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 to slow the rapid rate.  The Beta Blocker drug 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.

The Endocrinologist

The endocrinologist saw Carol and ran a thyroid lab panel showing a suppressed TSH of .001. Other lab tests showed a Free T3 of 1200 (normal less than 420) and a FreeT4 of 4.4 (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 high thyroid function.  Carol was started on a thyroid blocking drug, Methimazole 30 mg daily.

Carol Goes to a Health Resort

Unhappy with conventional treatment, Carol traveled to health resort 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.  The other thyroid labs, the FreeT3 and FreeT4 had also normalized.  However, the TSI remained quite elevated with little change.

Carol returned home and visited the endocrinology office.  Her endocrinologist reviewed the labs, and then stopped the methimazole blocking drug.  He said it was no longer needed.  However, the Graves’ antibodies, the 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 Iodine on Graves’ Disease, showing complete remission with a 65 mg potassium iodine tablet given at a health resort as part of a vitamin program. (1)

Symptoms  of Graves Thyrotoxicosis

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

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 Accidently Discovers Iodine Treats Thyrotoxicosis of Graves’ Disease.

In 1863, Trousseau was called to visit a sick woman with tachycardia caused by Graves’ Hyperthyroidism.  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 the patient took 75-100 mg of Iodine overnight.  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.(4)

In addition, Iodine inhibits release of Thyroxine (T4) from the thyroid gland, first demonstrated 1970 by Wartofsky who showed reduction in T4 levels even after massive doses of 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. 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 will decline promptly after excess Iodine administration, accounting for the success in treating Graves Hyperthyroidism.

Here I should mention that the inhibitory effect of Iodine works in autoimmune thyroid patients, both Graves and Hashimotos.  However, the effect is only temporary in normal healthy people because of autoregulation which compensates for the increased intra-thyroidal Iodine by decreasing activity of the NIS (sodium iodide symporter) the active transport for Iodine into the thyroid cells. This reduces concentration of iodine in the thyroid gland, compensating for the effect. Serum hormone levels eventually return to normal after about 4 weeks. In a few selected groups of patients this autoregulatory function has been lost, such as in auto-immune thyroid patients (Graves’ Disease and Hashimoto’s). In these Graves’ Disease patients in whom Iodine is successful, there is loss of this autoregulation and Iodine continues its inhibitory function.  Other groups of patients with similar loss of autoregulatory function are post-thyroiditis, post radiation therapy with Iodine, and a few others.(7-8)

Over the years, early pioneers used Iodine for treatment of Graves’ Disease.

In 1920’s, success in treating Graves Disease with high dose iodine, Lugol’s Solution, was reported by Drs. Plummer, Starr, Lahey and Charles Don. (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 is 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 theri hyperthyroidism worse, and they become thyrotoxic.  Toxic nodular goiter is a contraindication to the use of Iodine. This topic is discussed more completely in the chapter on Hyperthyroidism from 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 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 the3 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 Iodine, Inhibition of Organification, Inhibition of Release

As mentioned above, Iodine Inhibits its own organification, as well as inhibits release of thyroid hormone, thyroxine, 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. Thyroglobulin undergoes hydrolysis to yield thyroxine, thyroid hormone. The thyroid cells lining the follicles are the worker cells that secrete thyroglobulin into the follicles. In Graves’ Disease, hypertrophy of the thyroid cells lining the follicles is directly caused by stimulatory effect of abnormally high levels of TSI and TRAB antibodies which stimulate TSR receptors.  Although high TSH will cause an increase in hydrogen peroxide generation, the anti-TSH Receptor antibodies in Graves do not increase hydrogen peroxide generation. TSH receptor stimulation from TSH causes increased production of hydrogen peroxide and thyroglobulin, making the follicles larger and the entire gland larger than the normal thyroid gland. Histology of the thyroid gland in treated Graves disease may vary.

In 1986, Dr Hirota studied thyroid histology after long term methimazole treatment with 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 test for TRAb and TSI antibodies. Another way Hashitoxicosis can be differentiated from Graves Thyrotoxicosis is with iodine uptake after injection of radionuclide.  Uptake is high in Graves disease (over 30%), and very low in Hashitoxicosis (under 5%).

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, howebver, the radionuclide thyroid scan will typically show a diffusely enlarged gland with diffusely increased radiotracer uptake. Occasionally, in long standing Graves diease 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 demoonstrate 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 antiboody after end of methimazole treatment is associated with a 50% chance for relapse. (27-31)

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

Graves’s Hyperthyroidism is an auto-immune disease in which anti-thyroid antibodies, TSI and TRAB, attack and stimulate the TSH receptor. This stimulation causes hyperplasia of the thyroid gland which enlarges and increases production and release of thyroxine (thyroid hormone), thus causing hyperthyroidism. TSH stimulates virtually all steps in thyroid hormone synthesis.  In some patients, these same antibodies 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, the older iodine treatments were replaced by new anti-thyroid thionamide drugs such as PTU (propylthiouracil) and Methimazole (Tapazole).  Lugol’s Iodine or Potassium Iodide  is still in use as a short-term treatment for pre-operative preparation of the thyrotoxic Graves’ patient for thyroidectomy, usually in the hospital setting. The usual 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 usual practice by conventional endocrinology for fear of iodine escape, also called “rebound effect”.  (40-41)

Thyroid Ablation with Radio-Active Iodine or Surgery

Definitive treatment with thyroid ablation can be accomplished with two techniques.  The first is surgery with thyroidectomy. Both forms of thyroid ablation leave the patient hypothyroid requiring life-long thyroid hormone replacement medication.

