
“In individuals with Graves’ disease, an up-regulation of thyroid function, as reflected in increased intake of IÂ–and increased hormone production as a result of increased H2O2 generation and synthesis of thyroid peroxidase and thyroglobulin, appears to contribute to both the progression and duration of the disease. We have now shown that the amounts of NIS mRNA and protein are increased in thyroid tissue from Graves’ patients.”
Hypothyroidism and NIS malfunction
Is there any link between findings suggesting hypothyroidism and malfunction of the NIS? Levy (10) states:
“Patients with congenital lack of I– transport do not accumulate I– in their thyroids, often resulting in severe hypothyroidism. A single amino acid substitution in the thyroid Na+/I– symporter (NIS)…was recently identified as the cause of this condition in two independent patients.”
Causes of NIS malfunction – Genetics
As was suggested in the above quote, many studies have demonstrated that genetic mutations of the NIS are fairly common (11). These genetic mutations can not only have an impact on the creation of hypothyroid findings as suggested by Levy et al (10) above but on hyperthyroid function, as suggested by Breous et al (12):
“In the present work, we demonstrate for the first time that hNIS gene expression in Graves’ disease is up-regulated by Graves’ IgG.”
Of course, the fact that patients can have genetically predetermined variations in the rate that they deliver iodine into the thyroid which, in turn, can have an impact on expression of hyper- or hypothyroid signs and symptoms, in my way of thinking, must profoundly alter our attitudes and discussions on the milligram iodine dosing controversy. For, it removes us from the faith based, anecdotally oriented, ‘which-nutritional-guru- do-you-believe-in’ discussions that seem all too common in relation to this controversy and places us squarely into the realm of the scientific method. In turn, as you will see, when an understanding of the science of the NIS and iodine transport into the thyroid cell in general is gained, statements such as “No one has adverse reactions to milligram dosing of iodine” or “Everyone adversely reacts to milligram dosing of iodine” are clearly inappropriate. In contrast, as you will see, it is not only possible but probable that, based on variations in function of NIS, certain patients will adversely react to iodine supplementation at virtually any amount higher than the RDA. Conversely, it is clearly possible and probable that many patients, because of certain aspects of their individual and unique NIS function, will have no adverse reactions even at the highest doses recommended by Abraham and his colleagues.
Interestingly, with the above in mind, it must be acknowledged that the studies which address the issues of genetics and NIS function also make it clear that NIS dysfunction due to genetic aberrations is fairly rare. Therefore, from a practical standpoint, should this issue of iodine transport be considered when trying to decide whether to give milligram doses of supplemental iodine to patients? As you will see, the answer to this question is certainly “Yes”. Why? There exist some powerful and quite prevalent environmental factors that also affect NIS function both individually and in combination with genetic aberrations.
Causes of NIS malfunction – Inflammation
As we now know, inflammation has a powerful impact of virtually every physiologic process relating to chronic illness. Certainly, NIS related thyroid dysfunction should be no exception. In agreement, Riesco-Eizaguirre and Santisteban (13) state:
“Cytokines, such as tumor necrosis factor (TNF)-α, TNF-b, interferon (IFN)-g, interleukin (IL)-1α, IL-1b, and IL-6 have been proven to inhibit NIS mRNA expression and iodide uptake activity in FRTL-5 and human thyroid cells.”
Causes of NIS malfunction – Environmental chemicals
As I noted in my first thyroid newsletter series written several years ago, environmental chemicals derived from industrial sources can adversely impact thyroid function in several ways. An excellent review on the impact of environmental chemicals on thyroid function can be found in the paper “Environmental chemicals and thyroid function” by Boas et al (14). If you would like a copy of this excellent paper, please feel free to contact Moss Nutrition to obtain one at no charge. As you might expect, many different chemicals affect the thyroid in many different ways. However, in the context of this discussion, two very common families of chemicals have a profound impact on NIS function. Boas et al (14) state:
“Perchlorate compromises iodine uptake to the thyroid follicular cells by inhibiting NIS. In contrast, phthalates such as DIDP, butyl benzyl phthalate and DnOP increased the activity of the NIS and enhanced NIS mRNA expression.”
