A Perspective on High Dose Iodine Supplementation – Part X

More Thoughts on Abraham’s Perspective on the Wolff-Chaikoff Effect and the Overall Risks of Supplemental Iodine on Thyroid Function

As I resume my exploration of controversies relating to the biochemistry, physiology, and clinical applications of high dose iodine, I would like to thank you for your many kind comments on the detour I have taken over the last three issues of the Moss Nutrition Report where I explored the subject of fear as it relates to the practice of clinical nutrition.  While, at first glance, I admit it might have seemed a bit abrupt and out of place, I hope you can relate to my desire to fully address and understand a key question that has been buzzing in my mind right from the time I first began this iodine series:

Why are so many proponents of clinical use of milligram dosing of iodine so bound and determined to convince everyone that, unlike every other substance on earth, iodine is totally and completely risk free for everyone at doses that are several thousand times the RDA?

For me, and hopefully for you, the research that I presented in the just completed “Fear and loathing in Clinical Nutrition” series provides at least a satisfactory answer as to why so many are so driven on this issue.  In turn, now that this question is no longer buzzing around in my mind and creating a distraction, I am ready to focus again more fully on iodine physiology, biochemistry and clinical application.  As a review, I would like to present some conclusions that can be made about milligram dosing of supplemental iodine based on the literature and commentary presented thus far:

  1. Abraham and his colleagues appear to be in agreement with a large body of research that suggests iodine has important physiologic applications outside of the thyroid.  In turn, doses higher than the RDA (150 mcg per day) appear to be warranted in a large percentage of both healthy and chronically ill populations.
  2. Abraham and his colleagues appear to be in agreement with a large body of research that suggests different forms of supplemental iodine may be appropriate depending on patient need.  More specifically, iodide appears to be more appropriate for thyroid related issues and molecular iodine appears to be more appropriate for extrathyroidal issues such as breast health.
  3. It is my opinion that use of the term “medical iodophobe” to describe researchers and authors who disagree with the positions taken by Abraham and colleagues is highly unprofessional and has no place in scientific publications.
  4. The claim by Abraham and colleagues that double-digit levels of daily iodine intake are completely without risk to anyone is primarily based on two hypotheses.  The first relates to the Japanese experience with dietary iodine intake from kelp.  My examination of the literature suggests that the claim made by Abraham and colleagues that the population at large should be ingesting 12-13 mg of iodine per day based on epidemiologic observations that the Japanese have long been ingesting the same amount daily without any side effects via the kelp content of their diets is not in agreement with published data.  As you may recall, concerning quantity, the reference used by Abraham to justify this claim was incorrectly quoted. Furthermore, the recently published paper by Nagataki (1) makes it clear that the average daily intake of the Japanese is 1.2 mg per day.  Finally, Nagataki (1) is in agreement with several other researchers I have quoted who state that daily double-digit doses of dietary iodine have been linked with many cases of thyroid-related side effects among Japanese populations.  The second hypotheses made by Abraham and colleagues suggests that the Wolff-Chaikoff effect, in fact, does not exist and is purely a conspiracy by Wolff and colleagues to suppress clinical use of milligram doses of supplemental iodine.  Several papers I have reviewed are not in agreement with this hypothesis.  Furthermore, my examination of the references used by Abraham and colleagues to support this hypothesis, which I will complete in this installment, suggests that these references were not quoted correctly.

ABRAHAM’S STANCE ON THE WOLFF-CHAIKOFF EFFECT – WERE THE REFERENCES QUOTED ACCURATELY AND DO THEY ADEQUATELY SUPPORT THE STANCE?

In the August 2008 Moss Nutrition Report, my commentary on Abraham’s stance on the Wolff-Chaikoff effect left off with the following quote that comes from Abraham’s paper “The Wolff-Chaikoff Effect: Crying Wolf?” (2)

“Concerning iodide goiter, Wolff stated: ‘The most common form of iodide goiter is that seen in Hokkaido.’  The Japanese authors investigating the Hokkaido goiter did not think iodide was the cause of thyroid enlargement since Japanese subjects from Tokyo without goiter excreted similar levels of iodide in their urine.  Excess goitrogens in the diet of those subjects could explain their normal thyroid function in the presence of goiter, and this problem has since been solved.  In 1994, 27 years after the original publication by Suzuki, et al, Konno, et al, stated: ‘Kelp-induced endemic goiter was reported to occur in the coastal regions of Hokkaido nearly 30 years ago.  Such goiter has now disappeared.’  Please note that Konno, et al called it ‘kelp-induced goiter’ whereas Wolff called it ‘iodide-goiter,’ without any evidence that iodide was the cause.  Wolff blamed iodide for the Hokkaido goiter without any scientific data, and further, he stated that this iodide goiter was probably caused by the W-C effect a double assumption.”