Radioablation of the thyroid gland is performed by giving the patient by mouth a capsule containing radioactive Iodine (I-131).  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 becasue 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 L-thyroxine reduces the TSI (Graves Antibodies) and increases chance for remission.  In my opinion, Block and Replace is justified in patients who have an undulating course with frequent biochemical relapse. The advantage of block and replace is the TSH is reduced, preventing TSH stimulation of the thyroid which may increase damaging hydrogen peroxide and cause a bout of 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 medication dosage is not reduced, thus maintaining inhibition of TPO (with methimazole and iodine) and inhibition of thyroid hormone release (with iodine). (52-53)

Switching from Methimazole to Iodide for Pregnant Patients

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

The mean age of the 240 pregnant women was 33 years. Of the 240 patients, or 55%, went into remission and the Iodine could be completely tapered during the pregnancy.  The other 45% were still taking medication at delivery.  Of these, roughly half were taking potassium iodide (KI) alone and half were taking an anti-thyroid drug (such as methimazole) with or without KI.  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)

In 2020, Dr. Elizabeth Pearce concluded potassium iodide therapy for Graves’ should not be recommended outside of Japan because of the 9% worsened group, indicating escape from the anti-thyroid effect of iodine in the 2015 Yoshihara study.   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. (30) Emphasis Mine

Selenium Status and Escape from Iodine

Although there was a 91 per cent success rate with switching patients from methimazole to potassium iodide for treatment of hyperthyroidism, there was a 9.2 % escape rate in which hyperthyroidism worsened, requiring higher doses of methimazole for control. There was no obvious explanation for why this occurs in some patients and not others.

By the way, this 90 per cent success rate in Dr. Yoshihara’s study was similar to the success rate in a 1924 study by Dr Paul Starr at the Massachusetts General Hospital, treating 25 patients with exophthalmic goiter (Graves’ Disease) with Iodine alone (90 mg per day). A similar 88% success rate was obtained in 1930 by Dr. Thompson who treated 24 Graves’ Disease patients with Lugols 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 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. (7-8)

Predicting Iodine Escape

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.

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 abiltiy normalizes the TSH through downregulation of the the Na/Iodide Symporter, the active transport mechanism..This usually happens before the excess iodine has a chance to cause thyroiditis.

In Autoimmune Thyroid Disease, the autoregulatory ability is lost, and the suppressive effects of excess dietary iodine may continued indefinitely.  In this group, there may be intermittent episodes of thyroiditis. Hashitoxicosis is such an example of thyroiditis causing thyrotoxicosis, with low radio-iodine uptake.

Selenium/magnesium levels could be the defining factor in these intermittent bouts of thyroiditis.  According 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.

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 Endemic Goiter

Myxoedematous cretinism is a from of thyroid destruction first described in Zaire Africa.  In both Graves Hyperthroidism, and in myxoedematous endemic cretinism, there is massive stimulation of TSH Receptors. In Graves Disease this is a result of auto-Immune antibodies, while in myxoedematous cretinism, iodine deficiency and resulting hypothyroidism caused severe elevation of TSH.  In both cases there is marked stimulation of the TSH receptors, causing upregulation of all steps in thyroid hormone synthesis. One of these steps in production of hydrogen peroxide which is upregulated. In the selenium deficient population of Zaire, the selenium-based antioxidant system is dysfunctional and excess Hydrogen Peroxide cannot be neutralized. The hydrogen peroxide accumulates in the follicles causing oxidative damage to thyrocytes (cells lining the follicles), thyroiditis, inflammatory changes with apoptosis and necrosis. This thyroiditis leads to release of thyroid hormone, and a form of thyrotoxicosis with low radio-iodine uptake relatively resistant to Methimazole.  These features are similar to thyroiditis as seen in Hashitoxicosis.

A similar mechanism has been describe as the 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 to TPO and Throglobulin. In 2007, Dr Yue Song writes:

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 Graves’ Disease patient who is euthyroid from methimazole, a drug which irreversibly blocks the TPO enzyme.  Unfortunately, methimazole does not block hydrogen peroxide (H2O2) production which is still working. This amount of H2O2 may still be enough to overwhelm thyroid in selenium deficiency, causing intermittent bouts of thyroiditis. This is especially true if the methimazole dosage is high enough to suppress Free T3 and FreeT4 below the reference range. This will cause increase in TSH which may reach quite high levels.

The higher TSH stimulates production of hydrogen peroxide, and stimulates the production of thyroglobulin causing thyroid enlargement and goiter. Noticing the elevated TSH, the physician may be tempted to reduce the dosage of methimazole as was done in the Dr. Yoshihara’s study.

In the 2015, Dr. Yoshihara study, in some of these Graves Disease patients who had elevated TSH after starting Iodine, rather than reduction of methimazole dosage, these were treated with “block and replace”. Levothyroxine was added to bring down the TSH.  Perhaps in Block and Replace which prevents severe elevation of TSH, there is some protection from thyroiditis.

However, for the majority of patients being switched from Methimazole to Iodine, lowering the methimazole dosage allows the TSH to rise, which then stimulates production of thyroid hormone, including increased H202 and thyroiditis.  This may trigger massive oxidative damage leading 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, causing thyrotoxicosis. One might suggest a similarity with Hashi-toxicosis, an inflammatory process associated with decreased radiotracer Iodine uptake. This mechanism was confirmed in 2022 by Dr. Ken Okamura who reviewed 100 patients who presented with unexpected relapsing hyperthyroidism while decreasing dosage under treatment for Graves’ disease with Potassium Iodide, methimazole or PTU. Dr. Ken Okamura reports painless thyroiditis may mimick relapse of hyperthyroidism during or after potassium iodide or thionamide (Methimazole) therapy for Graves’ disease. The thyroiditis is a destructive inflammatory process within the thyoid gland representing a form of “self-ablation”, leading to remission (62)

In 2017, Dr Mara Ventura proposed this exact same mechanism for myxomatous cretinism, a combined iodine and selenium deficiency disease in young children in Zaire, Africa, causing destruction of the thyroid gland.  Dr Mara Ventura proposed the following mechanism: the 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 strongly 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 studued magnesium levels in hyperthyroid cats, finding hyperthyroidism increases renal ecretion 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. (66-69)(77-80)

I propose Selenium/Magnesium deficiency as an explanation for 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)

In 2017, Dr. Jan Calissendorf reviewed current status of use of Iodine 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 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 (Graves’ Disease) which has been described as common. 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…(8)

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…(8)

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…Reactivation of thyrotoxicosis could to some extent be explained by a stimulation of the immune system as elevation of TSH receptor antibodies has been noted in euthyroid patients preoperatively with 60 mg iodide twice daily for 10 days. However, in long-term treatment with iodide these antibodies have been reported to decline. (8)

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, writing a case report in 2004, a 40-year-old female with Graves’ Disease with undetectable TSH<0.01 μU/ml, and elevated Free T4 = 5 ng/dL. (Normal ranges: free T4 = .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 Lugols 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, we do not have studies to answer this question as yet. 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 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 the 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 hyperthyroidism from toxic multinodular goiter or autonomous nodule. For example, in 2000, Dr. Warren Heymann reviews the knowledge required of dermatologists before prescribing Iodine, mostly concerned with Iodine suppression of thyroid function, the Wolf-Chaikoff Effect (WCE) causing elevation of the TSH, reversible discontinuing the Iodine. Dr. Warren Heymann writes:

For dermatologists who use KI, 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 iodine use in clinical practice may dissuade the average clinician from using iodine.