In “Genetic factors that might lead to different responses in individuals exposed to perchlorate” by Scinicariello et al (15), more detail is given as to how perchlorate adversely affects NIS function:
“Perchlorate is a competitive inhibitor of the sodium iodide symporter (NIS), the thyroid cell-surface protein responsible for transporting iodide from the plasma into the thyroid. Therefore, it prevents further synthesis of the thyroid hormone (TH). It has no effect on the iodination process itself; rather, it displaces iodide by competitive uptake at the NIS.”
The authors also mention other chemicals that can be found both in the diet and environmentally that inhibit NIS function:
“Several other inorganic anions such as thiocyanates and nitrate that are present in dietary and environmental sources have goitrogenic effects. Similar to perchlorate, they both competitively inhibit iodide uptake at NIS.”
However, what I find most interesting about this paper is the fact that it provides another important facet of the impact of NIS function on determination of optimal amounts of supplemental iodine. As most of us now know, issues relating to genetics and issues relating to environment do not act upon our patients independently of each other. Rather the two interact in sometimes complex ways to create the clinical picture with which we must deal. The relationship between perchlorate exposure and NIS related genetics is no exception. Scinicariello et al (15) point out:
“Perchlorate does not undergo metabolism, but genetic defects of its target, that is, the NIS, may lead to low iodine uptake in the thyroid gland, thus depressing production of thyroid hormones. In this scenario, exposure to perchlorate may further reduce the already low iodide uptake and decrease production of thyroid hormones. The combined effects of perchlorate with a genetic decrease in thyroid hormones would hence delineate a population at risk for decreased thyroid function.”
I am assuming that, by now, many of you may have noticed an aspect of this discussion that is somewhat inconsistent with all the concern about excessive dosing of supplemental iodine. Since this discussion has primarily focused on the many environmental factors that decrease iodine transport into the thyroid, it would seem that, as suggested by Abraham, any concern about overdosing is an over reaction. However, there is one other important environmental factor that affects NIS function that I have not yet mentioned, one that makes high doses of iodine a significant concern in relationship to optimal NIS function. How important is this factor? I would guess that this factor, more than any other factor, is responsible for the majority of the biochemical controversy over what exactly happens to the thyroid when milligram dosing of supplemental iodine is administered. What is this environmental factor that has such a major and controversial impact on NIS function? Ironically, it is iodine itself. Therefore, I would now like to delve into the large body of very controversial literature that suggests iodine itself can profoundly influence mechanisms that are responsible for iodine transport into the thyroid cell.
Causes of NIS malfunction -supplemental iodine
As you will see, a large body of research suggests that iodine itself affects iodine transport into the thyroid cell via the NIS in many different ways. Probably the best known and most notorious way is what is commonly called the Wolff-Chaikoff Effect, which I described in parts I and II of this series. As you may recall, Abraham vehemently, passionately, and aggressively denies that the Wolff-Chaikoff Effect actually exists, maintaining that this so-called effect is actually a plot by Dr. Wolff and others to remove milligram dosing of supplemental iodine from the repertoire of our country’s health care professionals. Because the issue of the Wolff-Chaikoff Effect is so central to Abraham’s biochemical argument for routine administration of milligram dosing of supplemental iodine, I will examine it in detail, including Abraham’s point of view, in the next installment of this series. Now, though, I would like to present an overview of the many studies that, to me, make it clear that iodine itself will affect the NIS and thus transport of iodine into the thyroid cell.
First, Ferreira et al (16) state the following based on this experiment on rats:
“…we showed that not only are high doses of iodine able to block NIS activity, but also thyroid iodine content within the physiological range modulates NIS activity. Moreover, regulation of NIS activity by iodide can be more important than regulation by TSH, as rats with high TSH concentrations showed a decrease in NIS activity when their pool of organic iodine increased.”