I would now like to discuss the studies used to reference the claims made above and determine if these studies truly substantiate these claims.  The second sentence in the above quote was referenced by two studies, “Endemic coast goiter in Hokkaido Japan” by Suzuki et al (3) and “Thyroid function in chronic excess iodide ingestion: Comparison of thyroidal absolute iodine uptake and degradation of thyroxine in euthyroid Japanese subjects” by Nagataki et al (4).  Abraham suggests that the authors of these two studies concluded that iodine was not the cause of thyroid enlargement in goiter patients in Hokkaido, Japan.  However, the following quote from the Suzuki et al (3) suggests that the authors arrived at a conclusion that is the exact opposite:

“The major cause of the endemic coast goiter seems to be excessive and longstanding intake of iodine from seaweed, and the similarities of iodine metabolism between the endemic coast goiter and iodide goiter are discussed.”

What about the second paper by Nagataki et al (4)?  The study was performed on Japanese patients who were euthyroid.  Furthermore, as far as I can tell from my reading of the paper, no mention is made about goiter patients in Hokkaido, Japan.

The next referenced statement in the above quote by Abraham is:

“In 1994, 27 years after the original publication by Suzuki, et al, Konno, et al, stated: ‘Kelp-induced endemic goiter was reported to occur in the coastal regions of Hokkaido nearly 30 years ago.  Such goiter has now disappeared.'” 

Does the Konno et al (5) paper actually contain the sentence quoted by Abraham?  Indeed, it can be found in the first paragraph of the paper.  However, can we conclude, as inferred by Abraham, that Konno et al (5) are claiming that iodine cannot induce adverse changes in thyroid function?  The following quote that can be found in the abstract of this paper suggests that the answer to this question is “No”:

“These results indicate that 1) the prevalence of hypothyroidism in iodine sufficient areas may be associated with the amount of iodine ingested; 2) hypothyroidism is more prevalent and marked in subjects consuming further excessive amounts of iodine; and 3) excessive intake of iodine should be considered an etiology of hypothyroidism in addition to chronic thyroiditis in these areas.”

In “The Wolff-Chaikoff Effect: Crying Wolf?,” does Abraham present any other references to support his claim that the Wolff-Chaikoff effect is, in reality, a fabrication of Dr. Wolff that was designed to mislead clinicians about clinical use of milligram levels of iodine?  Interestingly, while the rest of the paper presents many statements referenced by papers other than those authored by Abraham that suggest supplemental iodine is totally benign in terms of thyroid function, none actually refer specifically to the Wolff-Chaikoff effect.  Therefore, since it appears that Abraham has been unable to produce references that clearly and unmistakably refute the existence of the Wolff-Chaikoff effect, and given the fact that, as stated in part VII of this series, a large body of published research supports its existence, I feel it must be concluded that Abraham’s position is without merit.  In turn, since it also appears to me that there is no credible research documentation for Abraham’s clams about daily iodine intake of Japanese populations or his claims about the Wolff-Chaikoff effect, I feel that we must reject Abraham’s claim that milligram levels of supplemental iodine are totally benign for all people at high doses.