If Iodine is used in Graves’ thyrotoxicosis, the patient must be followed more closely than is usually done in todays’ busy medical office, running on insurance business model.  Such patients require more frequent lab testing and follow up, or 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 simply choose to avoid Iodine.

Can Grave’s Disease be Cured?

In 2019, Dr Wilmar Wiersinga from Amsterdam asked the important question, “Can Grave’s 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 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 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 more severe undulating course, “Block and Replace” strategy may be justified.

Conclusion: Ignoring the use of Iodine in the Graves Disease patient is an error of modern endocrinology. Early studies suggested that Iodine alone could control thyrotoxicosis in the Graves’ Disease patient long term. However later studies found that about 9 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 Iodine only Short-Term, as is commonly done in preparation of the thyrotoxic patient for thyroidectomy, or in using Iodine in combination with another drug, either 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

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Extra References

DeCourcy, Joseph L. “THE USE OF LUGOL’S SOLUTION IN EXOPHTHALMIC GOITRE: AN EXPLANATION FOR THE BENEFICIAL RESULTS OF PRE-OPERATIVE MEDICATION.” Annals of Surgery 86.6 (1927): 871.

Quote from De Courcy 1927: Helmholz,’6 in i926, reported on the use of Lugol’s solution as a pre-operative measure for exophthalmic goitre in children. In thirty cases occurring in children under the age of fifteen, compound iodine solution, administered in doses of from 5 to IO minims three times a day, reduced the basal metabolic rate and controlled the toxic symptoms to a marked degree. In fourteen of the cases, the average reduction following iodine medication was I9 points. In the last eleven cases, the treatment made preliminary operation unnecessary.

They concluded that the use of Lugol’s solution by mouth produces abrupt remissions in many cases of exophthalmic goitre. In a later communication, Starr, Walcott, Segall and Means showed that the remission after iodine treatment is as immediate and extensive as that following subtotal thyroidectomy, but that iodine alone cannot suppress Graves’ disease permanently.

The explanation I have given would account for the fact that improvement from iodine medication is only temporary.

HISTOLOGY of the Thyroid after Iodine for Graves

Quote from De Courcy 1927:

This observation has led me to believe that the beneficial effects of iodine medication are brought about by a rapid formation of colloid material in a gland famished for iodine,

===== the administration of large doses of iodine (especially inorganic) causes a rapid accumulation of colloid in the alveolar spaces just as the administration of iodine to cases with marked hyperplasia of other clinical associations in man, dogs, sheep, birds and fish….

In a comparative series of thirty patients with Graves’ disease, fifteen of whom were treated pre-operatively with iodine and fifteen without. Rienhoff 22 established the fact that preliminary iodine therapy is associated with a change in the histologic appearance of the gland from a hyperplastic to a colloid state, even though there is definite evidence of the hyperplasia-still remaining. He observed that after iodine treatment the size of the gland as a whole is increased but that its vascularity, and probably also the lymph flow through the gland, is diminished. There was a striking increase in the amount of colloid deposited within the gland and also a large increase in the amount of fibrous connective tissue. Definite changes were observed in the acini. They were transformed from lace-like papillomatous ingrowths to round, even-walled, smooth acini of regular size and form. High columnar epithelium gave way to flat cuboidal and occasionally low columnar epithelium. The large clear nuclei of the epithelial cells in the untreated glands were replaced by the small, irregular, pycnotic type in the treated glands. Mitotic figures in the nuclei, so common in untreated cases, were absent when the patient received preliminary iodine medication. Rienhoff likens the change produced by iodine medication to an artificial remission of the thyroid hyperplasia .

Autonomous Nodule

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

Here, we present a case of iodine-induced thyrotoxicosis in a patient with multinodular goiter with autonomously functioning tissue. Initially, the source of iodine was not obvious, especially as iodinated contrast agents, amiodarone, or topical antiseptics were not used. Finally, after intensive questioning it was revealed that the consumption of a kelp-containing tea was the sought-after source of excessive iodine.

Stanbury, J. B., et al. “Iodine-induced hyperthyroidism: occurrence and epidemiology.” Thyroid: official journal of the American Thyroid Association 8.1 (1998): 83-100.

We have critically reviewed the available information on iodine-induced hyperthyroidism (IIH) from published sources and other reports as well as the experience of the authors in Tasmania, Zaire, Zimbabwe, and Brazil. Administration of iodine in almost any chemical form may induce an episode of thyrotoxicosis (IIH). This has been observed in epidemic incidence in several countries when iodine has been given as prophylaxis in a variety of vehicles, but the attack rate as recorded has been low. IIH is most commonly encountered in older persons with long standing nodular goiter and in regions of chronic iodine deficiency, but instances in the young have been recorded. It customarily occurs after an incremental rise in mean iodine intake in the course of programs for the prevention of iodine deficiency, or when iodine-containing drugs such as radiocontrast media or amiodarone are administered. The biological basis for IIH appears most often to be mutational events in thyroid cells that lead to autonomy of function. When the mass of cells with such an event becomes sufficient and iodine supply is increased, the subject may become thyrotoxic. These changes may occur in localized foci within the gland or in the process of nodule formation. IIH may also occur with an increase in iodine intake in those whose hyperthyroidism (Graves’ disease) is not expressed because of iodine deficiency. The risks of IIH are principally to the elderly who may have heart disease, and to those who live in regions where there is limited access to medical care. More information is needed on the long-term health impact of IIH or “subclinical” IIH, especially in the course of prophylaxis programs with iodized salt or iodinated oil in regions where access to health care is limited.

