Graves Hyperthyroidism Remission with Iodine Part One

Graves’ Hyperthyroidism Remission with Iodine Part One

Case Report

Carol is a 56-year-old real estate agent who noticed a feeling of nervousness, warmth and rapid heart rate which worsened over a few days.  Carol called a friend who drove her to the Emergency Room where the doctors gave her propranolol, a Beta Blocker drug which slowed her heart rate, and she felt more comfortable. Lab testing showed elevated Free T3, Free T4, suppressed TSH confirming thyrotoxicosis. Carol was sent home with an appointment to see an endocrinologist a week later. left image iodine courtesy of wikimedia commons.

The Endocrinologist

The endocrinologist saw Carol and ran a thyroid lab panel showing a suppressed TSH of .001 mU/L. Other lab tests showed a Free T3 of 1200 pg/dL (normal less than 420) and a FreeT4 of 4.4 ng/dl (normal less than 1.8), both markedly elevated.  Her Thyroid Stimulating Immune-globulin (TSI) and TRAb test were very elevated, indicating Graves’ Hyperthyroidism. This is an autoimmune disease in which antibodies attack and stimulate the TSH receptor of the thyroid gland causing thyrot oxicosis, excessively high thyroid hormone production. Carol’s endocrinologist started her on a thyroid blocking drug, Methimazole 30 mg daily.

Carol Goes to a Health Resort

Unhappy with conventional treatment, Carol traveled to a Health Ranch in Arizona specializing in organic raw vegetarian meals and fresh vegetable juices.  She went to daily yoga classes, meditation and sauna treatments.  The doctor at the Health Resort started Carol on a vitamin supplement program for her thyroid condition which included a potassium iodide capsule containing 65 mg of iodide.

Carol Starts to Feel Better !!

At the Health Ranch, Carol started feeling much better, almost normal, and her repeat her lab panel showed the TSH had gone back up to the normal range of 3.2 mU/L.  The other thyroid labs, the FreeT3 and FreeT4 had also normalized.  However, the TSI and TRAb antibodies remained quite elevated with little change.

Carol returned home and visited the endocrinology office.  Her endocrinologist reviewed the labs, and then stopped the methimazole thyroid-blocking drug.  He said it was no longer needed.  However, the Graves’ antibodies, the TRAb and TSI thyroid stimulating antibodies, were still very elevated, so the endocrinologist recommended a thyroidectomy, a surgical procedure to remove the thyroid gland.  Carol was unhappy with this recommendation.  She was not keen on having thyroid surgery, and came to see me in the office to get a second opinion.

Coming for a Second Opinion

This case illustrates the beneficial effect of potassium iodide for Graves’ Disease, showing complete remission with a 65 mg potassium iodine tablet given at a health resort as part of a vitamin program.

Symptoms  of Graves’ Thyrotoxicosis

Typical symptoms of thyrotoxicosis include: Weight loss, Nervousness, Rapid Heart Rate, Palpitations, Feeling hot, Sweatiness, Loose bowel movements, Poor stamina, Restlessness, Breathlessness, Tremulousness, Poor concentration, loss of appetite.

Signs of Graves Thyrotoxicosis

Typical signs of thyrotoxicosis include:  Weight loss,Tachycardia, Sweating, Fine tremor, Atrial fibrillation, Apathy (older people), Goiter, Exopthalmos (Eye signs)* , Pretibial* dermopathy, Finger clubbing*

*Features specific to Graves’ disease (1)

The History of Iodine Use for Hyperthyroidism- Exopthalmos Goiter

1811- Discovery of Iodine by Courtois. In 1811, Bernard Courtois, a French chemist accidentally discovered a purple substance which he named, Iodine. (2)

1863 – Dr. Trousseau Accidentally Discovers Iodine Treats Thyrotoxicosis of Graves’ Disease.

In 1863, Trousseau was called to visit a sick woman with tachycardia (rapid heart rate) caused by Graves’ Disease.  Dr. Trousseau intended to write a prescription for tincture of Digitalis to slow the heart rate, but instead wrote for tincture of Iodine by mistake.  Upon initial examination, the woman’s heart rate was 140 to 150 times per minute.   When Trousseau returned the next day, the lady’s heart rate had slowed to normal.  It was then he realized his mistake and discovered over night the patient had taken 75-100 mg of Iodine.  He cancelled the Iodine and again prescribed tincture of Digitalis.

The next day, Trousseau again examined the patient and found the pulse had again gone up to 150 beats per minute.  Trousseau realized the Iodine induced a beneficial slowing of the heart rate, and remission of hyperthyroid symptoms.  Trousseau then returned to the use of iodine, placing the patient back on her original iodine prescription. (2-3)

How Does Iodine Work in Graves’ Disease? What is the Mechanism of Inhibition?

It has been more than 150 years since Trousseau’s accidental discovery of the inhibitory effect of Iodine on hyperthyroidism in Graves’ Disease patients.  The question you might ask is: How does it work? What is the mechanism of inhibition?  A basic science study by Corvilain in 1988 explains that Iodide inhibits hydrogen peroxide generation in the thyroid follicle, an important step in the organification of iodine to the thyroglobulin molecule, and the production of thyroid hormone.(4)

In 1981, Dr. Chiraseveenuprapund studied the hydrogen peroxide generating system in bovine thyroid slices under conditions of iodine excess, finding that iodide inhibited its own organic binding,also called organification. However this inhibition was prevented by high TSH levels, which stimulates the generation of hydrogen peroxide. His findings suggested the inhibition of organic binding by iodine was due to diminished generation or decreased availability of hydrogen peroxide.  This study suggests that a high TSH level stimulating generation of hydrogen peroxide may result from overtreatment with MMI or iodine, and this may be the causative factor in iodine escape or iodine resistance in the iodine treated Graves’ disease patient. A high TSH after treatment with a thyroid blocking drug would then justify the use of “Block and Replace”:

In bovine thyroid slices, the inhibition of organic binding of iodide by excess iodide in the range 5–10 μg/ml was prevented by incubating the slices in the presence of TSH…TSH and hydrogen peroxide enhanced the synthesis of both iodotyrosines and iodothyronines [organification]. … These findings suggest that the inhibition of organic binding of iodine in the presence of excess iodide may be due to a diminished generation or a decreased availability of hydrogen peroxide in the thyroid.(100)

Excess Iodine Inhibits Release of Thyroid Hormone

In addition, Iodine inhibits release of thyroxine (T4) from the thyroid gland, first demonstrated in 1970 by Wartofsky who showed reduction in T4 levels. The iodine induced inhibition of T4 release is independent of treatment with other thyroid blocking drugs such as Methimazole.(5)

This inhibition of thyroid hormone release by Iodine was studied in vitro in 1985 by Dr. Bagchi finding inhibition of thyroglobulin hydrolysis, a key step in thyroid hormone release which is stimulated by the TSH hormone.  Dr Bagchi writes:

Thyrotrophin (TSH) administered in vivo acutely stimulated the rate of thyroglobulin hydrolysis. Addition of NaI (sodium iodide) to the culture medium acutely inhibited both basal and TSH-stimulated thyroglobulin hydrolysis. The effect of iodide was demonstrable after 2 h, maximal after 6 h and was not reversible upon removal of iodide. (6) Emphasis Mine.

Thus, by inhibiting both organic binding of iodine as well as thyroid hormone release, thyroid hormone levels decline promptly after excess potassium iodide (KI) administration, accounting for its success in treating Graves’ Hyperthyroidism.

Here I should mention that the inhibitory effect of KI works best in Graves’ and Hashimotos’ autoimmune thyroid disease patients in whom thyroid auto-regulation has been lost.

Fortunately, in healthy normal patients, the inhibitory effect of KI is only temporary. Thyroid auto-regulation compensates for the increased intra-thyroidal iodide by decreasing the activity of the NIS (sodium iodide symporter) the active transport for Iodine into the thyroid cells. This type of autoregulation is mediated by formation iodo-lactones by the high intracellular iodide levels as discussed in 1996 by Dr. Dugrillon.(92)

In normal healthy patients, the autoregulatory reduction in NIS (sodium iodide synporter) activity reduces iodine uptake and reduces concentration of iodine in the thyroid gland. The elevated TSH and low serum hormone levels eventually return to normal after about 2-4 weeks, a phenomenon called “Escape from the Wolf Chaikoff Effect”.

Autoregulation Lost in AutoImmune Thyroid Disease

As mentioned above, in some patients this auto-regulatory function has been lost, such as in auto-immune thyroid patients with Graves’ Disease or Hashimoto’s Disease. In Graves’ Disease patients in whom high dose iodine for treatment of thyrotoxicosis is successful, iodine continues its inhibitory function, without escape, indicating loss of autoregulation with inability to compensate. Others types of patients with loss of autoregulation include following an episode of thyroiditis, and following radio-iodine thyroid ablation. (7-8)

Early Use Iodine for Treatment of Graves’ Disease.