OTHER EVIDENCE THAT SUGGESTS ABRAHAM’S CLAIMS ABOUT WOLFF AND HIS SUPPOSED INTENTIONS TO DECEIVE ARE IN ERROR

As I have stated in previous installments of this series, Abraham and colleagues have taken the position that Wolff was a “medical iodophobe” who deliberately fabricated and/or misinterpreted data to convince clinicians in this country that use of milligram levels of supplemental iodine can pose a risk to thyroid health in selected individuals.  In addition, Abraham and colleagues suggest, as I have pointed out, that no published papers existed before the publication of Wolff’s papers that documented adverse effects.  In contrast, according to Abraham and colleagues, all papers only reported positive findings with no suggestion of side effects.  In response to this claim, I would like to present a quote from a paper that Abraham has used as a reference, “The range of effective iodine dosage in exophthalmic goiter” by Thompson et al (6).  This paper was published in the Archives of Internal Medicine in 1930.  As the title suggests, the paper considered the use of an iodine solution that contained milligram levels of iodine per dose as a method to counteract the effects of hyperthyroid function.  As you might expect, this therapy was successful in many of the patients.  However, was it totally free of side effects as suggested by Abraham and colleagues?  Please note the following, keeping in mind that this paper was published in 1930, 18 years before Wolff published his first paper:

“In some experiences we have had with the prolonged treatment of exophthalmic goiter by iodine alone, we have seen the condition grow worse after temporary improvement during the continuous administration of small doses (1 drop daily), just as during the continuous administration of large doses (from 15 to 30 drops daily).”

Please note that each drop contained 6 mg of iodine.

What is even more interesting, though, is that Thompson et al (6) were not the first researchers to report adverse effects from milligram doses of iodine.  In their report of earlier research, Thompson et al (6) state the following:

“Jagic and Spengler, in 1924, reported on the treatment of sixteen thyrotoxic patients with 3 drops of a 5 per cent solution of sodium iodide three times a day (about 25 mg of iodine per day).  In eight patients the condition improved and in two became worse.”

Thus, I certainly accept Abraham’s claim that many, if not most patients, over the years have experienced benefits with no side effects from milligram dosing of supplemental iodine.  However, given the fact that reports of side effects in a small but significant amount of patients go back over 80 years, I cannot accept as scientifically valid his claim that no one has ever experienced clinically significant side effects.

MORE EVIDENCE THAT MILLIGRAM LEVELS OF SUPPLEMENTAL IODINE ARE NOT TOTALLY SAFE FOR EVERYONE

I would like to begin this section by reviewing a paper I mentioned in part I of this series, “Effects of chronic iodine excess in a cohort of long-term American workers in West Africa” by Pearce et al (7).   In this paper the impact of drinking water in which iodine was used as a bacterial disinfectant was examined.  The reason I would like to begin with this paper is because Abraham offered comments on this study in his paper entitled “The history of iodine in medicine part III: Thyroid fixation and medical iodophobia” (8).  As you might expect, Abraham deems this study “iodophobic” and then offers quotes from the study to substantiate this claim:

“The following quotes from Pearce’s publication are evidence of a faulty experimental design.  It is very surprising that such a mediocre manuscript made it through just because it is iodophobic.

‘Corps volunteers were authorized to receive a follow-up evaluation by an endocrinologist after returning from Niger.  Some follow-up evaluations were incomplete, as some subjects chose not to visit an endocrinologist upon returning, and different endocrinologists obtained different follow-up laboratory studies…Ultrasound evaluation was not performed…No volunteers had overt symptoms of thyroid dysfunction as evaluated clinically.'”

Unfortunately, the above quote leaves out some vital information contained in the study.  First, as the following quote states, another legitimate, clinically recognized method of determining the presence of goiter was used, palpation:

“The presence or absence of goiter was assessed by palpation by two physicians before correction of the iodine excess.  Goiter size was graded per WHO recommendations; the least severe classification was assigned in the five cases where observers disagreed.  The presence or absence of goiter was evaluated again an average of 30 wk after correction of the iodine excess.”

Second, a battery of laboratory tests was performed on most, but not all, subjects:

“Serum TSH, T4, and free T4 levels were determined…”

In addition, levels of thyroid peroxidase (TPO) antibodies and levels of total serum iodine were determined.  What were the findings based on these digital and laboratory analyses?  Pearce et al (7) state:

“Goiter was present in 44% of subjects during excess iodine ingestion and in 30% after removal of excess iodine.  Mean serum iodine decreased from 293 µg/liter during excess iodine ingestion to 84 µg/liter after cessation of excess iodine.  Mean total serum T4 values increased from 100.4 to 113.3 nmol/liter (7.8 to 8.8 µg/dl).  Mean serum free T4 increased from 32.2 to 34.7 pmol/liter (2.5 to 2.7 ng/dl).  Mean serum TSH decreased from 4.9 to 1.8 mU/liter.  Mean serum thyroid peroxidase antibody levels decreased from 33,000 to 22,000 IU/liter (33 to 22 IU/ml).