2009 Iodide reduces NIS mRNA and protein levels

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

In vivo data suggest that high concentrations of iodide lead to reduction in both NIS mRNA and protein levels, partially by a transcriptional mechanism. In vitro results suggest that exposure to high doses of iodide results in a decrease in NIS protein levels that is, at least in part, due to an increase in NIS protein turnover

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alternating Graves and Hashi

Alzahrani, Ali S., et al. “Autoimmune thyroid disease with fluctuating thyroid function.” PLoS medicine 2.5 (2005): e89

following treatment with I131, she developed multiple alternating phases of hypothyroidism and hyperthyroidism (Figure 1). It is possible that the thyroiditis caused by I131 induced some immune reaction, with the formation of stimulating and inhibiting antibodies leading later to alternating phases of hypo- and hyperthyroidism.

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25) 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.

Calissendorff

26) 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.

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.

Lugol’s solution (LS) was developed 1829 by the French physician Jean Guillaume August Lugol, initially as a cure for tuberculosis. It is a solution of elemental iodine (5%) and potassium iodide (KI, 10%) together with distilled water.

Already in the 1920s LS was given as a pre-treatment to thyroid surgery [1]. By that time LS became the standard pre-operative treatment in patients with Graves’ disease (GD). Iodide treatment could also be given as a saturated solution of potassium iodide (SSKI) or tablets.

Antithyroid drugs are often chosen since these are mostly well-tolerated, and can induce cure in around 50% after 12–18 months of treatment [10]. These pharmacologic compounds, propylthiouracil, methimazole or carbimazole, block the thyroid hormone synthesis by inhibiting thyroid peroxidase.

In the short-term LS reduces the thyroid hormones, T4 and T3 by increasing iodine uptake and inhibiting the enzyme thyroid peroxidase [22], thus attenuating oxidation and organification of thyroid hormones [23]. Moreover, the release of thyroid hormones is also blocked [24, 25]. The mechanism could partly be explained by activation of substances as iodolactones and iodoaldehydes as these have been shown to inhibit nicotinamide adenine, dinucleotide phosphate oxidase, thyroid peroxidase, and TSH-induced cyclic adenosine monophosphate (cAMP) formation in the thyroid [26].

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 [27]. 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-patients treated with radioiodine or subtotal thyroidectomy [28]. Thus, these are more prone to develop hypothyroidism secondary to an iodine overload.

Hyperthyroidism more commonly occurs in iodine deficient subjects, and in patients with multinodular goiter.

The escape from acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter causing a reduction in intrathyroidal iodide concentration [29]. There is also a form of escape following iodide therapy in GD which has been described as common [30, 31]. Thus, in treating patients with hyperthyroidism with LS 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 [32]

However, in the investigation by Takata et al. a combination of iodide solution was used together with methimazole for up to 8 weeks [33]. 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 [34].  Uchida T, Goto H, Kasai T, Komiya K, Takeno K, Abe H, Shigihara N, Sato J, Honda A, Mita T, Kanazawa A, Fujitani Y, Watada H. Therapeutic effectiveness of potassium iodine in drug-naive patients with Graves’ disease: a single-center experience. The initial dose of MMI was 14.0 ± 8.2 mg/day and that of KI was 53.6 ± 11.7 mg/day. Three patients of the KI group did not respond to the monotherapy, requiring the inclusion of antithyroid drugs.

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 [35]Okamura.

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 [36].

Reactivation of thyrotoxicosis could to some extent be explained by a stimulation of the immune system as elevation of TSH receptor antibodies has been noted in euthyroid patients preoperatively with 60 mg iodide twice daily for 10 days [37]. However, in long-term treatment with iodide these antibodies has been reported to decline [35].

 

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Okamura QQQQQQQQQQQQQQQQQQQQQQQQQQQQ

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27) 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.

If the patient insisted on receiving antithyroid drug therapy, low-dose thionamide (5–10 mg of MMI or 50–150 mg of PTU) was carefully added to 100 mg of KI, excluding patients with a history of agranulocytosis. After the patient achieved a euthyroid status, the thionamide drug was carefully discontinued, and the patient was treated with only KI for years during follow-up. After the disappearance of thyroid stimulation indices, including positive TBII or TSAb and an enlarged goiter (16), patients were asked whether they wished to stop the drug or continue the KI therapy. If patients remained euthyroid for more than 2 years after stopping the drug, they were considered to have entered remission (R group). Otherwise, the patients were classified into the non-remission group (NR group). The long-term prognosis was compared with that of similarly treated patients who received thionamide after showing minor side effects.

 

Among

1388 patients with Graves’ hyperthyroidism treated with thionamides,

204 (14.7%) exhibited side effects, and

44 were treated with KI and followed for 17.6 (median; range, 8.6-28.4) years.

Results: The conditions of

29 (65.9%) of the 44 patients were well controlled with KI alone (10-400 mg/d) (A group), and

17 (38.6%) patients went into remission after 7.4 (1.9-23.0) years.

The conditions of 15 (34.1%) patients were not controlled with KI alone (B group), even at a high dose (100-750 mg/d), but

seven patients (15.9%) were controlled with a combination of KI and low-dose thionamides, resulting in remission after 7.2 (2.8-10.8) years.

The initial parameters did not predict the response to KI or long-term prognosis. However, remission occurred in 70.8% of the patients treated with less than 200 mg of KI, compared with 35.0% of the patients who required 200 mg or more of KI (P < .05).

 

Iodide therapy alone was not effective in 15 patients in the B group. However, seven patients became euthyroid by adding small doses of thionamide without side effects for a few years and then were kept euthyroid with only KI, resulting in remission.

the effect of iodide on the inhibitory effect of thionamides on thyroid peroxidase activity is very complicated (28). The inactivation of thyroid peroxidase by thionamide can be prevented by increasing the iodide concentration (28). However, our clinical study suggested that the effects of thionamides and excess iodide are additive when a large amount of iodide required for the Wolff-Chaikoff effect is administered concomitantly. Seven other patients in the B group were successfully treated with RI as usual. After the withdrawal of KI and iodide restriction, most of the iodide administered was excreted into urine within a few days, suggesting that the KI therapy did not interfere with the efficacy of RI therapy..

 

Conclusions: Among hyperthyroid patients with thionamide-associated side effects, KI therapy was effective in two-thirds of cases, and about 40% of the patients experienced remission after KI therapy alone. The chance of remission was small among the patients refractory to KI.