In 1920’s  Drs. Plummer, Starr, Lahey and Charles Don  reported success with high dose Iodine in treating Graves’ Disease using Lugol’s Solution.(9-13)

In the 1930’s and 1940’s, successful use of Iodine to treat Graves’ Hyperthyroidism was reported by Drs. Thompson  and Redisch. (14-15)

Iodine Contra-Indicated for Toxic Nodular Goiter and Autonomous Nodule

In 1940, Dr. Redisch reported the importance of distinguishing Graves’ hyperthyroidism from toxic nodular goiter. Both may cause thyrotoxicosis. However, while iodine may be used to treat Graves Disease, Iodine is contra-indicated in Toxic Nodular Goiter. Dr. Redisch writes:

Iodine should never be given to patients with old nodular goiters become toxic. (15)

The reason for this is the toxic nodular goiter has one or more autonomous nodules which harbor a mutation in the TSH receptor.  These autonomous nodules convert iodine into thyroid hormone rapidly and uncontrollably, outside of normal TSH control.  When such a patient consumes iodine, it makes their hyperthyroidism worse, and they become thyrotoxic.  Toxic nodular goiter is an absolute contraindication to the use of KI. This topic is discussed more completely in the chapter on the Autonomous Nodule. (16-19)

The Autonomous Thyroid Nodule

In the patient with thyrotoxicosis caused by the autonomous thyroid nodule, the clinical history usually includes some form of Iodine exposure. Perhaps the patient recently obtained iodized salt or iodine supplements from the health food store. Ultrasound thyroid Imaging usually shows a dominant thyroid nodule or multiple nodules.  Radionuclide imaging of the thyroid using Iodine-123 or Technetium 99M usually shows the “Hot Nodule” causing the thyrotoxicosis.  The toxic nodule may be solitary, or may be present against a background of multiple nodules, ie. toxic nodular goiter. (20-21)

Mechanism of KI Inhibition of Organification and Inhibition of Release

As mentioned above, Iodide Inhibits its own organification, as well as inhibits release of thyroid hormone from the thyroid gland. Inhibition of organification is done by inhibition of hydrogen peroxide production. In 1948, Drs. Wolff and Chaikoff published a report which concluded iodine inhibits organification, writing:

we do believe that our findings justify the conclusion that an interference in organic binding of iodine by the gland is an integral part of the mechanism by which iodine brings about a remission in Graves’ disease. (22) Emphasis Mine.

Inhibition of Release

The second mechanism of Iodine, namely, the inhibition of hormone release was proposed in 1970 by Dr. Wartofsky, and later confirmed in 1985 by Dr. Bagchi finding Iodine inhibits hydrolysis of thyroglobulin, thus decreasing secretion of thyroid hormone by the thyroid gland.  Hydrolysis of thyroglobulin in the major step in release of thyroid hormone. (5-6)

Microscopic Appearance of Thyroid in Graves’ Disease

On microscopic evaluation of the thyroid gland in Graves’ Disease, one sees hyperplasia of thyroid cells lining the follicular spaces.  The thyroid follicles are the spherical areas for collection and storage of thyroglobulin, the precursor to thyroid hormone. In order to release thyroid hormone into circulation, the thyrocytes take in the thyroglobulin, liberate the free thyroid hormone through a process of enzymatic digestion called hydrolysis to yield thyroxine, T4 which can be released into the blood stream.

Diffusely Enlarged Hyperactive Thyroid Gland

The thyroid cells lining the follicles are the worker cells that secrete thyroglobulin into the follicles. In Graves’ Disease, thyroid cells lining the follicles are enlarged and more numerous, the result of stimulation from TSH receptor antibodies (TSI and TRAB antibodies). Although high TSH (thyroid stimulating hormone) will cause an increase in hydrogen peroxide generation, the anti-TSH Receptor antibodies in Graves’ Disease DO NOT increase hydrogen peroxide generation. Rather this is done by TSH hormone itself. In Graves’ Disease, auto-antibodies stimulate the TSH Receptor making the follicles and entire gland larger. At first clinical presentation, the thyroid gland in Graves’ Disease is diffusely enlarged (diffuse epithelial hyperplasia) and hypervascular, without the lymphocytic infiltrates as usually seen in Hashimotos’ thyroiditis. Over many years, this pristine histology may change.

Graves Disease After Treatment

Once under treatment however, the histology of the thyroid gland in Graves’ disease may change.  For example, in 1986 Dr Hirota studied thyroid histology after long term methimazole treatment and repeated bouts of thyroiditis, finding  diffuse epithelial hyperplasia was no longer seen, as this was replaced with chronic lymphocytic thyroiditis.(24)

After I-131 therapy for Graves Disease, the histology pattern changes to multiple adenomatous nodules, some with cystic changes, with various degrees of chronic thyroiditis. (25)

After treatment with potassium iodide in Graves Disease, follicular cells revert back to their normal shape, and some of the hyperplastic features regress. In 2009, Dr Thompson writes:

Potassium iodide causes involution, as follicular cells revert to their normal cuboidal or flattened appearance, alternating with areas that have retained some of the features of hyperplasia. (23-26)

Is It Graves’ Disease or Autonomous Nodule ?

The most reliable way to differentiate Grave’s Disease from Toxic Nodular Goiter is the serum antibody tests for TRAb and TSI antibodies. With only rare exceptions, Graves’ disease will show elevated TRAb while autonomous nodule will not.  The ultrsound scan will show a nodule, and the radionuclide scan will show the nodule is “hot’ with greater activity in the nodule than the surrounding thyroid tissue.

Using the Radioactive Iodine Uptake to Differentiate Hashitoxicosis from Graves’ Disease.

Hashitoxicosis is thyrotoxicosis in a Hashimotos patient and may be confused with the thyrotoxicosis of Graves disease. Hashitoxicosis can be differentiated from Graves’ thyrotoxicosis by doing a radionuclide uptake scan with I-123 or technetium 99M. The 24 hr. radioactive iodine uptake is high in Graves’ Disease (over 50%), and very low in Hashitoxicosis (less than 5%) as reported in 2016 by Dr. Ashley Schaffer. (86)

The low radio-iodine uptake of hashitoxicosis is similar to that seen in subacute thyroiditis which is less than 1 per cent as discussed in 1998 by Dr. Douglas Ross writing:

mechanism of thyrotoxicosis in subacute thyroiditis is inflammation of thyroid follicles with release of preformed hormone into the circulation. In this group of disorders, the 24-hour radioiodine uptake is almost always less than 1%.(87-89 )

In 1975 Dr. Savoie, and in 1980 Dr. Skare reported low radio-iodine uptake in a cases of iodine induced thyrotoxicosis in apparently normal thyroid glands. The low radio-iodine uptake indicates thyroiditis, however, the authors were unable to explain the mechanism or cause. I would speculate these cases of thyroiditis in “normal thyroid glands” are related to selenium and iodine deficiency.  These thyroid glands are unable to neutralize the excess hydrogen peroxide induced by an acute iodine load. In the future, measuring selenium and iodine levels in these types of cases might be useful.(90-91)

Ultrasound Imaging

In toxic nodular goiter, ultrasound imaging will show a typical appearance of multiple thyroid nodules. If a radionuclide scan is done, one of nodules may stand out a “hot nodule” against a background of variable reduced uptake. This is the autonomous nodule. In Graves’ Disease, however, the radionuclide thyroid scan will typically show a smooth, diffusely enlarged thyroid gland with increased radiotracer uptake. Occasionally, in long standing Graves’ disease after many years of medical treatment, nodules may also be present.  Palpation of the thyroid gland in Graves’ Disease will typically reveal a diffuse, smoothly enlarged gland. On the other hand, in the patient with Toxic Multi-Nodular Goiter, the thyroid gland is usually irregular and bumpy with either solitary or multiple nodules on palpation which are also easy to demonstrate with imaging. (20-21)

Graves’ Disease TSI and TRAb Antibodies

As mentioned above, Graves’ Disease is an autoimmune thyroid disease with anti-thyroid antibodies specific for the TSH Receptor. The two antibody tests for Graves’ disease are the TSI, Thyroid Stimulatory Immune Globulin, and the TRAb, Thyroid Receptor Antibody test. The newer TRAb test, is specific for Graves’ Disease.  The TRAb antibodies come in three varieties, stimulatory, inhibitory and neutral. Unfortunately, the TRAb test cannot distinguish between these three types.  However, if the thyroid gland is smoothly enlarged without nodularity and the TSI and TRAb are elevated, this is a most reliable way to make to make the diagnosis of Grave’s Disease and exclude Toxic Nodular Goiter. Persistent elevation of TRAb antibody following the end of methimazole treatment is associated with a 50% chance for relapse. (26-31)

In 2004, Dr Wallaschofski from Germany writes the TRAb test should be performed on all patients to differentiate Graves’ from Toxic Multinodular Goiter, writing:

the h-TBII (TRAb antibody test) should be performed in all patients with hyperthyroidism to differentiate Graves’ disease from non-autoimmune hyperthyroidism such as toxic multinodular goitre. (27)

Graves’ Orbitopathy

In some patients, these same antibodies (TSI and TRAb) attack the extra-ocular muscles and peri-orbital fat. This causes inflammation and enlargement of the muscles behind the eye which control eye movement, pushing the eye forward, causing the characteristic exophthalmos, a medical term for “the eyes bulging out”. There may be proptosis and lid retraction with a reddened inflamed conjunctiva resembling dry eye syndrome. If severe, the optic nerve can be compromised at the orbital apex resulting in loss of vision.  Studies show the fibroblast cells in the peri-orbital fat contain TSH Receptors in Graves Orbitopathy.  Other fat and connective tissue areas of the body may contain TSH receptors explaining pretibial myxedema, and thyroid acropachy seen on examination. In 2006, Dr. Tani writes:

autoimmunity against TSH-r [TSH Receptor], expressed in fat and connective tissue, could explain the development of pretibial myxedema, acropachy and the OCT [Orbital Connective Tissue] component of TAO [thyroid-associated ophthalmopathy]. (32-36)