We found that during prolonged excess iodine exposure there were marked increases in serum total iodine concentrations, and the prevalence of goiter, elevated serum TSH values, and elevated serum thyroid peroxidase antibody values increased.  The prevalence of all abnormalities decreased after removal of excess iodine from the drinking water system.”

Of course, I would guess that you may be wondering what level of daily iodine intake was creating the findings reported above.  According to the authors:

“As the arid climate in Niger results in the daily consumption of 5-9 liters of water, the volunteers consumed at least 50 mg iodine daily…”

Before leaving this study, I do want to make it clear that the results indicate that the majority of subjects did not experience adverse thyroid-related effects.  However, some did.  Therefore, the paper affirms, as I have suggested, the statement that milligram levels of supplemental iodine are safe for most people.  However, it also affirms my claim that, contrary to the claim made by Abraham and colleagues, levels of iodine intake seen in this study are not safe for everyone in relation to thyroid function.

The paper “Iodine induced thyrotoxicosis in apparently normal thyroid glands” by Skare and Frey (9) published in 1980 provides two case reports where it appears very apparent that milligram dosing of supplemental iodine created thyroid-related side effects.  Case one involved a male born in 1927.  The following is stated by the authors concerning the patient’s initial presentation:

“He sought medical advice because of thyrotoxic symptoms, having a weight loss of 4 kg over the last 3 months.  At the first examination he was agile with a regular pulse, rate 100/min, fine finger tremor and lid lag.”

As suggested by the title of the paper:

“The thyroid gland was not palpable.”

However, TSH was low at 0.2 µg/l and T4 was 238 nmol/l.  In addition, both serum and urine total iodine were elevated.  Interestingly, despite these findings, tests for thyroid-related antibodies were negative, suggesting that no autoimmune phenomena were responsible for the signs and symptoms reported.  What did the history reveal about iodine intake?  Skare and Frey (9) state the following:

“For about one year he had consumed one spoonful (approximately 10 mg iodine according to the producer) of dried, powdered sea-kelp (Vitalia taremel’).”

What findings were noted after ingestion of the sea-kelp was discontinued?  The authors state:

“Iodine was stopped and his condition gradually improved.  He was euthyroid after 11 weeks.”

Also, after 22 weeks TSH had risen to 0.30 µg/l.  What about T4?

“Shortly after becoming euthyroid, serum T4 dropped transiently to 70 nmol/l.”

The final comment on this patient by the authors indicated that thyroid function had remained normal through 18 months after discontinuing the sea-kelp product.

Case two involved a male born in 1942 who had a history of sporadically ingesting sea-kelp (Vitalia taremel) for some years that was a constituent of bread dough.  Concerning thyroid-related findings, Skare and Frey (9) state the following:

“Mild thyrotoxic symptoms had been present for about a year, weight loss at 3 kg.  At the first examination, he had fine finger tremor, regular pulse, rate 74/min and lid lag.  The thyroid gland was not palpable.”

In addition, TSH was 0.30 µg/l and antibodies against thyroglobulin, follicular cell microsomes, and TSAB were not detectable.  T4 was 166 nmol/l.  Finally:

“High values of total iodine were found in serum and urine.”

After ceasing iodine intake, the following was noted:

“His condition gradually improved after stopping iodine intake, and he was euthyroid 9 weeks later.”

Furthermore:

“Shortly after being euthyroid, serum T4 dropped transiently to 72 nmol/l.  After 4 weeks, it was in the mid-normal range.  After he had been euthyroid for 6 weeks, he was experimentally exposed to 2 mg of iodine per day for 8 weeks.  Daily urinary iodine excretion rose to 18,000 nmol/l, which was higher than during the previous symptomatic episode.  He did not develop clinical or biochemical evidence of thyrotoxicosis…No relapse has occurred during 7 months of observation.”

Hopefully we can agree that the above case report provides further substantiation that milligram dosing of supplemental iodine will create thyroid-related adverse effects in some individuals.