Before 1990, a small amount of KI (13–39 mg) was administered. However, it became apparent that some patients required more KI, and the initial dose was increased to 39–65 mg in 1990, and then to 100 mg after 1996. The dose of KI was increased to 200–500 mg when euthyroidism was not achieved. Escape from the KI effect was suggested when the serum fT4 and/or free T3 (fT3) level again became elevated while taking KI. If the patient remained euthyroid for 2 years with KI alone, the initial response to KI was considered to be good (A group). If the response was poor and the serum fT4 and/or fT3 levels remained elevated, RI therapy was again recommended (B group). If the patient insisted on receiving antithyroid drug therapy, low-dose thionamide (5–10 mg of MMI or 50–150 mg of PTU) was carefully added to 100 mg of KI, excluding patients with a history of agranulocytosis. After the patient achieved a euthyroid status, the thionamide drug was carefully discontinued, and the patient was treated with only KI for years during follow-up.

In the B group, seven of the 15 patients became euthyroid with careful combined therapy of KI and a small amount of thionamides for 1–3 years. No side effects were observed with this small dose of thionamides, and the patients have since remained euthyroid with only KI. They finally stopped taking KI after 7.2 (2.8–10.8) years and remained in remission for 10.7 (4.0–16.5) years thereafter (B-R group). A dramatic decrease in the TBII and TSAb levels and estimated thyroid weight was observed in the B-R group (Figure 1).

BLOCK and Replace
Five patients in the A group (three in the A-R group, and two in the A-NR group) became hypothyroid while taking 20–200 mg of KI. The patients were successfully treated with combined therapy of KI and synthetic L-thyroxine (50–75 μg), and all drugs were withdrawn without relapse in the A-R group.

Among 103 patients who were continuously treated with thionamides even after showing adverse events, 84 patients were followed for more than 5 years. Forty-two (50%) of the patients went into remission with a negative TBII titer. After remission, the estimated thyroid weight significantly decreased from a median of 28 (range, 10–75) g to 10 (10–28) g (P < .001).

Iodide therapy alone was not effective in 15 patients in the B group. However, seven patients became euthyroid by adding small doses of thionamide without side effects for a few years and then were kept euthyroid with only KI, resulting in remission. The effect of iodide on the inhibitory effect of thionamides on thyroid peroxidase activity is very complicated (28). The inactivation of thyroid peroxidase by thionamide can be prevented by increasing the iodide concentration (28). However, our clinical study suggested that the effects of thionamides and excess iodide are additive when a large amount of iodide required for the Wolff-Chaikoff effect is administered concomitantly.

It must be stressed that, if the patients preferred KI therapy after showing side effects to thionamide, continuous administration of a large amount of KI was necessary until remission, and that 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.

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Okamura 2022 !!!!!!!!!!!!!!!!!!!!!!!!!!!!

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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.

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 [1]. These two conditions may represent a single disease entity with a wide range of manifestations. The concept of painless thyroiditis (painless low-uptake thyrotoxicosis without hyperthyroidism; PT) has been recognized since 1975 [2-10], and postpartum PT has been reported since 1977 The golden-standard factor to consider for the differential diagnosis is the thyroidal radioactive iodine uptake (RAIU), which is high in GD and almost null in typical PT 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 [38]. It is therefore plausible that a decreased ATD dosage might increase TPO activity and thereby increase the production of compound X, 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

As shown in Table 2-I, 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 [41, 42], KI treatment may precipitate the “iodide thyroiditis” reported by Edmunds in 1955 [43]. In the same year as Gluck reported convincing cases with PT [2], Savoie reported 10 cases of iodine-induced thyrotoxicosis in apparently normal thyroid glands, ranging from 1 to 40 months after exposure to excess iodine [44]. They all showed a typical clinical course of PT with a low RAIU followed by hypothyroidism.

Although Jod-Basedow or iodine-induced hyperthyroidism is well-known risk of administering iodine

for endemic goiter [45], iodine-induced hyperthyroidism [46, 47], exacerbation of Hashimoto thyroiditis with reversible hypothyroidism [48] and amiodaroneassociated thyroid dysfunction [49] have been reported in iodine sufficient areas. These functional abnormalities, in addition to pathological abnormalities [41, 42, 48], including a toxic effect observed on electron microscopy

[50, 51], suggested the possibility of slow chemical ablation by excess iodide in susceptible patients. This effect may be one of the reasons for the increased incidence of remission or spontaneous hypothyroidism observed following an episode of PT (Table 6). If patients lack serious signs and

symptoms of thyrotoxicosis, including atrial fibrillation, it may be wise to carefully follow those without ATD. If the serum fT4 and TSH levels normalize within 2 and 4 months, respectively, the diagnosis of PT is extremely likely (Table 5-III). Otherwise, the readministration of ATD should be considered. The diagnosis can be confirmed by the suppressed RAIU (<5%/5 h) in the thyrotoxic state, which remains a valuable factor for differentiating PT from relapse of GD.

 

 

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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.

iodide in higher doses is an established and time-honored treatment of GD

However, both MMI and PTU were still associated with severe notorious [22-26] or unfamiliar [27-29] 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. Compared with the era of Plummer [7] and Thompson [8], recent advances in thyroid function tests and medical screening have revealed many patients to have mild or even asymptomatic GD that may be  sensitive to excess iodide [20].

Between 1996 and 2004, a total of 504 patients with untreated GD who visited our hospital without impending serious symptoms were treated with KI (100 mg once daily after breakfast).

When the serum fT4 and/or fT3 levels became elevated after temporary reduction in serum fT4 levels while taking 100 mg KI within 180 days, they were diagnosed as showing escape from acute KI effects [10]

For patients in Group C and escaped or symptomatic patients in Group B, the KI dosage was reduced to 100 mg, and low-dose (5–15 mg) MMI (depending on the severity of thyrotoxicosis) was added to KI (combined KI and MMI therapy). In the patients who were resistant to these treatments, high-dose (20–30 mg) MMI was added to KI, or ablative therapy, such as radioactive iodine (RI) or surgery, was recommended. If MMI was added to KI before the fT4 level normalized within 180 days, they were classified as Group C.

Electron microscopic studies revealed an altered follicle shape and diminished numbers of microvilli [47] or apical blebbing, cytoplasmic fragments desquamation, endoplasmic reticulum vesiculation and accumulation of lipofuscin in secondary lysosomes [48] in the presence of 10–6 M or 10–5 M NaI.

The prevalence of KI-induced hypothyroidism was 18.3% (Group A1). This iodide-induced hypothyroidism would be troublesome in cases of Hashimoto thyroiditis [1, 2, 5, 6] but might be beneficial to GD ameliorating hyperthyroidism. It was very important to keep the serum iodide level above the threshold for the WC effect, avoiding the tapering method usually performed in MMI therapy.