Modern Treatment of Hyperthyroidism

Prior to 1980, Lugol’s Iodine was the treatment of Graves’ Disease.  After 1980, these were replaced by anti-thyroid drugs, the thionamides such as PTU (propylthiouracil) and Methimazole (Tapazole).  Lugol’s Iodine or Potassium Iodide is still in use today as a short-term treatment, for pre-operative preparation of the thyrotoxic Graves’ patient for thyroidectomy, usually in the hospital setting. The standard dosage is 50 mg of potassium iodide three times a day for 10 days prior to thyroidectomy. The Iodine is given with Beta Blockers to control heart rate, and methimazole or PTU may also be added as needed. In 2009, Dr. Sinem Kiyici reported the use of Lugol’s Iodine in combination with anti-thyroid drugs for preparation of the hyperthyroid patient for thyroidectomy. Note, this is short term use only.  Long term use of Lugol’s is avoided here because of the chance for rebound, or escape from the suppressive effects of iodine. Dr. Sinem Kiyici writes:

lugol [iodine] treatment with and without antithyroid drugs is safe and effective choice in rapid preparation of patients with hyperthyroidism to thyroidectomy when surgery cannot be delayed. (37-39)

Long term Use of Iodine for Graves’ Disease

In Japan the use of Potassium Iodide for long term treatment of Graves’ disease is widely accepted by thyroid specialists, However, in the United States long term use of Iodine for Graves’ disease is not accepted by conventional endocrinology for fear of iodine escape, also called “rebound effect”.  (40-41)

Thyroid Ablation with Radio-Active Iodine or Surgery

Thyroid ablation is considered definitive treatment and consists of two techniques.The first is surgery with thyroidectomy. The second is radioactive iodine. Both forms of thyroid ablation leave the patient hypothyroid requiring life-long thyroid hormone replacement, usually with levothyroxine.

Radioablation of the thyroid gland is performed by giving the patient a   radioactive Iodine (I-131) capsule by mouth. The thyroid gland takes up and concentrates the radioactive iodine, causing radiation damage to the thyroid gland. Afterwards, the patient is usually in a hypothyroid state requiring lifelong Levothyroxine treatment. Because of convenience, and ease of use with rare adverse side effects, radioactive iodine (I-131) has been the popular choice for the hyperthyroid patient. About 80% of patients achieve “remission” with a single dose of Iodine-131. The remaining 20% treatment failures require a second dose of I-131. Treatment failure is most commonly associated with very high levels of TRAb antibodies (an indicator of severity of the auto-immune disease) and patients with the larger goiters. These patients may opt for thyroidectomy rather than radioablation. Pretreatment with Lithium Carbonate increases Iodine-131 retention in the thyroid gland and is thought to make radioactive iodine more effective. (42)

Radioactive Iodine May Worsen Graves Orbitopathy

In 2013, Clinical Thyroidology,  Dr. Jerome M. Hershman cites studies from Italy showing radioactive-Iodine may worsens Thyroid Eye Disease. For this reason, patients with thyroid eye disease may choose thyroidectomy rather than radioablation. Selenium supplementation has been found beneficial for thyroid eye disease. A new Intravenous drug has recently been approved to treat Graves orbitopathy, the IGF Receptor blocker drug, Teprotumumab. (43-46)


Surgical Treatment for Graves’ Disease

Many Graves Disease patients will decide on thyroidectomy because it provides rapid and definitive control of hyperthyroidism.  Of course, thyroidectomy renders patients hypothyroid requiring lifelong thyroid hormone replacement. Thyroidectomy is not without risk for post-operative complications. The procedure may cause parathyroid glands to be removed or damaged resulting in hypocalcemia, treated with calcium tablets.  A second post operative complication is unintended injury to the recurrent laryngeal nerve causing temporary or permanent hoarseness. In 2019, Dr.  Calogero Cipolla from Palermo Italy did a single center retrospective review of 594 cases of total thyroidectomy for Graves’ Disease, writing:

Temporary and permanent hypocalcaemia developed in 241 (40.6%) and 3 patients (0.5%), respectively. Temporary and permanent recurrent laryngeal nerve palsy were recorded in 31 (5.2%) and 1 patient (0.16%) respectively…. This high-volume surgeon experience demonstrates that total thyroidectomy is a safe and effective treatment for Graves’ disease. It is associated with a very low incidence rate of post-operative complications, most of which are transitory; therefore, it offers a rapid and definitive control of hyperthyroidism and its related symptoms. (47)

Iodine Alone in Treatment of Grave’s Disease

In 2000, Dr. Jamieson reported on the successful treatment of Graves’ disease in pregnancy with Lugol’s iodine.(48)

In 2013, Dr. Gangadharan reported on the use of Iodine as first line therapy in a child with Graves’ Disease. Thionamide drugs were contraindicated because of neutrapenia. (49)

However, others have concluded concluded Iodine alone is not an ideal treatment for long term control of hyperthyroidism.

In 1975, Dr Charles Emerson studied serum hormone levels during Iodine treatment of 9 patients with hyperthyroidism.  Thyroid hormone levels fell initially in all 9 patients. However, after 11 days or so, levels began to rise again in 6 of the 9. In the remaining 3, thyroid hormone levels remained suppressed.  Dr. Emerson wrote:

These data support the concept that iodide alone is not an ideal agent for the treatment of hyperthyroidism. (50)

In 1992, Dr. George Phillppou studied 21 hyperthyroid patients given 150 mg of potassium iodide daily, compared to 12 healthy controls.  For the first three weeks, the 21 patients had a good response with a decline in thyroid hormone levels.  However, after 21 days, the Free T3 and Free T4 levels started increasing again in some cases. Dr. Phillppou concludes:

Iodides in hyperthyroidism have a variable and unpredictable intensity and duration of antithyroid effect. Their antithyroid effect is smaller in normal controls. (51)

Long Term Use of Iodide Alone, or Combined with Methimazole

In 2014, Dr. Ken Okamura in Japan treated 1388 patients with thionamides (methimazole) for Graves Hyperthyroidism.  However, 44 patients of the 1388 discontinued methimazole because of adverse side effects. These patients were then switched to KI (potassium iodide) long term at a dosage 10-400 mg/d, and followed for 8 to 28 years (median 17.6 years).

29 or 65% per cent of these 44 patients were well controlled with Iodide alone, and of these, about 40% of went into remission after an average of 7.4 years. The other 15 of the 44 patients (30%) could not be controlled with Iodide alone, even at high dosage (100-750 mg/d).  However, 7 of the 15 were controlled with a combination of Iodide and low dose methimazole for a few years, and then with iodide alone, resulting in remission after 7 years (2-11 years). The other seven were treated with radioactive iodine (I-131) uneventfully, after a period of iodine restriction.  Dr. Okamura felt that the effect of suppressive effect of methimazole and iodine were additive. He writes:

our clinical study suggested that the effects of thionamides [methimazole] and excess iodide are additive when a large amount of iodide required for the Wolff-Chaikoff effect is administered concomitantly… prompt re-evaluation of the treatment was required when escape occurred or thyrotoxicosis remained for more than 3 months requiring more than 200 mg KI. (27) Emphasis Mine. Note: The Wolff-Chaikoff effect refers to the suppressive effect of iodine on thyroid function.(52)

Block and Replace

For the five patients who became hypothyroid, with elevated TSH on Iodine-alone, Dr. Okamura used the “Block and Replace” technique, a combination of Iodine with Levothyroxine (50-75 mcg/d) to maintain euthyroid state.

In 1991, Dr Hashizume reports that “Block and Replace” with addition of Levothyroxine reduces the TSI (Graves’ Antibodies) and increases chance for remission.  In my opinion, Block and Replace is justified in Graves’ Disease patients who have an undulating course with frequent biochemical relapse. Block and Replace reduces the TSH, thus preventing TSH generation of damaging hydrogen peroxide which may trigger thyroiditis. It would be prudent to give the patient selenium and magnesium to maintain good antioxidant capacity needed for neutralization of excess hydrogen peroxide. In Block and Replace, anti-thyroid drug dosage is not reduced, thus maintaining inhibition of TPO with methimazole. KI maintains the Wolk Chaikoff Effect and inhibits of thyroid hormone release. (52-53)

Switching from Methimazole to Iodide for Pregnant Patients

In 2015, Dr. Yoshihara from Japan substituted potassium iodide (KI) for Methimazole (MMI) in 240 pregnant women to control hyperthyroidism in the first trimester.  This was done to avoid risk of fetal malformations associated with MMI.  About 90% of the patients responded well to the KI. However about 9% escaped from the suppressive effect of KI alone and required a higher dose of MMI (worsened group).