Next, consider some studies that examined populations in Mediterranean locales after nationwide iodinization programs were instituted.  In “Natural course of autoimmune thyroiditis after elimination of iodine deficiency in northwestern Greece” by Zois et al (10), 29 children (12-18 years old) with autoimmune thyroiditis for five years were examined to observe any changes in disease status after efforts to eliminate iodine deficiency nationwide were instituted.  What impact did additional iodine have on these children who were already diagnosed with autoimmune thyroiditis before iodinization was instituted?  The authors state:

“At diagnosis, thyroid peroxidase antibodies (TPOAbs) were positive in 25 children (86%) and became positive in all children during follow-up.  Thyroglobulin autoantibodies (TgAbs) were positive in 17 children at diagnosis (59%) and became positive in 3 more children (69%).  Both antibody types increased by the end of the observation period (P<0.005).  Regarding thyroid function, 7 children (24%) at diagnosis had subclinical hypothyroidism that persisted and 4 more children developed subclinical hypothyroidism during the study period (38%).  Only 5 of these children (45%) had positive TgAbs.  There was an increase in thyrotrophin (TSH) so that at the end of the study all children had TSH greater than 2.5 mU/L but none developed overt hypothyroidism.”

These findings led the authors to conclude:

“Thus, after the elimination of iodine deficiency of northwestern Greece, the development of autoimmune thyroiditis appears to be a persistent and progressive phenomenon.”

Interestingly, Zois et al (11) performed a similar study three years earlier in “High prevalence of autoimmune thyroiditis in schoolchildren after elimination of iodine deficiency in northwestern Greece” and found similar results leading to the following conclusion:

“In conclusion, silent iodine prophylaxis has resulted in the elimination of iodine deficiency in Greece, and this has been accompanied by an increase in the prevalence of autoimmune thyroiditis.”

Finally, Bastemir et al (12) found almost the same correlation after an iodinization program in Turkey:

“In conclusion, iodine supplementation in Turkey has resulted in the elimination of iodine deficiency in the Eastern Black Sea Region, and this has been accompanied by an increase in the prevalence of autoimmune thyroiditis and thyroid dysfunction.”

More recently, a study was conducted in Denmark to ascertain the impact of iodine fortification of salt on the incidence of hypothyroidism.  In “An increased incidence of overt hypothyroidism after iodine fortification of salt in Denmark: A prospective population study” by Pedersen et al (13) it was first noted that iodine fortification of salt was introduced in Denmark in 1998.  To see if this led to an increase in hypothyroidism in Denmark, the researchers performed the following study:

“…we registered all new cases of overt hypothyroidism in two areas of Denmark with previously mild and moderate iodine deficiency (ID), respectively.  The register was started before and included the first 7 yr after introduction of iodine fortification (IF) of salt.”

Specifically, the investigation began one year before the onset of IF and considered two populations.  310,124 individuals resided in an area considered to have moderate iodine deficiency.  225,707 individuals resided in an area considered to have mild iodine deficiency.  Interestingly, the rate of hypothyroidism after the onset of IF only increased in the area that had moderate iodine deficiency before the onset of IF.  The authors state:

“In this prospective epidemiological study of a cohort representative of the Danish population performed before and during the first 7 yr of IF of salt in Denmark, we found that the overall incidence rate of hypothyroidism increased significantly during the period of mandatory IF.  The increase was restricted to the subcohort with previous moderate ID, whereas the overall incidence of hypothyroidism was stable in the subcohort with previous mild ID.  Unexpectedly, the increase in hypothyroidism was observed only in young adults and middle-aged (aged 20-59 yr).”

Of course, due to the nature of the study, the authors readily admit that it cannot be conclusively be determined that IF was the absolute cause of these findings.  Nevertheless, they do provide some excellent theories as to why iodine would play a significant role in the mechanism underlying these findings.

In contrast to the findings of the studies reviewed above, Yang F et al (14) concluded the following after iodine supplementation in China:

“Iodine supplementation may not induce an increase in hyperthyroidism in a previously mildly iodine-deficient population.  Chronic iodine excess does not apparently increase the risk of autoimmune, hyperthyroidism, suggesting that excessive iodine intake may not be an environmental factor involved in the occurrence of autoimmune hyperthyroidism.”