Escape was observed in none of the patients in Group A, suggesting the importance of TSH in avoiding the escape phenomenon. The precipitating role of TSH in the WC effect has been suggested in cases of reversible iodide-induced hypothyroidism in humans [2, 5, 6] as well as in iodine deficient rat [40].The KI dosage could be reduced later when TBII became negative or patients had nearly achieved remission.

KI-resistant patients or continuous TSH suppression with escape were more frequent among patients with a larger thyroid volume (≥40 mL) and higher fT3 level (>10 pg/mL) than among other patients (Tables 2, 3).

increased fT3 level rather than an increased fT4 level would be a better predictor of KI resistance or escape (Table 1). T3 predominant synthesis and secretion is a good marker of the thyroid gland being strongly stimulated with high turnover of both Tg and iodide, as found in cases of iodine deficiency [55].

About 42.7% of the escaped patients belonged to Group C. 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 (Fig. 3) or RI therapy. The inhibitory effect of MMI on the thyroid gland depending on the iodine intake is very complicated [56, 57]. MMI was also considered to be actively incorporated into the thyroid gland, but the active transport mechanism for MMI was different from that for iodide [21, 41]. After the administration of 5–15 mg MMI in addition to 100 mg KI in this study, the time required for the normalization of the serum fT4 level was 49 (28–70) days, which was shorter than 54 (30–100) days observed when GD patients were initially treated by 15 mg MMI monotherapy [34]. The prevalence of iatrogenic hypothyroidism during treatment was 36.5% during combined KI and 5–15 mg MMI therapy in this study  (Fig. 2), much higher than 10.8% found in 15 mg MMI treated patients [34]. The additive effect of excess iodide and MMI was strongly suggested [58].

Regarding RI therapy, KI therapy may interfere with the efficacy of RI therapy, which is quite concerning.

However, most of the excess iodide that did not enter the thyroid gland was rapidly excreted into the urine, as reported previously [17] and confirmed in this study (Table 4). After RI treatment in Groups B and C, 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 RI.

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,

KI is the least expensive modality without any serious side effects. When we use drugs with serious side effects, such as MMI, it is better to try to reduce the dosage [63];

however, when we use drugs that are relatively inexpensive with extremely rare side effects, such as KI, a sufficient dosage may be administered from the beginning.

 

 

See (32) 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.

 

Block and replace:

28) 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.

Reduces TSI and increases chance for remission

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Yoshihara Substituting Potassium Iodide for Methimazole in the First Trimester of Pregnancy

29) 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

 

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.

Background: The clinical course of Graves’ disease (GD) in women who switched from methimazole (MMI) to potassium iodide (KI) during the first trimester of pregnancy has never been reported in detail. Objective: To investigate the characteristics of GD patients whose thyroid hormone levels increase after substituting KI for MMI. Patients: Two hundred forty women with GD who had been treated with MMI and switched from MMI to inorganic iodide to control hyperthyroidism during the first trimester between January 1, 2005, and March 31, 2018.

Results:
In 133 (55.4%) of the GD patients, medication was completely tapered during pregnancy, and

the other 107 (44.6%) GD patients were taking medication at delivery:
57 were taking KI alone and 50 were taking an antithyroid drug with or without KI.

It was difficult to control the maternal thyrotoxicosis of 22 of the 107 patients 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.

Pearce,

30) 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.

The mean age of the 240 participants at the time of delivery was 33 years. 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”(4). I do not think that the results of the current study (2) are likely to alter that guidance.

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Kubota, Sumihisa, et al. “The prevalence of transient thyrotoxicosis after antithyroid drug therapy (withdrawal)  in patients with Graves’ disease.” Thyroid 18.1 (2008): 63-66.

Background: Although transient thyrotoxicosis occurring after antithyroid drug (ATD) withdrawal in patients with Graves’ hyperthyroidism has been reported, the prevalence of transient thyrotoxicosis after ATD therapy is as yet unknown. When patients with transient hyperthyroidism are mistakenly regarded as recurrences, they receive unnecessary therapy. The aim of this study was to investigate the prevalence of transient thyrotoxicosis after ATD withdrawal.

 

Methods: We selected 110 consecutive patients with Graves’ disease whose ATD therapy was stopped from December 2002 to September 2004 prospectively. Patients were observed for more than 1 year after ATD withdrawal, and 12 patients dropped out. Serum levels of free thyroxine (FT(4)), thyrotropin, and thyrotropin-binding inhibitor immunoglobulin were measured at ATD withdrawal, and 3, 6, and 12 months after withdrawal. When the patients showed mild thyrotoxicosis (serum FT(4) level of less than 3.00 ng/dL), we followed them up for 1 month without medication.

 

Results: The remission rate of the study group was 61.8% (68/110). Twenty-eight patients became euthyroid after transient thyrotoxicosis, equivalent to 41.2% of the remission patients. Eight of 28 patients showed overt thyrotoxicosis, and the rest subclinical thyrotoxicosis. Transient thyrotoxicosis occurred mostly 3-6 months after ATD withdrawal.

 

Conclusions: Transient thyrotoxicosis after ATD withdrawal in patients with Graves’ disease is not a rare phenomenon. Clinicians should be aware that the recurrence of Graves’ disease after the withdrawal of ATD may be transient.

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Uncontrolled Graves’ disease Rx with LUGOLS then thyroidectomy

Calissendorff, Jan, and Henrik Falhammar. “Rescue pre-operative treatment with Lugol’s solution in uncontrolled Graves’ disease.” Endocrine connections 6.4 (2017): 200-205.

Twenty-six patients (96%) had a prior treatment with methimazole, 16 (59%)

had also tried to switch to propylthiouracil due to side effects. LS treatment was initiated in an

outpatient setting in twelve patients (44%) with a dose of drops containing 6.7 mg/drop, most

often 5 drops thrice, i.e., 100.5 mg iodine daily (timepoint 0). In all cases a set date for

surgery was decided before iodine treatment was started, 7-10 days before thyroidectomy.  Therapy was initiated at the ward in remaining fifteen patients (56%). In poor responders, measured as elevated heart rate >80 and/or still evidence of biochemical hyperthyroidism, the dose was doubled after 2-5 days (n=15, 58%) (timepoint 1). A further re-evaluation was made

at day 5 (5-9) (timepoint 2). All patients were admitted for the last part of the iodine treatment

(6 days (0-12)), and recovery after surgery (1 day (1-3)).

