Iodine Treatment of Graves Disease Part Two

Iodine Treatment of Graves’ Disease Part Two

Jeffrey Dach MD

This is Part Two, For Part One, Click HereHeader image: thyroiditis. Notice disruption of basal laminar membrane of the follicles with release of colloid. Notice inflammatory, lymphocytic infiltrate surrounding the damaged follicles. Courtesy of wikimedia commons.

The main objection to use of Iodine for first line therapy of Graves’ Disease is resistance or escape from the suppressive effects of iodine, leading to more difficult to treat thyrotoxicosis in about 9-12 per cent of patients.  This was described in a 2015 study by Dr. Ai Yoshihara switching pregnant women from Methimazole to Iodine treatment for Graves’ Disease.  Although 90 per cent successful, about 9-10% of patients escaped from the suppressive effects of Iodine and worsened the hyperthyroidism.  This was unpredictable with no obvious parameters to predict which patients would respond well, and which patients would worsen. (1-3)

Okamura Study 504 Graves’ Patients Treated with Iodine Alone

In 2022, Dr. Ken Okamura provided us with a protocol for treating Graves’ Disease with Iodine as first line therapy, including the management of Iodine escape, or Iodine resistance.  Proclaiming that “iodide in higher doses is an established and time-honored treatment of Graves’ Disease”, and is safer than thyroid blocking drugs such as methimazole, Dr. Ken Okamura recruited 504 untreated Graves’ Disease patients and began treatment with 100 mg of potassium iodide daily, seeking to avoid thionamide drugs, methimazole and PTU, which carry potentially severe adverse side effects. In Japan, one person dies annually from thionamide drug -induced suppression of the white blood cells (agranulocytosis). Dr. Ken Okamura writes:

iodide in higher doses is an established and time-honored treatment of GD [Graves’ Disease]…However, both MMI [methimazole] and PTU [propylthiouracil] were still associated with severe notorious or unfamiliar side effects. In Japan, one GD patient on average dies due to thionamide-induced agranulocytosis every year…The possibility of KI therapy was therefore suggested in general untreated GD from the beginning…many patients have mild or even asymptomatic GD that may be sensitive to excess iodide. (4)

Relapse of Hyperthyroidism on Iodine Therapy when Tapering

Left image: Ultrasound image of thyroid nodule courtesy of wikimedia commons

A subset of 92 of the 504 Graves’ patients so treated with Iodine as first line therapy, (18.3%) were overly sensitive to iodine. The iodine suppressive effects worked too well, rendering them hypothyroid with high TSH and low Free T4.

Before iodine treatment, the 92 patients were thyrotoxic with high Free T3 and T4 levels, and a suppressed, very low, TSH.  After Iodine treatment, the serum thyroid hormone levels plummeted to very low levels. The TSH rocketed up to very high levels. In the first half of the study, in 41 such patients with high TSH after iodine treatment, the Iodine dosage was tapered down. However, 71% then relapsed into hyperthyroidism.

This relapse in to hyperthyroidism can be avoided with Block and Replace. In the second half of the study, for 39 “overly sensitive to iodine” patients with high TSH and Low Free T4, the iodine was no longer tapered down. Instead, these 39 patients were treated with Block and Replace by adding levothyroxine to reduce the TSH. Using Block and Replace, none of these 39 patients had relapse of hyperthyroidism!  This is a justifiable use of Block and Replace. Note: Block and Replace is the addition of Levothyroxine to replace the missing thyroid hormone, thus bringing down the TSH and raising the Free T4. Dr. Ken Okamura writes:

in the latter half of this study, the patients were treated with the combination of 100 mg KI and LT4 [levothyroxine] when the serum fT4 level became low and the TSH level became detectable (combined fixed dose KI and LT4 therapy). In this combined therapy (n = 39) [Block and Replace], compared with tapering therapy (n = 41), a relapse of hyperthyroidism was not observed (0% vs. 71%, p < 0.0001) and the degree of TSH elevation was reduced (e.g. 10.7 [6.6–23.3] μU/mL vs. 27.3 [8.6–68.3] μU/mL), although the difference was not significant (p = 0.0561). … It was very important to keep the serum iodide level above the threshold for the WC [Wolf- Chaikoff] effect, avoiding the tapering method usually performed in MMI therapy. The KI dosage could be reduced later when TBII became negative or patients had nearly achieved remission. (4)

Relapse of hyperthyroidism was 71 per cent when the Iodine dosage was tapered down, and zero in the Block and Replace group. Block and Replace reduced the TSH from about 27μU/mL to 10μU/mL.

Lesson number One: Do not taper the Iodine dosage when T4 goes too low and TSH goes too high. Instead use Block and Replace with Levothyroxine.

Iodine Escape – Add Methimazole

202 patients were considered “Escaped” or resistant to Iodine Suppression. These were treated with a combination of potassium iodide (KI) 100 mg/per day and Methimazole 5-15 mg per day with good results. Once starting the combination of methimazole with KI, it was about 7 weeks until FreeT4 normalization.