With these divergent findings, what are we to conclude?  I would hypothesize that these findings support my conclusion that supplemental iodine is well tolerated in relation to thyroid function in the majority of the population.  Therefore, as suggested by all the studies discussed above, iodine fortification to eliminate iodine deficiency is certainly justified.  However, as the majority of these studies also suggested, we need to be aware that certain members of the populations that receive iodine supplementation may have adverse, thyroid-related side effects.  Do these findings suggest a need to eliminate the practice of iodine fortification?  In my opinion, no, given the low rate of occurrence of side effects.  Nevertheless, we do need to be aware that the possibility exists and inform patients accordingly.  To provide still more support for this position, please consider the findings by Papanastasiou et al (15) in their study “Thyroid autoimmunity in the current iodine environment,” which are noteworthy because they are based on an overview of several studies that considered the impact of iodine fortification on thyroid function:

“It seems that both iodine deficiency and iodine excess should be avoided because of increased morbidity that might be induced.  Iodine prophylaxis and treatment programs remain even nowadays important for iodine deficiency correction, but follow-up over time and continuous control of iodine intake must be sustained.  Although iodine-induced thyroid autoimmunity in the current iodine-sufficient environment is of scientific interest, it seems that it is a transient and/or subclinical phenomenon.  Thus, the suspicion for increased prevalence of iodine-induced thyroiditis in previously iodine-deficient areas should not be held, in any case, as an argument against the…iodine supplementation of these areas.”

Of course, as clinicians who deal with individuals and not populations, we need to regard the situation a bit differently than the researchers who have a “scientific interest.”  For even if only one in a million of our patients has a negative reaction of even a transient nature, the discomfort this patient feels is no less real.  Furthermore, if the patient who we have not informed in advance about the possibility of even transient side effects discusses these side effects with others, including friends and conventional practitioners, who, like the patient, lack the knowledge of supplemental iodine that we have, the impact on our practices may also be no less real.  Therefore, I feel it is important to acknowledge that, from both clinical and practice-management standpoints, the claim by Abraham and colleagues that milligram dosing of supplemental iodine is safe for everyone in relation to thyroid function is clearly not supported by a preponderance of available reputed studies and clinical reports.

HOW CAN WE DETERMINE WHICH PATIENTS ARE MOST LIKELY TO HAVE ADVERSE, THYROID-RELATED REACTIONS TO SUPPLEMENTAL IODINE?

Given that it clearly appears that a small but significant percentage of patients will experience thyroid-related adverse effects to iodine supplementation, is there a way we can determine in advance which patients are more likely to experience such reactions?  The recently published in vitro study by Kostic et al (16) provides a possible answer.  In this study, potassium iodide (KI) alone or in combination with the inflammatory cytokine interferon-gamma (IFN-g) were added to a cell culture containing primary human thyroid cells.  Then several factors were measured, including thyroglobulin (Tg) and the inflammatory mediator intercellular adhesion molecule-1 (ICAM-1).    The authors found that KI alone had no effect on Tg and gradually increased ICAM-1.  However, the combination of KI and IFN-g had a much more profound effect:

“Augmented ICAM-1 in the presence of iodide excess and low-dose IFN-g could induce secretion of proinflammatory cytokines and lymphocytic infiltration in the thyroid gland. Decreased Tg production in the presence of KI excess and IFN-g could explain the development of hypothyroidism after adding iodide in a diet of subjects that already have lymphocytic infiltration and/or mild inflammation in the thyroid gland.”

In more simple terms, according to Kostic et al (16) if inflammation is already present in the thyroid, supplemental iodine has the potential for increasing this inflammation and adversely affecting thyroid function.