In all, patients received 1005 mg iodine (168-2110 mg)(Fig. 1). Initial dose in three patients was 1 drop thrice daily, and the one patient later treated with radioiodine was only taking LS for three days, explaining the wide range.

Admission was planned in 22 patients (81%), while five patients (19%) were

admitted acutely with a combination of atrial flutter and heart failure in one, rash in two and

agranulocytosis and sepsis in two patients. A heart rate <80 was required before surgery.

All but one of the patients (96%) was also treated with the beta-blocker propranolol as a part of

the pre-operative treatment. The dose was initially 120 mg daily (40-240), and was increased

during LS therapy to 130 mg (80-320) (P=0.005). Treatment with adjunctive therapy as

cholestyramine or corticosteroids was not used

 

An intriguing aspect is the risk of exacerbating hyperthyroidism by time with

prolonged iodine treatment. The therapeutic window has been claimed to be 10–14 days after iodine administration before the blocking effect vanishes. It has been reported that T4 and T3 start to increase again after 21 days of iodine treatment in hyperthyroid patients [33]. Phillppou,  see  (21)

On the other hand, in Japan long-term treatment with iodine has been used, alone or together with anti-thyroid drugs, to achieve euthyroidism with good results [34]. Okamura, K  See above:  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

Whether this also works in patients with other ethnic backgrounds and iodine intake is not known and should be explored in future trials.

In conclusion, treatment of uncontrolled hyperthyroidism with LS is safe and

decreases thyroid hormones and pulse frequency. Side effects were limited. LS could be

recommended pre-operatively in GD with failed medical treatment, especially if side effects

to antithyroid drugs have occurred

Phillppou,  see  (21)

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.

Note 2% Lugols        2 drops = 5 mg iodine
20 drops = 50 mg
40 drops = 100 mg iodine

================

BRAVERMAN, LEWIS E., et al. “Enhanced susceptibility to iodide myxedema in patients with Hashimoto’s disease.” The Journal of Clinical Endocrinology & Metabolism 32.4 (1971): 515-521.

——————————

 

26) From GOODMAN & GILMAN’S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS – 11th Ed. (2006) :

 

Mechanism of Action.

 

High concentrations of iodide appear to influence almost all important aspects of iodine metabolism by the thyroid gland (Roti and Vagenakis, 2005). The capacity of iodide to limit its own transport has been mentioned above. Acute inhibition of the synthesis of iodotyrosines and iodothyronines by iodide also is well known (the Wolff-Chaikoff effect). This transient, 2-day inhibition is observed only above critical concentrations of intracellular rather than extracellular concentrations of iodide. With time, “escape” from this inhibition is associated with an adaptive decrease in iodide transport and a lowered intracellular iodide concentration, most likely due to a decrease in NIS mRNA and protein (Eng et al., 1999). The mechanism of the acute Wolff-Chaikoff effect remains elusive and has been postulated to be due to the generation of organic iodo-compounds within the thyroid (Pisarev and Gartner, 2000).An important clinical effect of high [I-]plasma is inhibition of the release of thyroid hormone. This action is rapid and efficacious in severe thyrotoxicosis. The effect is exerted directly on the thyroid gland and can be demonstrated in the euthyroid subject as well as in the hyperthyroid patient. Studies in a cultured thyroid cell line suggest that some of the inhibitory effects of iodide on thyrocyte proliferation may be mediated by actions of iodide on crucial regulatory points in the cell cycle (Smerdely et al., 1993).In euthyroid individuals, the administration of doses of iodide from 1.5 to 150 mg daily results in small decreases in plasma thyroxine and triiodothyronine concentrations and small compensatory increases in serum TSH values, with all values remaining in the normal range. However, euthyroid patients with a history of a wide variety of underlying thyroid disorders may develop iodine-induced hypothyroidism when exposed to large amounts of iodine present in many commonly prescribed drugs (Table 56-6), and these patients do not escape from the acute Wolff-Chaikoff effect (Roti et al., 1997). Among the disorders that predispose patients to iodine-induced hypothyroidism are treated Graves’ disease, Hashimoto’s thyroiditis, postpartum lymphocytic thyroiditis, subacute painful thyroiditis, and lobectomy for benign nodules. The most commonly prescribed iodine-containing drugs are certain expectorants, topical antiseptics, and radiological contrast agents.

 

———-

 

27) http://rnjournal.com/journal-of-nursing/thryoid-storm-and-the-aacn-synergy-model

 

nursing case report of thyroid storm treated with Lugols

RN Journal 2014 Journal of Nursing Deborah L. Bray, RN, BSN, CNS Graduate Student Murray State University

Critical care nurses should be familiar with the regimen of medications administered during thyroid storm. The first medication administered should be an anti-thyroid medication such as propylthiouracil (PTU) which blocks the synthesis of thyroid hormones and inhibits the peripheral conversion of T4 to T3. The dosage is 200-250mg every 4 hours orally or via gastric tube. The nurse should monitor for signs of bleeding and a decreased platelet count. Methimazole, another anti-thyroid medication does not work in the periphery as PTU does; therefore, PTU is the anti-thyroid medication of choice during thyroid storm (Dahlen, 2002; Dulak, 2005; Kaplow & Hardin, 2007).

 

One to two hours later, a potassium iodide solution such as Lugol’s solution should be administered to prevent the release of stored thyroid hormone into the system. Timing of this medication is important as early administration of iodide may cause the body to synthesize more T4, worsening the toxic state.

Th dosage is 8 drops every 6 hours orally or via gastric tube

(Dahlen, 2002; Dulak, 2005; Kaplow & Hardin, 2007).(Dahlen, 2002; Dulak, 2005; Kaplow & Hardin, 2007).

 

———-

preo-op preparation of graves patient using iopanoic acid GB radiographic contrast,  iodineated contrast material instead of iodine full pdf available

 

28) Panzer, Claudia, Robert Beazley, and Lewis Braverman. “Rapid preoperative preparation for severe hyperthyroid Graves’ disease.” The Journal of Clinical Endocrinology & Metabolism 89.5 (2004): 2142-2144.