Treatment with Ablative Therapy

During this study, 126 (25.0%) patients were treated by ablative therapy (RAI 104 patients and surgery 22 patients), usually 2-3 years after starting medical therapy.  Patients treated with RAI (Radioactive Iodine) had the 100 mg potassium iodine withheld for 4-7 days and then had 60% Iodine uptake prior to RAI treatment. This uptake  is similar to untreated Graves’ Disease, so Iodine Treatment was not an issue for RAI. Dr Ken Okamura writes:

After RAI treatment in Groups B and C [iodine escaped or resistant], 86% of the patients achieved a euthyroid- or hypothyroid status with a decrease in thyroid volume. It was then concluded that KI therapy did not interfere with the efficacy of RAI.(4)

Features Predicting Escape, Goiter Size, Free T3 Levels, and TSH

Escape or Iodine Resistance was more frequent in patients with larger thyroid goiters, and with higher Free T3 levels (greater than 10 pg/ml). Dr. Ken Okamura thought this high Free T3 was a marker of strong TSH receptor stimulation (and therefore thyroid stimulation), either from Graves’ antibodies or elevated TSH, with a high turnover of both thyroglobulin and Iodide. The third factor was TSH level, as there was no escape in patients who responded early to Iodine with normalization of TSH and T4 levels. Escape from Iodine was seen only in those patients with continued TSH suppression after iodine treatment. Dr. Ken Okamura comments on the similarity between Graves’s Disease and an Iodine Deficiency state, as both have T3 predominant synthesis/secretion indicating strong stimulation, writing:

T3 predominant synthesis and secretion is a good marker of the thyroid gland being strongly stimulated with high turnover of both Tg [thyroglobulin] and iodide, as found in cases of iodine deficiency.

Timing of Adding Methimazole- 60 Day Window

Dr. Ken Okamura feels that the 60-day window for achieving euthyroid status is important.  If the patient fails to achieve euthyroid status (normal Free T4) or “escapes” within 60 days, then methimazole (MMI) 5-15 mg/day should be added to the Potassium iodide 100 mg/day. The addition of MMI to Iodine overcomes Iodine resistance or escape. In the event the patient is still resistant to medical therapy, Radioactive Iodine therapy was effective. Note: iodine escape means the patient initially achieves normal Free T4, then later relapses with high T4. Dr. Ken Okamura writes:

When treating GD with KI, the timing for adding MMI is important. If patients fail to achieve euthyroid status within 60 days or escape occurs, it may be better to begin combined KI and MMI therapy…The important conclusion from this study was that KI resistance or escape from the KI effect could be overcome either by combined KI and MMI therapy…or RAI [radioactive iodine] therapy…In conclusion, the serum fT4 levels declined in all patients with GD [Graves Disease] following KI therapy. Among GD patients treated with 100 mg KI, 34% were KI-sensitive with detectable TSH and a good prognosis, 50% were KI-sensitive with TSH suppression and 16% were KI resistant. KI was immediately excreted into urine without serious side effects. Escape was only observed in TSH suppressed patients. KI-resistant and escaped patients were able to be treated with a combination of KI and a small dosage MMI, or RAI, as usual. We can minimize the use of thionamide with serious side effects by adopting the “KI or RAI” strategy for the treatment of GD without impending serious symptoms. (4) Emphasis mine.

Note: Graves’s patients with exopthalmos usually prefer ablation with surgical thyroidectomy rather than RAI (radioactive iodine) which may worsen thyroid eye disease.

Eighty Per Cent Remission Rate for Responders

Dr. Ken Okamura found that for patients who show an early good response to iodine with normalization of TSH (34% of total), these will ultimately achieve an 80% remission rate. If the patient does not achieve euthyroid status within 60 days, then additional MMI is indicated as these patients would otherwise have a high rate of escape from Iodine, (33-83%). This combined group has a 50% chance for remission.  Dr. Ken Okamura writes:

Regarding the strategy for GD treatment depending on the early response to 100 mg KI, KI treatment could be continued in Group A [responders]. Nearly 80% remission or spontaneous hypothyroidism could be expected. If the serum fT4 and fT3 levels do not normalize within 60 days, the patients may belong to Group B or C [poor responders, resistant or escaped]. Combined KI and MMI therapy is then recommended, as a 33%–82% chance of escape is expected later…. (4)

Dr. Nami Suzuki KI Potassium Iodide Treatment for Mild Graves Disease

As discussed previously, many authors of KI for GD studies had no explanation and no criteria for determining which patients to be at risk for non-responders or resistant to KI therapy. Credit and thanks goes to Dr. Namu Suzuki for her work in unraveling this nonresponder criteria. In 2020, Dr. Nami Suzuki studied the use of potassium iodide for mild newly diagnosed Graves’ Disease, defined as FreeT4 < 5.0 ng/dl,  in 122 patients (13 males, 109 females), concluding this is a safer and effective option for about 60% of females with Graves Disease.  Dr. Nami Suzuki found that males had a 3.6 fold greater risk of non-responder compared to females. The initial Free T4 of 2.76 ng/dl or less could be used to predict which patients most likely to be responders to KI treatment. Another factor affecting efficacy of KI is prior Methimazole treatment which causes degeneration of thyroid tissue.