The mean age of the 240 pregnant women was 33 years. Of the 240 patients, or 55%, went into remission, and KI could be completely tapered during the pregnancy.  The other 45% were still taking thyroid blocking medication at delivery.  Of these, roughly half were taking potassium iodide (KI) alone and half were taking an anti-thyroid drug (MMI) with or without KI. Higher TRAb values predicted continuation of anti-thyroid medication. Dr. Yoshihara writes:

Treatment of Graves’ Disease (GD) with Potassium Iodide (KI) is widely accepted by Japanese thyroid specialists, and its efficacy has been reported …It was difficult to control the maternal thyrotoxicosis of 22 of the 107 patients [9% of the total 240 pts.] with KI alone, and a higher dose of MMI compared with the dose at the time of conception was required (worsened group). Multivariate analysis revealed that the TRAb value at the time of switch from MMI to KI was the only factor that predicted continuation of the thyroid suppression medication, but none of the parameters was a predictor of the worsened group…Conclusions: It must be kept in mind that a certain proportion of GD patients escape from the antithyroid effect of iodide and that careful follow-up is necessary after switching a pregnant patient’s medication to KI.(29) Emphasis Mine. Note: TRAb is Thyroid Receptor Antibody, a general measure of severity of Grave’s Disease Auto-immunity. (40)

Not Recommended Outside of Japan

In 2020, Dr. Elizabeth Pearce reviewed Dr. Yoshihara’s 2015 study concluding KI for Graves’ Disease should not be recommended outside of Japan because of the 9% worsened group with “Escape” from the anti-thyroid effect of KI.   Dr. Elizabeth Pearce writes:

The switch from MMI to KI treatment occurred at a median of 6 weeks of gestation (range, 4–12). The mean initial KI dose was 20 mg daily. Of the 133 (55%) patients who were able to taper off of all medication during pregnancy, 4 then needed levothyroxine therapy by the time of delivery. Women who were able to discontinue therapy required lower MMI doses prior to the switch to KI, had lower TRAb titers, higher serum TSH levels, and were on lower KI doses as compared with women who needed treatment for hyperthyroidism throughout gestation…Worsened hyperthyroidism occurred in 22 patients (9.2%) following the switch to KI, requiring higher MMI doses by the third trimester than before the medication switch…incidence of birth defects was lower in children of the mothers who were switched to KI…The current American Thyroid Association guideline for management of thyroid disease in pregnancy cautions, with regard to KI treatment for Graves’ disease, that, “at present, such therapy cannot be recommended outside Japan until more evidence on safety and efficacy is available“. I do not think that the results of the current study are likely to alter that guidance. (91) Emphasis Mine

Selenium Status and Escape from Iodine

Although there was a 91 per cent success rate with switching patients from MMI to KI for treatment of Graves’ hyperthyroidism, there was a 9.2 % escape rate in which hyperthyroidism worsened, requiring higher doses of MMI for control. There was no obvious explanation for why this occurs in some patients and not others. A few possible explanations will be offered below.

Same Success Rate as in 1920’s and 1930’s

By the way, this 90 per cent success rate in Dr. Yoshihara’s 2015 study was similar to the success rate in a 1924 study by Dr Paul Starr at the Massachusetts General Hospital, treating 25 patients with Graves’ Disease (exophthalmic goiter)  with KI alone, at the dosage of 90 mg per day.(11)

A similar 88% success rate was obtained in 1930 by Dr. Thompson who treated 24 Graves’ Disease patients with Lugol’s Solution (iodine). Dr Thompson writes:

Twenty-four patients with exophthalmic goiter (14 mild and 10 severe or moderately severe cases) have been treated in this clinic with iodine [Lugol’s] alone, either continuously or intermittently for periods ranging from one and one-half months to three years. The period of treatment was a year or more in 13 instances. With three exceptions (all unsatisfactory responses to iodine) the patients pursued their daily work throughout the period of observation, thus eliminating the effect of rest. (14)

Predicting Escape from KI

Although Dr. Yoshihara had no parameter to predict Iodine escape, it may be possible to suggest a mechanism based on understanding the production of thyroid hormone, and its pathophysiology.  As yet, this hypothesis is speculation without confirmatory studies.

Firstly, it is known that in normal humans and animal studies, toxic effects of excess iodine may cause thyroiditis, an inflammatory condition known to cause hyperthyroidism from rupture of follicles with release of preformed thyroid hormone.

In normal people consuming dietary excess iodine, there is an initial inhibition of thyroid function with elevation of TSH. However, a few weeks later, the thyroid autoregulatory ability normalizes the TSH and thyroid hormone levels through downregulation of the the Sodium/Iodide Symporter, the active transport mechanism. The reduced iodide uptake normalizes intra-thyroid iodide content. Once TSH is normalized, this reduces the TSH stimulated generation of excess hydrogen peroxide, with no further risk of thyroiditis, even if patient is at high risk with selenium and magnesium deficiency. (7)

Autoimmune Thyroid Disease patients have no autoregulatory ability. The suppressive effects on thyroid function of excess iodide continues indefinitely, producing a high TSH.  In this group, there may be intermittent episodes of thyroiditis. If the patient has underlying Hashimotos’ Thyroiditis, these episodes of thyroiditis cause a form of thyrotoxicosis with low radio-iodine uptake, called Hashitoxicosis. A reliable way to differentiate Graves’ thyrotoxicosis from Hashitoxicosis is the radio-iodine uptake scan which shows high high iodine uptake in Graves’ disease, while iodine uptake is low in Hashitoxicosis. (86-89)

TSH Receptor Antibodies Do Not Stimulate Hydrogen Peroxide

High radio-iodine uptake in Graves’ Disease means NIS function is hyper stimulated by TSH receptor antibodies. However, unlike TSH which  stimulates hydrogen peroxide generation, TSH receptor antibodies do not, thus explaining the smooth diffuse enlargement of the thyroid gland with lack of thyroiditis in the early onset presentation of Graves’ Disease patients.

NIS Auto-Antibodies and Iodine Escape

In 2010, Dr.  Anna-Maria Eleftheriadou found that about 12 per cent of Graves’ Disease patients have auto-antibodies to NIS, the sodium iodide symporter, the active transport for iodide. A second speculative explanation for KI “resistance or escape” in Graves’ disease is the presence of NIS antibodies in about 12 per cent of Graves’ disease patients. The NIS is embedded in the basolateral membrane of the thyrocyte, and mediates active transport of iodine into the thyroid cell, concentrating iodine 100 times to that of plasma. However, NIS antibodies are the monkey wrench in the machinery, inhibiting iodine uptake and concentration, thus explaining the iodine “Escape” or “Resistance” in a subset of Graves’ disease patients treated with KI. (93-95)

Immune Complex Deposits at Basolateral Membrane of Follicles

In 1977, Dr. Kalderon identified immune complex deposits at the follicular basal lamina of the follicles in the thyroid glands of patients with Hashimotos’ and Graves’ autoimmune thyroid disease. Note this the location of NIS, the sodium iodine symporter. Dr. Kalderon also identified this same finding in a hereditary model of autoimmune thyroid disease in obese chickens.  One might speculate deposition of immune complexes in this location could interfere with the NIS function and impact thyroid autoregulation.(96-97)

Selenium Levels in Graves’ Disease

Selenium/magnesium levels could be the defining factor in these intermittent bouts of thyroiditis.  According to studies in which animals are fed excess Iodine by Drs. Jian Xu, Christine Thomson,  and Ioana Vasiliu, excess iodine causes selenium depletion and selenium deficiency, In addition, Selenium alleviates the toxic effects of excess iodine. One of these toxic effects is increased accumulation of colloid in the follicles causing goiter.  Similar thyroid morphology was described in Graves’ Disease patients after Iodine treatment in pioneering thyroid surgeons in 1925, Dr. FW Rienhoff, and in 1927, Dr.Joseph DeCourcy. (54-59)

To reiterate, under conditions of iodine excess, in both humans and mice, there is enlargement of the follicles with colloid formation (goiter). Colloid contains thyroglobulin, some which is organified.

Selenium Alleviates Toxic Effects of Iodine

In 2011, Dr. Christine Thomson studied the effect of excess iodine intake on thyroid hormones and selenium status in older New Zealanders, agreeing with Dr. Jian Xu. selenium alleviates the toxic effects of Iodine in humans as well as mice. Dr. Thomson advised co-administration of selenium along with Iodine, writing:

Our results agree with those of Xu et al. who showed in mice that decreased activities of GPx [Glutathione Peroxidase] resulting from excessive iodine intake could be restored through supplementing with selenium. These observations indicate that when high iodate [iodine] supplements are used to eliminate iodine deficiency, it would appear important to co-administer selenium to ensure adequate selenium intake. (55)(70-76)

Myxoedematous Cretinism in Zaire Africa

Myxoedematous cretinism is a from of thyroid destruction first described in Zaire Africa.  In myxoedematous endemic cretinism, iodine deficiency and resulting hypothyroidism caused severe elevation of TSH with  marked stimulation of the TSH receptors, causing upregulation of all steps in thyroid hormone synthesis. One of these upregulated steps is production of hydrogen peroxide. In the selenium deficient population of Zaire, the selenium-based antioxidant system is dysfunctional and excess hydrogen peroxide cannot be neutralized. Thus, hydrogen peroxide accumulates in the follicles at the apical villous membrane causing oxidative damage to thyrocytes (cells lining the follicles), thyroiditis, inflammatory changes with apoptosis and necrosis. This type of thyroiditis leads to release of thyroid hormone, and a form of thyrotoxicosis with low radio-iodine uptake. Treatment with thyroid blocking drugs which block the TPO enzyme such as Methimazole is usually ineffective, since the thyrotoxicosis is caused by rupture of of follicles with release of preformed thyroid hormone, and is not caused by the usual TPO organification machinery.  One might suggest the mechanism of thyroiditis in myxoedematous cretinism resembles that of thyroiditis of Hashitoxicosis. Indeed, a similar mechanism has been described for etiology of autoimmune thyroid disease, in which excess hydrogen peroxide causes oxidative damage to Thyroglobulin and TPO.  These damaged proteins are then recognized by the immune system as foreign proteins, causing the immune system to produce antibodies against Thyroglobulin and TPO (thyroid peroxidase) . In 2007, Dr Yue Song studied the role of hydrogen peroxide in thyroid physiology and disease, writing:

It is proposed that various pathologies can be explained, at least in part, by overproduction and lack of degradation of H2O2 (tumorigenesis, myxedematous cretinism, and thyroiditis) and by failure of the H2O2 generation or its positive control system (congenital hypothyroidism).(60)

The Selenium/Magnesium Deficient Patient

Let us consider the case of the methimazole treated Graves’ Disease patient. If the methimazole dosage is high enough to suppress Free T3 and FreeT4 below the reference range, feedback to the HPA (hypothalamic pituitary axis) will eventually cause a very high TSH. As mentioned in the chapter on production of thyroid hormone, high TSH stimulates generation of hydrogen peroxide, thyroglobulin production and organification. The increased thyroglobulin (also called colloid) fills the follicles causing thyroid enlargement and goiter.