Please note again the last portion of this quote. As we know, patients with low thyroid function typically demonstrate elevated TSH levels. In turn, TSH, as you might expect, up regulates NIS activity (13). However, even in a high TSH situation where you might expect that iodine supplementation would certainly be helpful, too much iodine can still suppress iodine transport into the thyroid. Certainly, in my opinion, this could be an explanation why some patients demonstrate hypothyroid symptoms with milligram doses of supplemental iodine.
In another rat study, this time by Man et al (17), the following is concluded:
“Moderate iodine excess continuously suppresses the thyroid iodine uptake and organification, which presents a mechanism for iodine-induced thyroid failure.”
Finally, in this excellent review of the literature on NIS research, Riesco-Eizaguirre and Santiseban make the following statement that should leave little doubt that iodine supplementation itself has a significant impact on NIS activity:
“Apart from TSH, the main factor regulating the accumulation of iodide in the thyroid and, thus, NIS activity, has long been considered to be iodide itself.”
Therefore, in my mind, there is little doubt that suboptimal iodine dosage can have an adverse impact on NIS activity. However, in relation to one aspect of this activity, the Wolff-Chaikoff effect, Abraham, as I mentioned, passionately disagrees. As I mentioned, I will examine in detail this controversy in the next installment of this series.
SOME FINAL, “BIG PICTURE” THOUGHTS ON IODINE DIGESTION, ABSORPTION, AND TRANSPORT INTO THE THYROID
As I mentioned in the introduction of this installment, my goal initially was to review studies that either support or refute the idea that milligram dosing of supplemental iodine poses a significant risk for thyroid related side effects. However, without understanding how these side effects might occur, I fear that a review of the studies would become reduced to a situation where which ever side has the most studies wins. As I suggested in my guidelines for judging controversies in clinical nutrition, I strongly feel we need to possess other criteria for judgment that will obviate the need for such a superficial method of determining scientific validity. The best criterion I can think of in this regard is to know enough about iodine digestion, absorption and metabolism to determine if the idea of side effects with milligram dosing of supplemental iodine is physiologically and biochemically plausible.
First, consider the subject I just discussed, iodine transport into the thyroid via the sodium iodide symporter (NIS). It seems very plausible to me that a patient who has up regulated NIS activity could possibly experience hyperthyroid-type signs and/or symptoms if milligram dosing of supplemental iodine is not adjusted with the patient’s unique NIS activity in mind. Conversely, it seems very plausible to me that a patient who has down regulated NIS activity due to many reasons that can vary from genetics to inflammation to environmental toxicity might experience hypothyroid-type signs and symptoms if it is not kept in mind that milligram dosing of supplemental iodine could further down regulate already low functioning NIS.
Next, consider the issue of digestion and absorption. As was demonstrated earlier in this installment, in contrast to popular scientific belief, both molecular iodine (I2) and iodide (I–) are absorbed. As you will see in research that I will be presenting in the next installment, it is clear that these two forms of iodine have distinctly different impacts on NIS physiology. In turn, it seems plausible to me that, in a situation where the form of supplemental iodine and its digestion and absorption is not considered in relationship to the patient’s unique NIS activity, hyper- or hypothyroid-type signs and symptoms could possibly ensue.
Of course, keep in mind that I am not claiming probability. That, based on what I have presented, ultimately depends on your ability to address other functional medicine issues besides iodine need such as toxicity and inflammation. However, I do hope that we can all agree, based on what I have presented, that adverse reactions to milligram dosing of supplemental iodine are possible and plausible.
As I promised, I will eventually be reviewing research performed on western populations that examines the risk of adverse effects on thyroid function when milligram dosing of supplemental iodine is administered. However, it is my hope that by presenting a biochemical and physiological rationale of how side effects might occur you can evaluate the relative validity of conflicting studies using criteria that is more intelligent than just counting the amount of studies on each side or trying to empirically decide which of Jeff’s presentations is more believable.