In terms of details of the study, all patients were newly diagnosed and never treated with methimazole.  KI dosage was started at 50 mg/day and increased to 100 mg for non-responders, defined as not reaching a FreeT4 of 1.6 ng/dl (upper range of normal). After about 6 months of treatment, about 60 per cent were responders and 40 per cent non-responders. Non-responders were most likely male, with FreeT4 remaining above 2.8 ng/dl.  For responders with TSH within normal range (0.2–4.5 μU/mL), the KI dose was tapered down by 10 mg/day.  Medication was stopped when TSH and TRAb normalized for 6 months on 10 mg KI every other day. There were no adverse side effects from KI treatment. Note: this tapering method differs from Dr. Okamura’s study above, in which better results were obtained with “Block and Replace”.

Non-Responders Are Switched to Methimazole

51 of the 122 patients were KI non-responders and were switched from KI to ATDs (Anti-Thyroid Drugs, Methimazole). 5 of the 51 patients (about 10 per cent) had adverse side effects from ATDs. Two patients developed agranulocytosis (low white count) due to methimazole (MMI), 1 patient developed liver injury due to propylthiouracil (PTU), and 2 patients developed drug eruption (skin rash) from MMI.(31)

Note: switching non-responders to Methimazole was also done in the Okamura study above. Dr. Okamura felt that a trial of 6 weeks of KI was sufficient to determine if a patient is a non-responder, at which time non-responders are switched to MMI. Dr. Nami Susuki’s treatment duration required to judge non-responsiveness to KI was considerably longer, 5.9 months. Another difference was the use of Block and replace in Dr. Okamura’s study, while Dr. Suzuki used KI tapering.(4)

Thyroid Volume Increase

Dr. Suzuki reported a significant increase in thyroid volume in both responders and non-responders, with greater volume increase after one year in the non-responder group. This represents increased colloid formation and enlargement of thyroid follicles after KI administration. Dr. Suzuki writes:

Excessive iodine intake is well known to reduce thyroid hormone secretion and production, as excess iodine inhibits iodine organification in the thyroid gland. This phenomenon is known as the Wolff-Chaikoff effect. A detailed animal experiment showed that excess iodine reduces the expression of thyroid peroxidase (TPO) mRNA, and expressions of sodium/iodine symporter (NIS) mRNA and protein…The effect of excess iodine supplementation has been used as a treatment for GD [Graves’ Disease] for decades , especially during thyroid crisis, in combined use with anti-thyroid drugs (ATDs) for patient with severe hyperthyroidism and as a surgical preparation. However, that effect is not believed to last long, with the loss of effect termed “escape from the Wolff-Chaikoff effect”. Although almost seven decades have passed since ATDs were first used in the treatment of GD, potassium iodide (KI) has seen preferential use for patients with GD in Japan who display adverse reactions to ATDs…This study enrolled patients newly diagnosed with mild GD, defined as free thyroxine (FT4) <5.0 ng/dL, between July 2014 and June 2016. KI was started at a dose of 50 mg/day, and if FT4 values did not decrease after initiation of treatment, doses were increased to 100 mg/day. Patients for whom thyroid hormone levels could not be controlled with KI at 100 mg/day were regarded as non-responders. Of the 122 patients (13 males, 109 females) included in this study, 71 (58.2%) responded to KI therapy. The remaining 51 patients (41.8%) were non-responders. The median duration required to judge non-responsiveness was 5.9 months. Multiple logistic regression analysis performed on parameters measured at the initial visit indicated FT4 …and male sex… were significantly associated with KI responsiveness. Receiver operating characteristic (ROC) curve analysis of the relationship between FT4 and KI responsiveness indicated an FT4 cut-off of 2.76 ng/dL was optimal for differentiating between responders and non-responders. KI therapy was effective and safe for about 60% of patients with mild GD.(31) Emphasis Mine

Dr. Nami Suzuki writes KI therapy is safer than ATD’s and is effective in about 60 percent of females with mild Graves Disease, defined as initial Free T4 less than 2.76 ng/dl (FT4 <5.0). Males with severe GD defined as FreeT4 >2.76 ng/dl are more likely to be non-responders. Compared to female non-responders, males were 3.6 fold more likely to be non-responders. In prior unfavorable KI (potassium iodide) studies, patients had been previously treated with ATD’s (Methimazole, MMI) , a drug associated with degenerative changes in thyroid tissue. This factor may have impacted the efficacy of KI. Dr. Nami Suzuki writes:

the present study confirmed that KI therapy is effective for GD in patients with FT4 values <5.0 ng/dL…subjects in previous studies had also been treated with ATDs as a first-line treatment. ATDs are known to induce morphological changes in thyroid tissue, such as increased cellularity and diminished amounts of colloid [13]. Considering this fact, thyroid tissues from subjects analyzed in previous reports [10-12] were likely to have been affected by ATDs, and such degeneration might have impacted the efficacy of KI...KI monotherapy appears potentially safer as a treatment for patients with GD…In the present study, males displayed a 3.6-fold higher risk of KI non-responsiveness than females...KI therapy appears to offer an effective and potentially safer therapy for about 60% of female patients with mild GD, and thus could represent a third drug option for these patients.(31)

In 2017, Dr. Akira Honda switched to Potassium Iodide 24 Graves’ Disease patients who had adverse effects and could not tolerate thionamides (methimazole).  Responders maintained euthyroid function for 6 months, while non-responders did not. Dr. Honda found the efficacy of KI therapy was inversely correlated with thyrotoxicosis severity. This is in agreement with Dr. Suzuki’s study. (48)

Escape from Iodine, or Painless Thyroiditis?