The treating physician will see the elevated TSH and low Free T4, and will be tempted to reduce the dosage of MMI.  In the 2015 study by Dr. Yoshihara, in a subset of Graves’ Disease patients with elevated TSH after starting Iodine, rather than reduce the MMI dosage, these patients were treated with “Block and Replace”.  The thyroid is blocked with MMI and replaced with Levothyroxine. The added Levothyroxine serves to bring down the TSH and raise the FreeT4. “Block and Replace” suppresses the TSH, thus turning off hydrogen peroxide generation and reducies the risk of thyroiditis. However, for those not treated with “Block and Replace”, lowering the MMI while the TSH is still elevated allows TSH stimulated generation of hydrogen peroxide, and subsequent thyroiditis.  This may trigger massive oxidative damage leading to inflammation, apoptosis and necrosis of thyrocytes. The inflammatory process may stimulate thyroid auto-immunity as well as spill preformed thyroid hormone from the follicles into the bloodstream. Although we are discussing a scenario in the Graves’ Disease patient, this mechanism of thyroiditis bears a similarity with Hashitoxicosis, an inflammatory process associated with decreased radio-iodine uptake. Indeed, 70% of Grave’s disease patients will also have anti-TPO and anti-thyroglobulin antibodies, indicating coexisting Graves’ and Hashimoto’s thyroiditis, suggesting these are not separate disease entities but merely two variations of the same disease as suggested by in 2016 Dr. Ashley Schaffer. (61)

Thyroiditis Causing Unexpected Relapsing Hyperthyroidism

This thyroiditis mechanism was confirmed in 2022 by Dr. Ken Okamura who reviewed 100 Graves’ Disease patients who presented with unexpected relapsing hyperthyroidism while decreasing dosage of anti-thyroid drug Methimazole (MMI), PTU. or Potassium Iodide.

Dr. Ken Okamura reports when dosage of antithyroid medication (MMI or KI) is decreased, this may provoke an episode of painless thyroiditis (PT) which mimics a relapse of Graves’ hyperthyroidism. This form of thyroiditis causes thyrotoxicosis with low radio-iodine uptake, a destructive inflammatory process within the thyroid gland representing a form of “self-ablation”. Dr. Okamura discusse another explanation for thyoiditis when the MMI dosage is reduced, and TPO activity is turned back on. This allows organification of iodide with produciton of iodolactones which inhibit the NIS, and inhibit iodine uptake.  Thus, this can be seen as restoring autoregulation in the Graves’ Disease patient. Dr. Okamura  writes:

The golden-standard factor to consider for the differential diagnosis is the thyroidal radioactive iodine uptake (RAIU), which is high in GD [Graves Disease] and almost null in typical PT [painless thyroiditis] cases. PT is also suggested when thyroid-stimulating hormone (TSH) receptor antibody (TRAb), measured by the TSH Binding Inhibitor Immunoglobulin (TBII) or thyroid-stimulating antibody activity (TSAb), is negative and thyrotoxicosis resolves spontaneously without antithyroid drugs (ATDs) followed by an episode of transient hypothyroidism...Autoregulatory mechanisms in the thyroid gland are well known, and thyroid hormone synthesis was thought to be regulated by organified iodine compound X, probably an iodoaldehyde and/or  iodolactone, which requires active thyroid peroxidase (TPO) to be synthesized, although the mechanisms underlying the effects of compound X remain elusive . It is therefore plausible that a decreased ATD dosage might increase TPO activity and thereby increase the production of compound X [iodolactones] , which suppresses the thyroid function, including that of sodium-iodide symporter (NIS), resulting in a decreased iodine uptake possibly accompanying Tg proteolysis and thyroid hormone release. From a therapeutic perspective, it is very important to keep in mind that PT can occur during ATD treatment of GD, especially when the dosage is reduced [and TSH goes high]…PT was frequently observed during KI treatment. In Group A, 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. (62)

Painless Thyroiditis (PT) When Switching from Methimazole to Iodine

In 2021, Dr. Keiichi Kamijo studied potassium iodide induced painless thyroiditis (PT) in 11 Graves Disease patients finding 10 of the 11 patients also harbored Hashimoto’s antibodies (TPO or Thyroglobulin Abs), suggesting a resemblance with Hashitoxicosis. Physicians should be alerted to induction of Painless Thyroiditis in patients discontinuing ATD (anti-thyroid drug such as MMI) and switching to potassium iodide (KI),  writing:

Painless thyroiditis (PT) is characterized by transient hyperthyroidism with a low Tc-99m uptake… We herein describe 11 cases of PT that occurred during treatment with potassium iodide (KI) for Graves’ disease (GD)…the administration of stable iodine to hyperthyroid patients produces clinical benefits by inhibiting the release of thyroid hormone and its synthesis due to a decrease in TPO mRNA…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 [anti thyroid drug, methimazole] due to side effects, should be alert for KI-induce PT. (86) Emphasis Mine

Myxedamatous Cretinism Combined Iodine / Selenium Deficiency

In 2017, Dr Mara Ventura proposed combined iodine and selenium deficiency as a mechanism for Myxedematous Cretinism, a form of destruction of the thyroid gland in young children in Zaire, Africa.  Dr. Mara Ventura proposed combined Iodine/selenium deficiency causes thyroid failure and increased TSH which stimulates thyroid hormone production, creating excess hydrogen peroxide which cannot be neutralized, leading to thyroiditis and fibrosis.  Dr. Mara Ventura writes:

In fact, it was found that selenium deficiency decreases the synthesis of thyroid hormones, as it decreases the function of selenoproteins, in particular iodothyronine deiodinases (DIOs), which are responsible for the conversion of T4 to T3. This decreased production of thyroid hormones leads to the stimulation of the hypothalamic-pituitary axis due to the lack of negative feedback control, increasing TSH production. TSH stimulates the DIOs to convert T4 to T3 [12], with consequent production of hydrogen peroxide, which is not adequately removed by less active glutathione peroxidases (GPx) and accumulates itself in the thyroid tissue causing thyrocyte damage with subsequent fibrosis. (63)

In 1993, Dr. Bernard Contempre reproduced this mechanism of thyroid destruction in selenium deficient mice fed perchlorate for a month (a thyroid blocking drug that prevents iodine uptake). This simulates iodine deficiency. After perchlorate withdrawal, the mice were fed iodine. The Selenium deficient mice had markedly reduced Glutathione Peroxidase levels (anti-oxidant levels).  The perchlorate treated mice developed goiters and were hypothyroid, with elevated TSH. After iodide refeeding, thyroid hormone levels markedly increased and necrotic thyrocyte cells were observed, in numbers three times greater in the selenium deficient mice. Dr. Bernard Contempre writes:

These experimental data demonstrate the detrimental role of selenium deficiency in one experimental case of thyroid disease. Such reduction of cell defenses could contribute to the thyroid failure of African myxedematous cretins. (64-65)


Magnesium Deficiency Worsens Selenium Deficiency

In 2006, Dr  Cornelia V. Gilroy studied magnesium levels in hyperthyroid cats, finding hyperthyroidism increases renal excretion of magnesium and causes magnesium deficiency. This correlates with severity of hyperthyroidism. Dr  Cornelia V. Gilroy writes:

Hyperthyroidism can increase the renal excretion of magnesium and thus cause hypomagnesemia in various species…the severity of hyperthyroidism may contribute to a decrease in the ionized magnesium concentration. (77-80)

Magnesium deficiency worsens the defect in selenium deficiency, while oral supplementation with magnesium potentiates the glutathione peroxidase antioxidant system. Thus, magnesium supplementation is recommended for the Graves ‘ Disease patient. (66-69)(77-80)

Perhaps Selenium/Magnesium deficiency could explain the 9% percent worsened group in the 2015 Yoshihara study. Could insufficient levels of Selenium/Magnesium be predictive of escape from the suppressive effects of iodine? Unfortunately, Dr. Yoshihara’s study did not measure either one.  Measuring selenium and magnesium levels in future studies might answer this question.(66-69)(77-80)

Current Status of KI for Graves’

In 2017, Dr. Jan Calissendorf reviewed current status of Iodine (Ki or Lugol’s) for treatment of Graves’ Disease, discussing the Iodide escape phenomenon, writing:

Iodide has been shown to decrease thyroid hormone levels and reduce blood flow within the thyroid gland. An escape phenomenon has been feared as the iodide effect has been claimed to only be temporary…. Antithyroid drugs [methimazole] are often chosen since these are mostly well-tolerated, and can induce cure in around 50% after 12–18 months of treatment. These pharmacologic compounds, propylthiouracil, methimazole or carbimazole, block the thyroid hormone synthesis by inhibiting thyroid peroxidase… In the short-term LS [Lugol’s Iodine Solution] reduces the thyroid hormones, T4 and T3 by increasing iodine uptake and inhibiting the enzyme thyroid peroxidase, thus attenuating oxidation and organification of thyroid hormones. Moreover, the release of thyroid hormones is also blocked… Wolff-Chaikoff is the effect of iodide in normal mice which lead to an increase of intrathyroidal iodine concentration within 24–48 h and a subsequent decrease of thyroid hormone synthesis. In healthy subjects there is an adaption to iodine excess by an autoregulatory mechanism within the thyroid, which serves as a defense against fluctuations in the supply of iodine and permits escape from the paradoxical inhibition of hormone synthesis that a very large quantity of iodine induces. Defective or absent autoregulation can occur in predisposed patients, as in those with euthyroid Hashimoto’s thyroiditis and in GD [Graves’ Disease]-patients treated with radioiodine or subtotal thyroidectomy. Thus, these are more prone to develop hypothyroidism secondary to an iodine overload…The escape from acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter causing a reduction in intrathyroidal iodide concentration. There is also a form of escape following iodide therapy in GD which has been described as common [thyroiditis?]. Thus, in treating patients with hyperthyroidism with LS [Lugol’s Solution] an exacerbation of thyroid hormone levels could be a consequence after a period of blocking the thyroid, as the gland has become loaded of iodine substrate for hormone synthesis…However, in the investigation by Takata et al. a combination of iodide solution was used together with methimazole for up to 8 weeks. Iodide was discontinued when patients showed normal free T4. Eleven patients (25%) escaped from the Wolff-Chaikoff effect, and 3 derived no benefit at all.  Moreover, in another study including patients with mild GD who received primary treatment with LS (50–100 mg daily), control of hyperthyroidism after 12 months was comparable with that seen in patients receiving low-dose methimazole treatment…How often and how early escape occurs is not clear, but in an observational study from Japan long-term treatment with LS alone or in combination with antithyroid drugs has been used, with 29/44 (66%) being well-controlled on 100 mg LS daily alone for 7 years. In another study of 21 patients with hyperthyroidism given iodide daily, hormone levels started to increase again after 3 weeks in some, but others remained euthyroid even after 6 weeks. (8)(98-99)

Iodine Plus Magnesium Pretreatment for Graves’ Disease

Dr. Guy Abraham, the inventor of the Iodoral tablet, recommends Iodine alone for treatment of Graves’ Hyperthyroidism.  However, Dr. Abraham advocates Magnesium as a pretreatment prior to using Iodine. In his 2004 discusses a 40-year-old female with Graves’ Disease, undetectable TSH <0.01 μU/ml, and elevated Free T4 = 5.0 ng/dL. (Normal ranges: free T4 = 0.8 and 1.8 ng/dL,  TSH =0.3-3.0 μU/ml.)  Dr. Guy Abraham writes:

A complete nutritional program in our experience improved further the response to orthoiodosupplementation [using Lugol’s or Iodoral] in Graves’ disease and other thyroid disorders…. 40-year-old female patient with severe hyperthyroidism… She was a classic case of Graves’ disease with exophthalmia… She was placed on the nutritional program, including 1,200 mg of magnesium/day for one month prior to iodine supplementation, followed by the same program with the addition of 12.5 mg elemental iodine (1 tablet Iodoral®) daily afterward… Following one month on this program, she slept better and was better organized with improved social activities. Her palpitation decreased markedly with normal pulse rates. Serum TSH became normal at 2.3 μU/ml; Total T4, Total T3 and Free T4 were all within the normal range at 8.0 μg/dL, 195 ng/dL, and 1.2 ng/dL. (2)

Complete Nutritional Supplement Protocol:

Although Dr. Abraham did not mention selenium supplementation, it is obvious from the above discussion, selenium is at the heart of the issue and is not to be ignored. Our supplement program includes Selenium 200-400 mcg/d, magnesium 500-1200 md/d, unrefined sea salt 1/2 tsp. or more per day, vitamin C 3,000-10,000 mg per day and Omega-3 fatty acids.  The unrefined sea salt is to allow for Bromine detoxification (see the chapter on Iodine and Bromine Detoxification). (81-83)

What is the “Iodine escape rate” when using selenium and magnesium in the above supplement protocol ?  Unfortunately, as yet we do not have studies to answer this question. Dr. Abraham’s work gives value to magnesium supplementation. Can the iodine escape and/or episodes of thyroiditis be eliminated by the Guy Abraham supplement protocol ?  We await confirmatory studies. In the meantime, it might be prudent to incorporate such a protocol as well as initial testing and supplementation for Selenium, RBC Magnesium and spot urinary iodine levels. Other than selenium which may cause toxicity in excess, these supplements are labeled GRASS, generally regarded as safe, and not harmful when taken in the proper dosage range. The topic of nutritional supplementation with selenium is covered again in a later chapter. (84)

Medical Iodophobia

In 2004, Dr Guy Abraham coined the term “Medical iodophobia”, meaning fear of using iodine as a medical treatment for iodine deficiency.  Dr. Guy Abraham writes:

Medical iodophobia is the unwarranted fear of using and recommending inorganic, non-radioactive iodine/iodide within the range known from the collective experience  of three generations of clinicians to be the safest and most effective amounts for treating symptoms and signs of iodine/iodide deficiency (12.5-37.5 mg). (84)

Dr Abraham also recognizes this “iodophobia” began in the 1940’s with introduction of thyroid blocking drugs which he calls goitrogens, which replaced Iodine as a treatment for Graves’ Disease. Perhaps “Big Pharma” corporate financial interests are reasons for this shift. Additional reasons could very well be the complexity and nuances involved in the use of Iodine, requiring an extensive medical history,  pretesting for selenium, magnesium, vitamin C levels and pretreatment with supplements for good results. The average physician may not have knowledge of various thyroid disorders in which iodine is contraindicated such as hyperthyroidism from toxic multinodular goiter or autonomous nodule.

Iodine for Dermatologists

For example, in 2000, Dr. Warren Heymann reviewed the knowledge required of dermatologists before prescribing potassium iodide (KI). Dr. Warren Heymann is mostly concerned with KI suppression of thyroid function, the Wolf-Chaikoff Effect (WCE) causing elevation of the TSH, reversible with discontinuation of the KI. Dr. Warren Heymann writes:

For dermatologists who use KI [potassium iodide], knowledge of the WCE [Wolf-Chaikoff Effect], the inhibition of thyroid function by Iodine, is imperative. Before KI is prescribed, it would be prudent for the physician to inquire about any history of thyroid disease, autoimmune or otherwise. It is also essential to determine whether a patient is taking other medications, such as amiodarone, that could affect thyroid function. Unless there is a suspicion of underlying thyroid disease, baseline thyroid function studies (ie, TSH, T4, antithyroglobulin, and antimicrosomal antibodies) are not indicated. Fortunately, with the dermatoses for which KI is currently indicated, it is likely that any therapeutic effect will be apparent within a few weeks. This is within the time frame that thyroid autoregulatory processes will ordinarily allow for escape from the WCE. If therapy with KI is continued for more than 1 month, however, a screening TSH would be prudent to ensure that iodide-induced hypothyroidism does not ensue. If iodide-induced hypothyroidism is detected, these changes are reversible by discontinuing the administration of KI. In a study of 7 patients with iodide-induced hypothyroidism, serum T4, T3, and TSH concentrations returned to normal within 1 month of iodide withdrawal. (85)

The above description of the complexity of KI use in clinical practice may dissuade the average clinician from using potassium iodide (KI).

If KI is used in Graves’ thyrotoxicosis, the patient must be followed more closely than is usually done in todays’ busy medical office based on the insurance business model.  Such patients require more frequent laboratory testing and follow up, and even direct access to the physician’s cell phone number, not usually done by mainstream medical practitioners. For clinicians wishing to simplify their practice, they may choose to avoid KI.

Can Grave’s Disease be Cured?

In 2019, Dr Wilmar Wiersinga from Amsterdam asked the important question, “Can Graves’ Disease be Cured?”  If we exclude thyroid ablation as not a “cure”, and only include permanent remission while on medical therapy as a “cure”, then only about 30 per cent of Graves’ Disease patients achieve such a permanent remission on medical therapy.  Remission requires return to normal of Graves’ antibodies, the TSI and TRAB antibodies, as well as normalization of thyroid hormone levels. Regarding remission after long term treatment with antithyroid drugs [methimazole], Dr. Wiersinga writes:

Graves’ hyperthyroidism is not really cured as long as TSH receptor antibodies [TRAb] are present, and I quite agree with this line of thinking. (43-44)

Natural Course of Graves’ Disease

The chance of developing Graves’ Disease during one’ lifetime is about 3% for women and 0.5% for men. About Two Thirds (60-70 per cent) of patients exhibit an undulating course with alternating episodes of hyperthyroid and euthyroid states. In others words, most patients have a relapsing and remitting course over many years. Note: euthyroid means normal thyroid lab tests. For the patients with more severe undulating course, “Block and Replace” strategy may be justified.

Conclusion: Ignoring the use of Potassium Iodide (KI) in Graves’ Disease is an error of modern endocrinology. Early studies suggested that KI alone could control thyrotoxicosis long term in the Graves’ Disease patient. However later studies found that about 9-12 per cent of cases escape from the suppressive effects of Iodine for unknown reasons, with worsening of the thyrotoxicosis.  This escape phenomenon is avoided by using KI only as Short-Term treatment, as is commonly done in preparation of the thyrotoxic patient for thyroidectomy. Another option is KI in combination with another drug, such as Methimazole or Lithium, discussed in following chapters. Supplementation with Magnesium and Selenium ameliorate the toxic effects of iodine excess. and may hold value for the auto-immune thyroid patient.

Articles with Related Interest

Iodine for Graves Disease part two

Lithium/Iodine combination for Graves Disease

Addressing the Autoimmune Component of Thyroid Disease

Jeffrey Dach MD


1) Vaidya, Bijay, and Simon HS Pearce. “Diagnosis and management of thyrotoxicosis.” BMJ 349 (2014).