Finally, one last thought. By gaining a better understanding of iodine biochemistry and physiology, I do hope two major shifts in discussions of iodine can occur. First, I hope that we can finally move our focus away from the stifling, somewhat close-minded conservatism of those scientists in the iodine establishment who, even though I do not feel they deserve the moniker “medical iodophobe,” I do feel they could benefit from a fresh perspective. Second, I hope we can move away from the obsessive and fanatic tendencies demonstrated by Abraham and his colleagues that I feel have tainted some otherwise fine and extremely valuable presentations on iodine and the human condition.
Before closing, I would expect that, by now, you might be wondering if there is a way to determine NIS activity in patients. Interestingly, there is. This important issue will also be thoroughly explored in the next installment of this series.
Moss Nutrition Report #219 – 02/01/2008 – PDF Version
- Stipanuk MH. Biochemical, Physiological, & Molecular Aspects of Human Nutrition St. Louis: Saunders; 2006.
- Reed HL. Thyroid physiology: Synthesis and release, iodine metabolism, binding and transport. In: KL B, ed. Principles and Practice of Endocrinology and Metabolism, Third Edition. Philadelphia: Lippincott Williams & Wilkins; 2001:314-321.
- Abraham GE. Optimum levels of iodine for greatest mental and physical health. The Original Internist. 2002;5:5-20.
- Thrall KD & Bull RJ. Differences in the distribution of iodine and iodide in the Sprague-Dawley rat. Fundam Appl Toxicol. 1990;15(1):75-81.
- Thrall KD et al. Distribution of iodine into blood components of the Sprague-Dawley rat differs with the chemical form administered. J Toxicol Environ Health. 1992;37(3):443-9.
- Nuovo JA & Wartofsky L. Adverse effects of iodine. In: KL B, ed. Principles and Practice of Endocrinology and Metabolism, Third Edition. Philadelphia: Lippincott Williams & Wilkins; 2001:360-366.
- Smyth PPA & Dwyer RM. The sodium iodide symporter and thyroid disease. Clin Endocrinol (Oxf). 2002;56:427-429.
- Carrasco N. Thyroid hormone synthesis. In: Braverman LE & Utiger RD, ed. Werner & Ingbar’s The Thyroid: A Fundamental and Clinical Text, Eighth Edition. Philadelphia: Lippincott Williams & Wilkins; 2000:52-61.
- Saito T et al. Increased expression of the Na+/I– symporter in cultured human thyroid cells exposed to thyrotrophin and in Graves’ thyroid tissue. J Clin Endocrinol Metab. 1997;82(10):3331-3336.
- Levy O et al. Identification of a structural requirement for thyroid Na+/I– symporter (NIS) function from analysis of a mutation that causes human congenital hypothyroidism. FEBS Letters. 1998;429:36-40.
- De La Viega A et al. Molecular analysis of the sodium/iodide symporter: Impact on thyroid and extrathyroid pathophysiology. Physiol Rev. 2000;80(3):1083-1105.
- Breous E et al. Graves’ IgG activate upstream enhancer of the sodium/iodide symporter. Mol Cell Endocrinol. 2003;213:109-113.
- Riesco-Eizaguirre G & Santisteban P. A perspective view of sodium iodide symporter research and its clinical implications. Eur J Endocrinol. 2006;155:495-512.
- Boas M et al. Environmental chemicals and thyroid function. Eur J Endocrinol. 2006;154:599-611.
- Scinicariello F et al. Genetic factors that might lead to different responses in individuals exposed to perchlorate. Environ Health Perspectives. 2005;113(11):1479-1484.
- Ferreira ACF et al. Rapid regulation of thyroid sodium-iodide symporter activity by thyrotrophin and iodine. J Endocrinol. 2005;184:69-76.
- Man N et al. Long-term effects of high iodine intake: inhibition of thyroid iodine uptake and organification in Wistar rats (Article in Chinese). Zhonghua Yi Xue Za Zhi. 2006;86(48):3420-4.