A second paper in 2022 also by Dr Ken Okamura makes the bold assertion that many patients under treatment for Graves’ Disease who relapse into hyperthyroidism have thyroiditis, an inflammatory process, called painless thyroiditis (PT).  This may be true for both Iodine and Methimazole, and as mentioned above is usually associated with decreasing (tapering) the treatment dosage. This gives more support to the use of Block and Replace instead of tapering down the dosage of the  iodine or methimazole thyroid blocking drug.

Dr Okamura reviewed 100 patients who presented unexpected relapsing hyperthyroidism while decreasing dosage under treatment for Graves’ disease with Potassium Iodide, Methimazole or PTU. All had radionuclide iodine uptake scans. Many of these scans showed under 5 per cent uptake indicating thyroiditis as the cause of the thyrotoxicosis, rather than worsening Graves’ Disease.  In this regard, PT may resemble Hashitoxicosis, a type of thyrotoxicosis with very low radio-iodine uptake. Remember, 70 per cent of Graves patients are also positive for Hashimoto’s antibodies, indicating frequent co-existence of the two disease entities. Dr. Okamura writes:

Graves’ Disease (GD) and Hashimoto’s thyroiditis are recognized as being pathologically interrelated, as GD may occur in patients whose thyroid glands histologically show either Hashimoto’s thyroiditis alone or a mixture of both parenchymatous hypertrophy of GD and extensive lymphocytic infiltration. These two conditions may represent a single disease entity with a wide range of manifestations.(5) Emphasis Mine

A Single Entity with Different Manifestations

In agreement with Dr. Okamura’s statement that Hashimoto’s and Graves’ Disease are a single entity are Drs. Baral and Wartofsy in a 2019 case report of a patient with long standing Hashimotos’ Thyroiditis (HT) who transformed  into Graves’ Disease (GD). The authors commented patients with Hashimotos’ Thyroiditis may transform into Graves’ Disease at any point, writing:

Hashimoto’s Thyroiditis (HT) and Graves’ Disease (GD) reflect two extremes in the spectrum of autoimmune thyroid diseases….Patients with thyroid autoimmune disease have both thyroid hormone receptor stimulating and thyroid hormone receptor blocking antibodies and clinical manifestations depend upon the level of these antibodies and the state of the thyroid gland. Because patients with HT can transform to GD at any point due to a change of blocking to stimulating antibodies, clinicians should be aware of the potential for this transformation.(49-53)

Mechanism of Thyroiditis

What is the mechanism causing thyroiditis upon reduction in dosage of anti-thyroid medication?  Dr Okamura reminds us that excess iodine can cause a “toxic effect”, i.e. thyroiditis. Animal studies show that selenium supplementation ameliorates the toxic effects of iodine excess. Production of thyroid hormone requires oxidation of iodide to iodine by the TPO enzyme using hydrogen peroxide as a substrate. TSH stimulation of the thyroid gland increases all steps in thyroid hormone synthesis including hydrogen peroxide generation. I suggest the mechanism here involves increased hydrogen peroxide generation in the face of insufficient selenium-based antioxidant ability, caused by underlying selenium and/or magnesium deficiency. The excess hydrogen peroxide causes oxidative damage to adjacent structures which are thyroglobulin, TPO and thyrocytes, leading to inflammation, rupture of follicles and release of preformed thyroid hormone. (9-25)

Dr Okamura writes:

PT [painless thyroiditis] was frequently observed during KI treatment. In Group A [low radioiodine uptake], 19 (54.3%) patients were treated by KI alone or KI and MMI before the episode of PT. Given the effect of excess iodide on the morphological changes in the thyroid, KI treatment may precipitate the “iodide thyroiditis” reported by Edmunds in 1955. In the same year as Gluck reported convincing cases with PT, Savoie reported 10 cases of iodine-induced thyrotoxicosis in apparently normal thyroid glands, ranging from 1 to 40 months after exposure to excess iodine. They all showed a typical clinical course of PT with a low RAIU followed by hypothyroidism…From a therapeutic perspective, it is very important to keep in mind that PT [painless thyroiditis] can occur during ATD [anti-thyroid drug] treatment of GD, especially when the dosage is reduced…The diagnosis can be confirmed by the suppressed RAIU [radio iodine uptake] (<5%/5 h) in the thyrotoxic state, which remains a valuable factor for differentiating PT from relapse of GD. (5)(26-30)

Anti-Thyroid Drugs Contraindicated in Painless Thyroiditis

in 1975, Dr. Franklin Gluck reported on four cases of Painless Thyroiditis (PT) with low radio-iodine uptake, thyroid blocking drugs are ineffective and contraindicated, writing:

Thus, this form of thyrotoxicosis differs from the usual form found in Graves’ disease in that histologic features of Graves’ disease are absent, the radioactive iodine uptake is low, and specific antithyroid therapy is contraindicated.(27)

Differentiating Painless Thyroiditis from Graves’ Disease

In 2006, Dr. Afsana Begum explains how to differentiate Painless Thyroidits (PT) from Graves’ Disease (GD), noting in PT there is a disproportionate increase in T4 compared to T3, and the Radio-Iodine uptake is almost always less than 3 per cent:

Painless thyroiditis is more difficult to distinguish from Graves’ disease, but it is imperative for the clinician to distinguish between these two diseases since important therapeutic differences exist. The ESR (sedimentation rate) and white blood cell count are normal. T4 and triiodothyronine (T3) levels are initially elevated, with a disproportionate increase in T4 compared with T3. RAIU (radio-iodine uptake) is decreased in the hyperthyroid phase of the disease and is almost always less than 3 percent. This situation contrasts markedly with the elevated RAIU  found in patients with Graves’ disease.(47)

Histopathology Studies

Left Image is Fig. 4A. Graves Disease and 4B Painless Thyroiditis Courtesy of Meng Zhaowei, 2015.