How might we determine which patients are more likely to have the presence of pre-existing, often subclinical inflammation of the thyroid?  This question can best be answered by considering some functional medicine issues.  For example, as reported earlier in this series, environmental toxins such as perchlorate can adversely affect thyroid function.  In addition, as also reported, genetic factors can create susceptibility to thyroid dysfunction.  Still another contributing factor can be the dysbiotic organism Yersinia enterocolitica that has been reported in several studies to induce autoimmune thyroid disease (17).  However, there is yet another possible contributing factor to pre-existing thyroid inflammation that, even though, it is still vastly under appreciated, may be the most significant of all.  As you will see, it is now apparent that gluten sensitivity as seen in celiac disease (CD) can be a major contributor to thyroid inflammation.  In turn, given the ever increasing incidence of CD that is related to the ever increasing intake of gluten and gliadin containing foods, I feel it is important that we seriously consider the possibly that patients with diagnosed CD or clinical and/or laboratory findings consistent with CD may be at a much higher risk for thyroid-related adverse reactions to iodine supplementation.

To fully understand this relationship, it is important to understand one of the primary mechanisms underlying the development of CD.  This was concisely explained by Naiyer et al (18):

“The enzyme transglutaminase II (TGase II) is considered integral to the development of celiac disease.  It is responsible for deamidation of gliadin that has entered the lamina propria of the small intestinal mucosa, probably during infections.  Deamidated gliadin, with its altered structure and charge, becomes more immunogenic, interacting with HLA DQ2 or DQ8 on antigen presenting cells.  This results in an inflammatory cascade initiated by the liberation of proinflammatory cytokines, and villous atrophy results.  During this inflammatory process, antibodies to TGase II (anti-TGase II), as well as antibodies to other tissue components such as actin, are produced.  Anti-TGase II antibodies can be detected in the small intestine early in the disease process and later in the serum.”

The authors then go on to point out that a version of the above mentioned enzyme, transglutaminase, can also be found in the thyroid.  In turn, the anti-TGase II antibodies will start attacking the thyroid because of the presence of this enzyme:

“We explored the role of anti-TGase II IgA antibodies in thyroid autoimmunity in patients with celiac disease.  Tissue tranglutaminase is found in thyroid tissue, in both the cytosol and in the follicle lumen where it has been demonstrated to cross-link TG.  In our study, we demonstrate that the anti-TGase II IgA-positive serum from patients with celiac disease binds to thyroid follicular cells as well as extracellularly in the interfollicular space.”

With these findings in mind, Naiyer et al (18) conclude:

“In conclusion, TGase II- is ubiquitous and found within cytoplasm, cell nuclei, and extracellular matrix, and on cellular surfaces.  It is conceivable that in celiac disease, a systemic autoimmune reaction occurs in some individuals.  This has been suggested for cardiac, bone, and neurological tissues.  Our studies suggest that this applies to thyroid tissue as well.”

Before continuing, please note again that the enzyme TGase II is found in many tissues throughout the body.  Therefore, it should be no surprise that CD patients may possibly demonstrate inflammatory mediated signs and symptoms not only in the thyroid but many other organs not typically associated with the traditional CD picture.

Before closing this discussion on iodine, thyroid-related symptomatology, and CD, please consider this quote from the excellent review paper “Celiac disease and autoimmune thyroid disease” by Ch’ng et al (19) that I feel confirms the findings noted above by Naiyer et al (18) that the relation between gluten/gliadin sensitivity is very clinically significant and needs to be kept in mind whenever milligram dosing of supplemental iodine is being considered:

“Patients with CD may present with diverse clinical manifestations, or without symptoms, to specialists other than gastroenterologists.  There is ample evidence of a strong association between CD and several immune mediated diseases, including autoimmune thyroid disorders, type 1 diabetes mellitus, primary biliary cirrhosis, inflammatory bowel diseases and autoimmune adrenal failure.”

In turn:

“Thyroid function should be assessed in all CD patients at diagnosis and follow-up if clinically indicated.”

I would close this discussion by adding that thyroid function should be checked any time that you are considering milligram dosing of supplemental iodine with CD patients.  Furthermore, with all the above in mind, I feel to best determine which patients might be most susceptible to adverse, thyroid-related reactions to supplemental iodine, the type of functional medicine diagnostic work-up advocated by me and many others that takes into account all of the above should be considered.

Can patients who demonstrate pre-existing susceptibility to adverse, thyroid-related reactions to supplemental iodine still have outcomes that are both efficacious and free of side effects?  I believe so.  However, I feel that we need to approach these patients cautiously, starting with very low doses and increasing gradually, ascertaining patient response at every level of dosing.