2) Abraham, Guy E. “The safe and effective implementation of orthoiodosupplementation in medical practice.” The Original Internist 11.1 (2004): 17-36.

3) Trousseau, Armand. “Lectures on Clinical Medicine, trans. by P.” V. Bazire, London, New Sydenham Society (1868).

4) Corvilain, Bernard, Jacqueline Van Sande, and Jacques E. Dumont. “Inhibition by iodide of iodide binding to proteins: the “Wolff-Chaikoff” effect is caused by inhibition of H2O2 generation.” Biochemical and biophysical research communications 154.3 (1988): 1287-1292.

5) Wartofsky L, Ransil BJ, and Ingbar SH. “Inhibition by iodine of the release of thyroxine from the thyroid glands of patients with thyrotoxicosis.” J Clin Invest, 1970; 49:78-86.

6) Bagchi, N., B. Shivers, and T. R. Brown. “Studies on the mechanism of acute inhibition of thyroglobulin hydrolysis by iodine.” Acta endocrinologica 108.4 (1985): 511-517.

7) Bizhanova, Aigerim, and Peter Kopp. “The sodium-iodide symporter NIS and pendrin in iodide homeostasis of the thyroid.” Endocrinology 150.3 (2009): 1084-1090.

8) Calissendorff, Jan, and Henrik Falhammar. “Lugol’s solution and other iodide preparations: perspectives and research directions in Graves’ disease.” Endocrine 58.3 (2017): 467-473.

9) Plummer HS and Boothby WM. “The Value of iodine in exophthalmic goiter. ” J Iowa Med Soc, 1924; 14:65.

10) Plummer WA. “Iodin in the treatment of goiter.” Med Cl North America, 1925; 8:1145-1151.

11) Starr, Paul, et al. “The effect of iodin in exophthalmic goiter.” Archives of Internal Medicine 34.3 (1924): 355-364.

12) Lahey, Frank H. “The use of iodine in goitre.” The Boston Medical and Surgical Journal 193.11 (1925): 487-490.

13) Don, Charles SD. “The Treatment Of Exophthalmic Goitre.” British Medical Journal 1.3572 (1929): 1108.

14) Thompson WO, Thompson PK, Brailey AG, et al. “Prolonged treatment of exophthalmic goiter by iodine alone.” Arch Int Med, 1930; 45:481-502.

15) Redisch W and Perloff WH. “The medical treatment of hyperthyroidism.” Endocrinology, 1940; 26:221-228.

16) Cerqueira, Charlotte, et al. “Iodine Fortification and Hyperthyroidism.” Handbook of Food Fortification and Health. Humana Press, New York, NY, 2013. 243-254.

17) Stanbury, John Burton, et al. “Iodine-induced hyperthyroidism: occurrence and epidemiology.” Thyroid 8.1 (1998): 83-100.

18) Corvilain, Bernard, et al. “Autonomy in endemic goiter.” Thyroid 8.1 (1998): 107-113.

19) Müssig, Karsten, et al. “Iodine-induced thyrotoxicosis after ingestion of kelp-containing tea.” Journal of general internal medicine 21.6 (2006): C11-C14.

20) Mariani, Giuliano, et al. “The role of nuclear medicine in the clinical management of benign thyroid disorders, part 1: hyperthyroidism.” Journal of Nuclear Medicine 62.3 (2021): 304-312.

21) Mariani, Giuliano, et al. “The role of nuclear medicine in the clinical management of benign thyroid disorders, part 2: nodular goiter, hypothyroidism, and subacute thyroiditis.” Journal of Nuclear Medicine 62.7 (2021): 886-895.

22) Wolff J and Chaikoff IL. “Plasma inorganic iodide as a homeostatic regulator of thyroid function.” J Biol Chem, 1948; 174:555-564.

23) Livolsi, Virginia A., and Zubair W. Baloch. “The pathology of hyperthyroidism.” Frontiers in Endocrinology 9 (2018): 737.

24) HIROTA, YOSHIHIKO, et al. “Thyroid function and histology in forty-five patients with hyperthyroid Graves’ disease in clinical remission more than ten years after thionamide drug treatment.” The Journal of Clinical Endocrinology & Metabolism 62.1 (1986): 165-169.

25) Mizukami, Yuji, et al. “Histologic changes in Graves’ thyroid gland after 131I therapy for hyperthyroidism.” Pathology International 42.6 (1992): 419-426.

26) Thompson, Lester DR. “Diffuse hyperplasia of the thyroid gland (Graves’ disease).” Ear, Nose & Throat Journal 86.11 (2007): 666-667.

27) Wallaschofski, H., T. Kuwert, and T. Lohmann. “TSH-receptor autoantibodies-differentiation of hyperthyroidism between Graves’ disease and toxic multinodular goitre.” Experimental and clinical endocrinology & diabetes 112.04 (2004): 171-174.

28)  Pedersen, Inge Bülow, et al. “TSH‐receptor antibody measurement for differentiation of hyperthyroidism into Graves’ disease and multinodular toxic goitre: a comparison of two competitive binding assays.” Clinical Endocrinology 55.3 (2001): 381-390.

29) Kamath, C., M. A. Adlan, and L. D. Premawardhana. “The Role of Thyrotrophin Receptor Antibody Assays in Graves’ Disease.” Journal of Thyroid Research 2012 (2012).

30) Michalek, Krzysztof, et al. “TSH receptor autoantibodies.” Autoimmunity reviews 9.2 (2009): 113-116.

31) Macchia, Enrico, et al. “Assays of TSH-receptor antibodies in 576 patients with various thyroid disorders: their incidence, significance and clinical usefulness.” Autoimmunity 3.2 (1989): 103-112.

32) Bothun, Erick D., et al. “Update on thyroid eye disease and management.” Clinical ophthalmology (Auckland, NZ) 3 (2009): 543.

33) Yang, Dawn D., Mithra O. Gonzalez, and Vikram D. Durairaj. “Medical management of thyroid eye disease.” Saudi Journal of Ophthalmology 25.1 (2011): 3-13.

34) Boschi, Antonella, et al. “Quantification of cells expressing the thyrotropin receptor in extraocular muscles in thyroid associated orbitopathy.” British journal of ophthalmology 89.6 (2005): 724-729.

35) Tani, Junichi, and Jack R. Wall. “Autoimmunity against eye-muscle antigens may explain thyroid-associated ophthalmopathy.” CMAJ 175.3 (2006): 239-239.

36) Lahooti, Hooshang, Kishan R. Parmar, and Jack R. Wall. “Pathogenesis of thyroid-associated ophthalmopathy: does autoimmunity against calsequestrin and collagen XIII play a role?.” Clinical Ophthalmology (Auckland, NZ) 4 (2010): 417.

37) Feek, Colin M., et al. “Combination of potassium iodide and propranolol in preparation of patients with Graves’ disease for thyroid surgery.” New England Journal of Medicine 302.16 (1980): 883-885.

Abstract  We assessed the efficacy of the combination of propranolol and potassium iodide in the preparation of patients with Graves’ disease for thyroid surgery. Potassium iodide was given orally in a dose of 60 mg three times a day for 10 days before operation in 10 patients who were already receiving propranolol. In contrast to previous experience with either drug used singly, the combined regimen caused a significant fall in mean serum total thyroxine and triiodothyronine to levels in the euthyroid range before operation (P less than 0.001). There was also a significant fall (P less than 0.05) before operation and transient rise after operation in serum reverse triiodothyronine. These preliminary results suggest that the combination of potassium iodide and propranolol may prove to be the optimum preoperative preparation for patients with Graves’ disease.

38) Kaur, Sukhvender, et al. “Effect of preoperative iodine in patients with Graves’ disease controlled with antithyroid drugs and thyroxine.” Annals of the Royal College of Surgeons of England 70.3 (1988): 123.

39) Kiyici, Sinem, et al. “Rapid preparation of patients with hyperthyroidism for thyroidectomy.” Endocrine Abstracts. Vol. 20. Bioscientifica, 2009.

40) 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

41) 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.

42) Tay, Wei Lin, et al. “High thyroid stimulating receptor antibody titre and large goitre size at first-time radioactive iodine treatment are associated with treatment failure in Graves’ disease.” Ann Acad Med Singap 48.6 (2019): 181-187.

43) Hershman, Jerome M. “A Survey of Management of Uncomplicated Graves’ Disease Shows that Use of Methimazole Is Increasing and Use of Radioactive Iodine Is Decreasing.” children 95.3260 (2010).

44) Wiersinga, Wilmar M. “Graves’ Disease: Can It Be Cured?.” Endocrinology and Metabolism 34.1 (2019): 29-38.

45) Dharmasena, Aruna. “Selenium supplementation in thyroid associated ophthalmopathy: an update.” International Journal of Ophthalmology 7.2 (2014): 365.

46) Douglas, Raymond S., et al. “OR11-4 Teprotumumab Markedly Improves Disease-related Quality of Life: Lessons From Two Randomized, Placebo-controlled Trials.” Journal of the Endocrine Society 6.Supplement_1 (2022): A799-A800.

47) Cipolla, Calogero, et al. “The value of total thyroidectomy as the definitive treatment for Graves’ disease: A single centre experience of 594 cases.” Journal of clinical & translational endocrinology 16 (2019): 100183.

48) Jamieson, A., and C. G. Semple. “Successful treatment of Graves disease in pregnancy with Lugol’s iodine.” Scottish Medical Journal 45.1 (2000): 20-21.