In 2015, Dr. Zhaowei Meng studied the histopathology differences in new patients presenting with thyrotoxicosis when the diagnosis could be either Graves’ Disease (GD) or Painless Thyroiditis (PT), writing:

For GD, the follicular epithelial cells were tall and more crowded than those of a normal thyroid gland. Some small papillae were formed, which projected into the follicular lumen and encroached on the colloid. The colloid within the follicular lumen was pale, with scalloped margins. Lymphoid infiltrates were present in the interstitium (Fig 4A upper left)…For PT, the most prominent and specific histopathological feature was the massive lymphocytic infiltration with hyperplastic germinal centers within the thyroid parenchyma. Thyroid follicles were disrupted and collapsed.(Fig 4B upper left) It was evident that the tissue cellularity in PT was much higher than that in GD… (38)

What Was the Selenium Level ?

Returning to the 2015 Yoshihara study of pregnant Graves’ patients showing a 9-10 percent iodine escape rate when converting from MMI to Iodine, one wonders how many of these iodine escape cases are related to thyroiditis, an inflammatory process similar to Hashitoxicosis ?  A radionuclide uptake study would resolve the issue.  It would also be useful to know the selenium and magnesium status of these patients. One would ask the obvious question: Would the escape rate be decreased if patients had been given selenium and magnesium supplements? (9-22)

Why Not Use Block and Replace ?

Another question is, why not use Block and Replace strategy as was done is the 2015 Yoshihara study?  Painless thyroiditis (PT) and hyperthyroidism with low RAI uptake usually occurs when dosage of thyroid blocking drug is reduced, and TSH goes high. The  high TSH stimulates excess hydrogen peroxide (H202).  The damaging effect of H202 on thyrocytes is thought to be the trigger for thyroiditis. In Block and Replace strategy, instead of reducing dosage of thyroid blocking drug (iodine or methimazole), a replacement dose of thyroid hormone (Levothyroixine) is added.  Thyroid hormone medication will suppress the TSH, and alleviate the TSH stimulation for generate hydrogen peroxide. Block and Replace is a logical treatment to avoid episodes of hyperthyroidism from PT (painless thyroiditis) and prevent alternating extremes of thyroid function, the undulating course, with alternating relapse and remission seen in many patients with Graves’ disease.

One also wonders if duration of disease is a factor in determining success rate of iodine therapy.  If patients are treated early, upon first presentation of Graves’ Disease, would these patients have a higher success rate ? Alternatively, if patients have many years of Methimazole treatment with undulating course prior to switching to potassium iodide (KI) therapy, would this be a factor in decreasing the success rate for KI therapy, as suggested above by Dr. Nami Suzuki? (31)

Co-Existence of Graves’ and Hashimoto’s Antibodies

Another factor to be considered is the co-existance of Hashimotos’ antibodies in 70 per cent of Graves’ Disease patients. Would this be a factor in determining success rate with Iodine therapy as discussed by Dr. Okamura. Here is a quote from Dr. Kamijo in which elevated anti-thyroglobulin antibodies was associated with episodes of PT (Painless Thyroiditis). One is tempted to suggest Dr. Kamijo is describing Hashitoxicosis appearing in patients with Graves’ Antibodies:

Kamijo reported 11 patients with PT [Painless Thyroiditis] following KI treatment for GD. Anti-Tg antibody [Anti-thyroglobulin antibody] was positive in 10 of the 11 patients [54]. The role of antithyroid antibody and iodine in the clinical course of GD or PT should be re-evaluated in the future.(5)(32)  Note: elevated TPO antibodies are included here.

In 2021, Dr. Kamijo found 10 of 11 Graves’ Disease patients with iodine induced PT after switching from MMI to KI had elevated anti-thyroid antibodies (TPO or Thyroglobulin Antibodies), suggesting an auto-immune etiology, as well as a direct toxic effect of the excess iodide,  writing:

KI has a cytotoxic effect on only human thyroid follicles that is abolished by MMI. Furthermore, Xu et al. (20) showed a cytotoxic effect due to KI by demonstrating that excess iodine contributes to autophagy suppression and apoptosis of thyroid follicular cells using a cell line of human thyroid follicular epithelial cells. The pathogenesis of KI-induced PT is unclear but may be related to this cytotoxic effect of KI. In addition, because 10 of the 11 patients in our current study with KI-induced PT were positive for TgAb and/or TPOAb, an autoimmune mechanism may be involved in this process…Finally, we emphasize that clinicians who manage GD patients who received KI after discontinuing ATD due to side effects, should be alert for KI-induce PT.(32)