In the next installment of this series, I will explore the question that should inevitably follow the above discussion.  Given the risks just discussed, does published research give a good idea of just what doses of supplemental iodine above the RDA might be safe and effective in the majority of patients?  In addition, I will explore the research behind some fascinating anecdotal reports from some of you that iodine supplementation can be helpful in addressing clinical situations involving reproductive hormone imbalances. Next, I will explore the fascinating hypothesis put forth by Abraham and colleagues that suggest the side effects related to iodine supplementation can be an offshoot of the detoxification properties of iodine, most notably in relation to bromine.  Finally, I will explore research on still another of the great controversies involving iodine, use of diagnostic testing to determine need for iodine supplementation.

Moss Nutrition Report #226 – 04/01/2009 – PDF Version

REFERENCES

  1. Nagataki S. The average of dietary iodine intake due to the ingestion of seaweeds is 1.2 mg/day in Japan. Thyroid. 2008;18(6):667-668.
  2. Abraham GE. The Wolff-Chaikoff Effect: Crying Wolf? The Original Internist. 2005;12(3):112-118.
  3. Suzuki H et al. Endemic coast goitre in Hokkaido, Japan. Acta Endocrinologica. 1965;50:161-176.
  4. Nagataki S et al. Thyroid function in chronic excess iodide ingestion: Comparison of thyroidal absolute iodine uptake and degradation of thyroxine in euthyroid Japanese subjects. J Clin Endocrinol Metab. 1967;27(5):638-647.
  5. Konno N et al. Association between dietary iodine intake and prevalence of subclinical hypothyroidism in the coastal regions of Japan. J Clin Endocrinol Metab. 1994;78(2):393-397.
  6. Thompson WO et al. The range of effective iodine dosage in exophthalmic goiter. Arch Intern Med. 1930;45:261-281.
  7. Pearce EN et al. Effects of chronic iodine excess in a cohort of long-term American workers in West Africa. J Clin Endocrinol Metab. 2002;87(12):5499-5502.
  8. Abraham GE. The History of iodine in medicine part III:  Thyroid fixation and medical iodophobia. The Original Internist. 2006;13:71-78.
  9. Skare S & Frey HM. Iodine induced thyrotoxicosis in apparently normal thyroid glands. Acta Endocrinologica (Copenh). 1980;94(3):332-6.
  10. Zois C et al. Natural course of autoimmune thyroiditis after elimination of iodine deficiency in northwestern Greece. Thyroid. 2006;16(3):289-93.
  11. Zois C et al. High prevalence of autoimmune thyroiditis in schoolchildren afater elimination of iodine deficiency in northwestern Greece. Thyroid. 2003;13(5):485-9.
  12. Bastemir M et al. High prevalence of thyroid dysfunction and autoimmune thyroiditis in adolescents after elimination of iodine deficiency in the Eastern Black Sea Region of Turkey. Thyroid. 2006;16(12):1265-71.
  13. Pedersen IB et al. An increased incidence of overt hypothyroidism after iodine fortification of salt in Denmark: A prospective population study. J Clin Endocrinol Metab. 2007;92:3122-3127.
  14. Yang F et al. Chronic iodine excess does not increase the incidence of hyperthyroidism: a prospective community-based epidemiological survey in China. Eur J Endocrinol. 2007;156(4):403-8.
  15. Papanastasiou L et al. Thyroid autoimmunity in the current iodine environment. Thyroid. 2007;17(8):729-739.
  16. Kostic I et al. Influence of iodide excess and interferon-gamma on human primary thyroid cell proliferation, thyroglobulin secretion, and intracellular adhesion molecule-1 and human leukocyte antigen-DR expression. Thyroid. 2009;19(3):283-291.
  17. Corapcioglu D et al. Relationship between thyroid autoimmunity and Yersinia Enterocolitica antibodies. Thyroid. 2002;12(7):613-617.
  18. Naiyer AJ et al. Tissue transglutaminase antibodies in individuals with celiac disease bind to thyroid follicles and extracellular matrix and may contribute to thyroid dysfunction. Thyroid. 2008;18(11):1171-1178.
  19. Ch’ng CL et al. Celiac disease and autoimmune thyroid disease. Clin Med Res. 2007;5(3):184-192.