49) Gangadharan, Arundoss, Harsha Hanumanthaiah, and Sze May Ng. “The use of iodine as first line therapy in graves’ disease complicated with neutropenia at first presentation in a paediatric patient.” British Journal of Medicine and Medical Research 3.2 (2013): 324.

50) Emerson, Charles H., et al. “Serum thyroxine and triiodothyronine concentrations during iodide treatment of hyperthyroidism.” The Journal of Clinical Endocrinology & Metabolism 40.1 (1975): 33-36.

51) Phillppou, George, et al. “The effect of iodide on serum thyroid hormone levels in normal persons, in hyperthyroid patients, and in hypothyroid patients on thyroxine replacement.” Clinical endocrinology 36.6 (1992): 573-578.

52) Okamura, Ken, et al. “Remission after potassium iodide therapy in patients with Graves’ hyperthyroidism exhibiting thionamide-associated side effects.” The Journal of Clinical Endocrinology & Metabolism 99.11 (2014): 3995-4002.

53) Hashizume, Kiyoshi, et al. “Administration of thyroxine in treated Graves’ disease: effects on the level of antibodies to thyroid-stimulating hormone receptors and on the risk of recurrence of hyperthyroidism.” New England Journal of Medicine 324.14 (1991): 947-953.

54) Xu, Jian, et al. “Supplemental selenium alleviates the toxic effects of excessive iodine on thyroid.” Biological trace element research 141.1 (2011): 110-118.

55) Thomson, Christine D., et al. “Minimal impact of excess iodate intake on thyroid hormones and selenium status in older New Zealanders.” European journal of endocrinology 165.5 (2011): 745.

56) 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.

57) Vasiliu, Ioana, et al. “Experimental induced autoimmune thyroiditis in wistar rats: possible protective role of selenium.” Endocrine Abstracts. Vol. 70. Bioscientifica, 2020.

58) Rienhoff, F. W. “The Histological Changes Brought About in Cases of Exophthalmic Goiter.” Bull. Johns Hopkins Hosp. 37 (1925): 285.

59) DeCourcy, Joseph L. “The Use of Lugol’s Solution in Exopthalmic Goitre: An Explanation for the Beneficial Results of Pre-Operative Medication.” Annals of Surgery 86.6 (1927): 871.

60) Song, Yue, et al. “Roles of hydrogen peroxide in thyroid physiology and disease.” The Journal of Clinical Endocrinology & Metabolism 92.10 (2007): 3764-3773.

61) 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).

62) 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.

63) Ventura, Mara, Miguel Melo, and Francisco Carrilho. “Selenium and thyroid disease: from pathophysiology to treatment.” International journal of endocrinology 2017 (2017).

64) 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.

65) Goyens, Philippe, et al. “Selenium deficiency as a possible factor in the pathogenesis of myxoedematous endemic cretinism.” European Journal of Endocrinology 114.4 (1987): 497-502.

66) Ige, A. O., E. O. Adewoye, and E. O. Makinde. “Oral magnesium potentiates glutathione activity in experimental diabetic rats.” Int. J. Diabetes Res 5.2 (2016): 21-25.

67) Zhu, Zongjian, Mieko Kimura, and Yoshinori Itokawa. “Selenium concentration and glutathione peroxidase activity in selenium and magnesium deficient rats.” Biological trace element research 37.2 (1993): 209-217.

68) Jiménez, Alicia, et al. “Changes in bioavailability and tissue distribution of selenium caused by magnesium deficiency in rats.” Journal of the American College of Nutrition 16.2 (1997): 175-180.

69) Moncayo, Roy, et al. “The role of selenium, vitamin C, and zinc in benign thyroid diseases and of selenium in malignant thyroid diseases: Low selenium levels are found in subacute and silent thyroiditis and in papillary and follicular carcinoma.” BMC endocrine disorders 8.1 (2008): 1-12.

70) Wang, Weiwei, et al. “Effects of selenium supplementation on spontaneous autoimmune thyroiditis in NOD. H-2h4 mice.” Thyroid 25.10 (2015): 1137-1144.

71) Zheng, Huijuan, et al. “Effects of selenium supplementation on Graves’ disease: a systematic review and meta-analysis.” Evidence-Based Complementary and Alternative Medicine 2018 (2018).

72) Ruggeri, Rosaria M., et al. “Selenium exerts protective effects against oxidative stress and cell damage in human thyrocytes and fibroblasts.” Endocrine 68.1 (2020): 151-162.

73) Pekar, Joanna, et al. “Effect of selenium supplementation in thyroid gland diseases.” J. Elementol 22 (2017): 91-103.

74) Duntas, Leonidas H. “Selenium and the thyroid: a close-knit connection.” The Journal of Clinical Endocrinology & Metabolism 95.12 (2010): 5180-5188.

75) Rayman, Margaret P. “Multiple nutritional factors and thyroid disease, with particular reference to autoimmune thyroid disease.” Proceedings of the Nutrition Society 78.1 (2019): 34-44.

76) McGregor, Brock. “The role of selenium in thyroid autoimmunity: a review.” (2015): 83.

77) Gilroy, Cornelia V., et al. “Evaluation of ionized and total serum magnesium concentrations in hyperthyroid cats.” Canadian journal of veterinary research 70.2 (2006): 137.

78) Shibutani, Yuhei, et al. “Plasma and erythrocyte magnesium concentrations in thyroid disease: Relation to thyroid function and the duration of illness.” Japanese Journal of Medicine 28.4 (1989): 496-502.

79) Ford, Henry C., Michael J. Crooke, and Clare E. Murphy. “Disturbances of calcium and magnesiumm metabolism occur in most hyperthyroid patients.” Clinical biochemistry 22.5 (1989): 373-376.

80) Ko, Young Hee, Sangjin Hong, and Peter L. Pedersen. “Chemical mechanism of ATP synthase: magnesium plays a pivotal role in formation of the transition state where ATP is synthesized from ADP and inorganic phosphate.” Journal of Biological Chemistry 274.41 (1999): 28853-28856.

81) Nichol, R. W. “Bromism: The Sodium Chloride Treatment.” British Medical Journal 1.3405 (1926): 636.

82) Bechet, Paul E. “The Intravenous Administration of Sodium Chloride in Bromoderma.” Journal of the American Medical Association 87.5 (1926): 320-321.

83) Togawa, Go, et al. “Effects of Chloride in the Diet on Serum Bromide Concentrations in Dogs.” International Journal of Applied Research in Veterinary Medicine 16.3 (2018): 197-202.

84) Abraham, Guy E. “Facts about iodine and autoimmune thyroiditis.” The Original Internist 15.2 (2008): 75-76.

85) Heymann, Warren R. “Potassium iodide and the Wolff-Chaikoff effect: relevance for the dermatologist.” Journal of the American Academy of Dermatology 42.3 (2000): 490-492.

86) Kamijo, Keiichi. “Clinical Studies on Potassium Iodide-induced Painless Thyroiditis in 11 Graves’ Disease Patients.” Internal Medicine (2021): 6411-20.

87) Ross, Douglas S. “Syndromes of thyrotoxicosis with low radioactive iodine uptake.” Endocrinology and metabolism clinics of North America 27.1 (1998): 169-185.

88) 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.

89) 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.

90) Savoie, J. C., et al. “Iodine-induced thyrotoxicosis in apparently normal thyroid glands.” The Journal of Clinical Endocrinology & Metabolism 41.4 (1975): 685-691.

91) Skare, ståle, and Harald MM Frey. “Iodine induced thyrotoxicosis in apparently normal thyroid glands.” European Journal of Endocrinology 94.3 (1980): 332-336.

91) 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.

92) Dugrillon, A. “Iodolactones and iodoaldehydes—mediators of iodine in thyroid autoregulation.” Experimental and clinical endocrinology & diabetes 104.S 04 (1996): 41-45.

93) Eleftheriadou, Anna-Maria, et al. “Re-visiting autoimmunity to sodium-iodide symporter and pendrin in thyroid disease.” European Journal of Endocrinology 183.6 (2020): 571-580.

94) Czarnocka, Barbara. “Thyroperoxidase, thyroglobulin, Na (+)/I (-) symporter, pendrin in thyroid autoimmunity.” Frontiers in Bioscience-Landmark 16.2 (2011): 783-802.

95) Seissler, Jochen, et al. “Low frequency of autoantibodies to the human Na+/I− symporter in patients with autoimmune thyroid disease.” The Journal of Clinical Endocrinology & Metabolism 85.12 (2000): 4630-4634.

96) Kalderon, A. E., and H. A. Bogaars. “Immune complex deposits in Graves’ disease and Hashimoto’s thyroiditis.” The American journal of medicine 63.5 (1977): 729-734.

97) Kalderon, A. E., et al. “Electron-dense deposits in the follicular basal lamina of obese strain chickens with spontaneous hereditary autoimmune thyroiditis. An electron microscopic study.” Laboratory Investigation; a Journal of Technical Methods and Pathology 37.5 (1977): 487-496.

98) Takata, Kazuna, et al. “Benefit of short‐term iodide supplementation to antithyroid drug treatment of thyrotoxicosis due to Graves’ disease.” Clinical endocrinology 72.6 (2010): 845-850.

99) 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.

100) Chiraseveenuprapund, P., and I. N. Rosenberg. “Effects of hydrogen peroxide-generating systems on the Wolff-Chaikoff effect.” Endocrinology 109.6 (1981): 2095-2101.


Jeffrey Dach MD           954-792-4663

Last updated on by Jeffrey Dach MD

Leave a Reply