Conclusion:  Another error in Modern Thyroid Endocrinology is ignoring the use of KI (potassium iodide) in treatment of Graves’ Disease. Ki is safer the ATD drugs, and can achieve good response in 60 percent of females with mild Graves Disease. Dr. Okamura makes a brilliant case for the first line use of Iodine for Graves’ Disease. Firstly, Iodine is safer than thyroid blocking drugs. Secondly, early responders, enjoy a high complete remission rate. For those patients who escape or are resistant to Iodine, Dr Okamura presents a clear and well thought out protocol adding a second drug, methimazole to the Iodine, or if that fails, radioiodine ablation. One wonders what would have been the escape rate if all patients had been given selenium, magnesium and vitamin D, Vitamin C and tested for H Pylori and Anti-Gliadin antibodies?  Another question, what is escape rate with the Lithium/Iodine combination compared to Iodine alone ? (6-8)

Another error of modern endocrinology is failure to recognize the benefits of Block and Replace in reducing TSH and preventing generation of hydrogen peroxide induced thyroiditis as described in Dr. Ken Okamura’s study. (4)

Regarding “Escape” from the Inhibitory effects of iodine in Graves’ Disease patients, Dr Okamura proposes many of these cases are PI, Painless Thyroiditis with low radio-iodine uptake.  This occurs frequently when switching from MMI to KI and is thought related to toxic effect of excess iodine or auto-immune factors.

Our state of knowledge is still incomplete, and we have many more questions than answers. One can can only hope that basic science will continue to uncover knowledge about thyrotoxicosis and its treatments, and bring a better understanding of underlying pathophysiology.

Natural Thyroid Toolkit

If you liked this article, you might like my new book, Natural Thyroid Toolkit available on Amazon. If you purchase a book, remember to  leave a favorable review. That would be much appreciated. See the book cover, left image.

Jeffrey Dach MD
7450 Griffin Road, Suite 180
Davie, Fl 33314

Articles with Related Interest

Lithium Iodine Combination Treatment for Graves Disease

Addressing the AutoImmune Component of Thyroid Disease

Graves Disease Remission with Iodine Part One

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314

header image courtesy of wikimedia : thyroiditis


Note on definitions: Autoantibodies to thyroglobulin (Tg) (TGHA) and thyroid microsomal antigen (MCHA).Group A: KI-sensitive patients with recovered serum TSH. Group B: KI-sensitive patients with suppressed serum TSH. Group C: KI resistant patients. Escape: Re-elevation of the serum fT4 and/or fT3 levels after temporary reduction in serum fT4 levels while taking 100 mg KI within 180 days.

