Iodine Treatment of Graves’ Disease Part Two
Jeffrey Dach MD
One of the concerns about Iodine treatment of Graves Disease, is some patients do not respond to, or escape from the suppressive effects of iodine, leading to more difficult to treat thyrotoxicosis. This was decribed in a 2015 study by Dr. Ai Yoshihara of women during pregnancy, switching from Methimazole to Iodine. 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 Diease 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 to 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 (18.3%) were overly sensitive to iodine. The iodine rendered them hypothyroid. Efore treatment, the 92 patients were thyrotoxic with high Free T3 and T4 levels, and a suppressed, very low, TSH. After Iodine treatment, the thyroid hormone levels plummeted to very low, and the TSH rocketed up to very high levels. In the first half of the study, in 41 such patients with high TSH, the Iodine dosage was tapered down. However, 71% then relapsed into hyperthyroidism. In the second half of the study, for 39 “overly sensitive to iodine” patients, the iodine was no longer tapered down. Instead, these 39 patients were treated with Block and Replace, by adding levothyroxine to reduce the TSH. None of these 39 patients had relapse of hyperthyroidism. This is a justifiable use of Block and Replace. 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), 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)
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 – Strategy for KI-resistant and/or escaped patients: addition of low-dose thionamide
202 patients were considered have “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 combination of methimazole with KI, it was about 7 weeks until FreeT4 normalization.
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 writes:
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
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, methimazole 5-15 mg/day should be added to the Potassium iodide 100 mg/day. The addition of MMI to Iodine could overcome Iodine resistance or escape. In addition, Radioactive Iodine therapy was also effective to overcome iodine resistance. Note: escape means: 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 RI, as usual. We can minimize the use of thionamide with serious side effects by adopting the “KI or RI” strategy for the treatment of GD without impending serious symptoms. (4)
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. 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 (Table 3). Combined KI and MMI therapy is then recommended, as a 33%–82% chance of escape is expected later…. (4)
Escape from Iodine or Painless Thyroiditis?
A second paper in 2022 also by Dr Ken Okamura makes the bold suggestion 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 the treatment dosage.
Dr Okamura reviewed 100 patients who presented unexpected relapsing hyperthyroidism while decreasing dosage while 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 was 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. Indeed, 70 per cent of Graves patients are also positive for Hashimoto’s antibodies. Dr Okamura writes:
GRAVES’ DISEASE (GD) and Hashimoto thyroiditis are recognized as being pathologically interrelated, as GD may occur in patients whose thyroid glands histologically show either Hashimoto 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)
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 would suggest the mechanism involves increased hydrogen peroxide activity 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 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) Note: in PT, thyroid blocking drugs are usually considered contraindicated.
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. 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), levothyroixine is added. Thyroid hormone medication will suppress the TSH, and alleviate the TSH stimulation to generate hydrogen peroxide. Block and Replace is a logical treatment to avoid episodes of hyperthyroidism from PT (thyroiditis) and prevent alternating extremes of thyroid function, the undulating course, seen in many patients with Graves’ disease.
Conclusion: Another error in Modern Thyroid Endocrinology is ignoring the use of Iodine in treatment of 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 an 80 per cent remission rate. For those patients who escape or are resistant to Iodine, Dr Okamura provides us with 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, and tested for H Pylori and Anti-Gliadin antibodies? Another question, what would the iodine escape rate had been if Lithium Carbonate had been combined with the potassium iodide? (6-8)
Articles with Related Interest
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.
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- 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.
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Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
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