  1. Yoshihara, Ai, et al. “Substituting potassium iodide for methimazole as the treatment for Graves’ disease during the first trimester may reduce the incidence of congenital anomalies: a retrospective study at a single medical institution in Japan.” Thyroid 25.10 (2015): 1155-1161
  2. Yoshihara, Ai, et al. “Characteristics of Patients with Graves’ Disease Whose Thyroid Hormone Levels Increase After Substituting Potassium Iodide for Methimazole in the First Trimester of Pregnancy.” Thyroid: official journal of the American Thyroid Association 30.3 (2020): 451-456.
  3. Pearce, Elizabeth N. “Substituting Potassium Iodide For Methimazole In First-Trimester Pregnant Women With Graves’ Disease May Unpredictably Worsen Hyperthyroidism.” Clinical Thyroidology 32.3 (2020): 117-119.
  4. Okamura, Ken, et al. “Iodide-sensitive Graves’ hyperthyroidism and the strategy for resistant or escaped patients during potassium iodide treatment.” Endocrine Journal (2022): EJ21-0436.
  5. Okamura, Ken, et al. “Painless thyroiditis mimicking relapse of hyperthyroidism during or after potassium iodide or thionamide therapy for Graves’ disease resulting in remission.” Endocrine Journal (2022): EJ22-0207.
  6. Sharma, Pranjali P. “Use of Lithium in Hyperthyroidism Secondary to Graves’ Disease: A Case Report.” The American Journal of Case Reports 23 (2022): e935789-1.
  7. Nair, Gopalakrishnan C., et al. “Preoperative preparation of hyperthyroidism for thyroidectomy–Role of supersaturated iodine and lithium carbonate.” Indian Journal of Endocrinology and Metabolism 22.3 (2018): 392.
  8. Boehm, Timothy M., et al. “Lithium and iodine combination therapy for thyrotoxicosis.” European Journal of Endocrinology 94.2 (1980): 174-183.
  9. Vasiliu, Ioana, et al. “Protective role of selenium on thyroid morphology in iodine‑induced autoimmune thyroiditis in Wistar rats.” Experimental and therapeutic medicine 20.4 (2020): 3425-3437.
  10. Xu, Jian, et al. “Selenium supplement alleviated the toxic effects of excessive iodine in mice.” Biological Trace Element Research 111.1 (2006): 229-238.
  11. Xu, Jian, et al. “Intervention of selenium on injured thyroid hormone metabolism by excessive iodine.” Journal of Hygiene Research 38.4 (2009): 398-400.
  12. Xu, Jian, et al. “Supplemental selenium alleviates the toxic effects of excessive iodine on thyroid.” Biological trace element research 141.1 (2011): 110-118.
  13. Wang, Weiwei, et al. “Effects of selenium supplementation on spontaneous autoimmune thyroiditis in NOD. H-2h4 mice.” Thyroid 25.10 (2015): 1137-1144.
  14. Duntas, L. H. “The role of iodine and selenium in autoimmune thyroiditis.” Hormone and Metabolic Research 47.10 (2015): 721-726.
  15. Vanderpas, Jean B., et al. “Iodine and selenium deficiency associated with cretinism in northern Zaire.” The American journal of clinical nutrition 52.6 (1990): 1087-1093.
  16. Vanderpas, Jean-Baptiste, et al. “Iodine and selenium deficiency in northern Zaire.” The American journal of clinical nutrition 56.5 (1992): 957-958.
  17. Contempre, Bernard, et al. “Effects of selenium deficiency on thyroid necrosis, fibrosis and proliferation: a possible role in myxoedematous cretinism.” European Journal of Endocrinology 133.1 (1995): 99-109.
  18. Contempre, Bernard, et al. “Selenium deficiency aggravates the necrotizing effects of a high iodide dose in iodine deficient rats.” Endocrinology 132.4 (1993): 1866-1868.
  19. Davcheva, Delyana M., et al. “Serum selenium concentration in patients with autoimmune thyroid disease.” Folia Medica 64.3 (2022): 443-449.
  20. Bogusławska, Joanna, et al. “Cellular and molecular basis of thyroid autoimmunity.” European Thyroid Journal 11.1 (2022).
  21. Negro, Roberto. “Selenium and thyroid autoimmunity.” Biologics: Targets and Therapy 2.2 (2008): 265-273.
  22. Kimura, T. A. K. A. O., et al. “Thyrotropin-induced hydrogen peroxide production in FRTL-5 thyroid cells is mediated not by adenosine 3′, 5′-monophosphate, but by Ca2+ signaling followed by phospholipase-A2 activation and potentiated by an adenosine derivative.” Endocrinology 136.1 (1995): 116-123.
  23. Tsatsoulis, Agathocles. “The role of iodine vs selenium on the rising trend of autoimmune thyroiditis in iodine sufficient countries-an opinion article.” Open Acc J Thy Res 2.1 (2018): 12-14.
  24. Vasiliu, Ioana, et al. “Protective role of selenium on thyroid morphology in iodine‑induced autoimmune thyroiditis in Wistar rats.” Experimental and therapeutic medicine 20.4 (2020): 3425-3437.
  25. Giammanco, Marco, and Manfredi M. Giammanco. “Selenium: A Cure for Autoimmune Thyroiditis.” Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets-Immune, Endocrine & Metabolic Disorders) 21.8 (2021): 1377-1378.
  26. Edmunds, H. Tudor. “Acute thyroiditis from potassium iodide.” British Medical Journal 1.4909 (1955): 354.
  27. Gluck, Franklin B., Martin L. Nusynowitz, and Stephen Plymate. “Chronic lymphocytic thyroiditis, thyrotoxicosis, and low radioactive iodine uptake: report of four cases.” New England Journal of Medicine 293.13 (1975): 624-628.
  28. Savoie, J. C., et al. “Iodine-induced thyrotoxicosis in apparently normal thyroid glands.” The Journal of Clinical Endocrinology & Metabolism 41.4 (1975): 685-691.
  29. Skare, ståle, and Harald MM Frey. “Iodine induced thyrotoxicosis in apparently normal thyroid glands.” European Journal of Endocrinology 94.3 (1980): 332-336.
  30. Shilo, S., and H. J. Hirsch. “Iodine-induced hyperthyroidism in a patient with a normal thyroid gland.” Postgraduate Medical Journal 62.729 (1986): 661.
  31. Suzuki, Nami, et al. “Therapeutic efficacy and limitations of potassium iodide for patients newly diagnosed with Graves’ disease.” Endocrine Journal 67.6 (2020): 631-638.
  32. Kamijo, Keiichi. “Clinical Studies on Potassium Iodide-induced Painless Thyroiditis in 11 Graves’ Disease Patients.” Internal Medicine 60.11 (2021): 1675-1680.
  33. Calvi, Laura, and Gilbert H. Daniels. “Acute thyrotoxicosis secondary to destructive thyroiditis associated with cardiac catheterization contrast dye.” Thyroid: official journal of the American Thyroid Association 21.4 (2011): 443-449.
  34. Bogazzi, Fausto, et al. “Glucocorticoids are preferable to thionamides as first-line treatment for amiodarone-induced thyrotoxicosis due to destructive thyroiditis: a matched retrospective cohort study.” The Journal of Clinical Endocrinology & Metabolism 94.10 (2009): 3757-3762.
  35. Medić, Filip, et al. “Amiodarone and Thyroid Dysfunction.” Acta clinica Croatica 61.2 (2022): 327-341.
  36. Mushref, Malek, Kathrin Sandra Tofil, and Kathie Lynn Hermayer. “Amiodarone Induced Thyrotoxicosis: A Case of Refractory Disease Treated With Thyroidectomy.” Journal of the Endocrine Society 5.Supplement_1 (2021): A920-A920.
  37. Henzen, C., M. Buess, and L. Brander. “Iodine-induced hyperthyroidism (iodine-induced Basedow’s disease): a current disease picture.” Schweizerische Medizinische Wochenschrift 129.17 (1999): 658-664.
  38. Meng, Zhaowei, et al. “Differentiation between Graves’ disease and painless thyroiditis by diffusion-weighted imaging, thyroid iodine uptake, thyroid scintigraphy and serum parameters.” Experimental and therapeutic medicine 9.6 (2015): 2165-2172.
  39. Yang, Ji Wei, and Jacques How. “Lugol’s solution-induced painless thyroiditis.” Endocrinology, Diabetes & Metabolism Case Reports 2017 (2017).
  40. Hiraiwa, Tetsuya, et al. “High diagnostic value of a radioiodine uptake test with and without iodine restriction in Graves’ disease and silent thyroiditis.” Thyroid: official journal of the American Thyroid Association 14.7 (2004): 531-535.
  41. Yang, Ji Wei, and Jacques How. “Lugol’s solution-induced painless thyroiditis.” Endocrinology, Diabetes & Metabolism Case Reports 2017 (2017).
  42. LEUSTEAN, Letitia, et al. “Jod-Basedow effect due to prolonged use of lugol solution-case report.” The Medical-Surgical Journal 118.4 (2014): 1013-1017.
  43. Uchida, Toyoyoshi, et al. “Therapeutic effectiveness of potassium iodine in drug-naïve patients with Graves’ disease: a single-center experience.” Endocrine 47 (2014): 506-511.
  44. Suwansaksri, Nattakarn, Lukana Preechasuk, and Tada Kunavisarut. “Nonthionamide drugs for the treatment of hyperthyroidism: from present to future.” International journal of endocrinology 2018 (2018).
  45. Mao, Xiao-Ming, et al. “Prevention of relapse of Graves’ disease by treatment with an intrathyroid injection of dexamethasone.” The Journal of Clinical Endocrinology & Metabolism 94.12 (2009): 4984-4991.
  46. Roti, E., et al. “Effects of chronic iodine administration on thyroid status in euthyroid subjects previously treated with antithyroid drugs for Graves’ hyperthyroidism.” The Journal of Clinical Endocrinology & Metabolism 76.4 (1993): 928-932.
  47. Begum, Afsana, et al. “Thyroiditis, a Review.” Journal of Medicine 7.2 (2006): 58-63.  Differentiating Painless Thyroiditis from Graves Disease
  48. Honda, Akira, et al. “Relationship Between the Effectiveness of Inorganic Iodine and Severity of Graves Thyrotoxicosis : A Retrospective Study.” Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists 23.12 (2017): 1408-1413.
  49. Schaffer, Ashley, Vidya Puthenpura, and Ian Marshall. “Recurrent Thyrotoxicosis due to Both Graves’ Disease and Hashimoto’s Thyroiditis in the Same Three Patients.” Case Reports in Endocrinology 2016 (2016).
  50. Penaherrera, Carlos A., and Valentina Rodriguez. “SAT-482 Simultaneous Hashimoto/Graves Disease or Prolonged Hashitoxicosis? A Diagnostic Challenge with Therapeutic Implications.” Journal of the Endocrine Society 4.Supplement_1 (2020): SAT-482.
  51. Baral, Neelam, Leonard Wartofsky, and Meeta Sharma. “SUN-560 Thyrotoxic Hashimoto’s Disease: Is It Graves’ Thyrotoxicosis or” Hashitoxicosis”?.” Journal of the Endocrine Society 3.Supplement_1 (2019): SUN-560.
  52. Takasu, N., et al. “Graves’ disease following hypothyroidism due to Hashimoto’s disease: studies of eight cases.” Clinical endocrinology 33.6 (1990): 687-698.
  53. Aye, Thant, Amy Glover, and Moulinath Banerjee. “A Challenging Case of Oscillating Hashimoto’s thyroiditis and Hyperthyroidism.” Endocrine Abstracts. Vol. 86. Bioscientifica, 2022.
  54. Methimazole PDR Dosage and Administration

    For the treatment of thyrotoxicosis, including hyperthyroidism, Graves’ disease, toxic multinodular goiter, and thyroid storm†. For the treatment of thyrotoxicosis, including hyperthyroidism, Graves’ disease, and toxic multinodular goiter. Oral dosage Adults

    5 to 10 mg PO once daily for free T4 1 to 1.5 times the upper limit of normal; 10 to 20 mg PO once daily for free T4 1.5 to 2 times the upper limit of normal; and 30 to 40 mg PO once daily for free T4 2 to 3 times the upper limit of normal, initially. A split dose may be more effective than a single daily dose when more rapid biochemical control is needed in persons with severe thyrotoxicosis. Taper dose to 5 to 10 mg/day as the patient becomes euthyroid.[61515] The FDA-approved dosage is 15 mg/day PO for mild hyperthyroidism; 30 to 40 mg/day PO for moderately severe hyperthyroidism; and 60 mg/day PO for severe hyperthyroidism divided every 8 hours, initially. Usual maintenance dose: 5 to 15 mg/day.

    Methimazole undergoes hepatic metabolism with no active metabolites. Renal excretion is < 10%. The elimination half-life is approximately 5—9 hours. However, the intrathyroidal residence of methimazole is roughly 20 hours, and the duration of action 40 hours, which allows once-daily dosing some patients.

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