Conventional preoperative preparation for TX includes antithyroid drugs and iodine administration before surgery and often takes months to render patients euthyroid. Far more rapid control of thyrotoxicosis can be achieved by  the oral administration of iodinated radiographic contrast agents (IRCAs) such as iopanoic acid (IOP) or ipodate, often given in combination with corticosteroids and antithyroid drugs, and -blockers.IRCAs have a multitude of effects on thyroid physiology and thyroid hormone metabolism. They competitively inhibit types 1 and 2 5 -monodeiodinase in the liver, brain, and thyroid, thereby blocking the conversion of T4 to T3. This leads to a rapid and persistent reduction of T3, while reverse T3 levels increase due to decreased clearance of reverse T3 (5– 8). IRCAs also decrease serum T4 levels in hyperthyroid patients due to a decrease in the thyroidal organification of iodine and thyroid hormone secretion from the gland due to the iodine released from these agents (9 –11).

However, serum T4 levels decrease more slowly with IRCAs  than with potassium iodide treatment, probably reflecting the decrease in the plasma clearance rate of T4 and a decrease in the hepatic uptake of T4 by displacement of T4 from hepatic binding sites (12). Iodine released from IRCAs also reduces intraoperative blood loss by decreasing thyroid vascularity(13–15)

Modern MAnagement

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

Attempts to enhance remission rates so far failed. Administration of levothyroxine after discontinuation of ATD seemed to increase remission rate [36], but subsequent studies could not confirm the initially promising results and this particular treatment modality is not used any longer [37,38]. Likewise, adding selenium to ATD did increase remission rate in a pilot study [39], but not in a subsequent placebo-controlled RCT [40].

The average remission rate after a course of ATD is about 50% [21]. Most recurrences occur within 4 years after discontinuation of ATD [3]. Although prognosis is excellent after 4 years without relapse [30], late recurrences do occur and only one in three patients experiences permanent remission [21]. Remission rate after 10 years is in the order of 30% to 40%, and hypothyroidism has developed in 10% to 15% 15 years after ATD [59]. Taken into account the above reviewed literature, permanent cure of Graves’ hyperthyroidism is possible albeit at a low rate of about 27% (Fig. 2). The cure rate would be even lower if cure also supposes the absence of TSH receptor antibodies.

 

Adult studies have shown that RAI can trigger the development or exacerbation of pre-existing GO  Graves Orbitopathy

Thyroidectomy adverse effects : hypocalcaemia (22%) and recurrent laryngeal nerve injury (5.4%).36

 

30) 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).

The near-uniform avoidance of using RAI in patients with Graves’ ophthalmopathy is striking and attributable mainly to the Italian studies showing that RAI worsens ophthalmopathy and that this can be prevented by corticosteroids (4,5).  It is difficult to predict how patients with Graves’ disease will be treated 20 years from now, but I hope that we will have some rational therapy that is directed at the autoimmune origin and that makes our entire current armamentarium obsolete.

 

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1987 Methimazole

 

31) MESSINA, M., et al. “Initial treatment of thyrotoxic Graves’ disease with methimazole: a randomized trial comparing different dosages.” Journal of endocrinological investigation (Testo stampato) 10.3 (1987): 291-295.

 

We evaluated the efficacy of different doses of methimazole (MMI) as the initial therapy for Graves’ disease. Fourteen patients were treated with 15 mg/die of the drug (group A) and 14 with 30 mg/die (group B). Blood samples for T3, T4, FT3 and FT4 were obtained before beginning therapy, every 48 h during the first 12 days and on the 45th day of treatment. All these hormonal parameters fell significantly from the 2nd day of therapy in both groups. All the patients, except for one in group B, had normal or subnormal levels of thyroidal hormones on the 45th day of treatment. The comparison between the two groups of regression coefficients over the first 12 days showed no significant differences. The absolute decrease of each examined parameter on day 12 was positively correlated with the relevant pretreatment value. These results demonstrate that doses of MMI (15 mg/die) much lower than those commonly recommended are able to rapidly control thyroidal overproduction as effectively as 30 mg/die.

 

Takata  2010 use KI (SHORT TERM)  with Methimazole

 

32) 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

 

Combined treatment with anti-thyroid drugs (ATDs) and potassium iodide (KI) has been used only for severe thyrotoxicosis or as a pretreatment before urgent thyroidectomy in patients with Graves’ disease. We compared methimazole (MMI) treatment with MMI + KI treatment in terms of rapid normalization of thyroid hormones during the early phase and examined the later induction of disease remission.

DESIGN AND PATIENTS: A total of 134 untreated patients with Graves’ disease were randomly assigned to one of four regimens: Group 1, MMI 30 mg; Group 2, MMI 30 mg + KI; Group 3, MMI 15 mg and Group 4, MMI 15 mg + KI. For easy handling, KI tablets were used instead of saturated solution of KI. KI was discontinued when patients showed normal free thyroxine (FT4) levels but MMI was continued with a tapering dosage until remission. Remission rate was examined during a 4- to 5-year observation.

MEASUREMENTS:  Serum FT4, FT3 and TSH were measured by chemiluminescent immunoassays. TSH receptor antibody (TRAb) was assayed with TRAb-ELISA. Goitre size was estimated by ultrasonography.

RESULTS:  After 2 weeks of treatment, normal FT4 was observed in 29% of patients in Group 1 and 59% (P < 0.05) of patients in Group 2. Furthermore, normal FT4 after 2 weeks of treatment was observed in 27% of patients in Group 3 and 54% (P < 0.05) of patients in Group 4. Similarly, FT3 normalized more rapidly in Groups 2 and 4 than in Groups 1 and 3. None of the patients showed an increase in thyroid hormones or aggravation of disease during combined treatment with MMI and KI. The remission rates in Groups 1, 2, 3 and 4 were 34%, 44%, 33% and 51%, respectively, and were higher in the groups receiving combined therapy but differences among four groups did not reach significance.

CONCLUSIONS:  Combined treatment with MMI and KI improved the short-term control of Graves’ hyperthyroidism and was not associated with worsening hyperthyroidism or induction of thionamide resistance.

 

33) Girgis, Christian M., Bernard L. Champion, and Jack R. Wall. “Current concepts in Graves’ disease.” Therapeutic advances in endocrinology and metabolism 2.3 (2011): 135-144.

Graves’ disease is the most common cause of hyperthyroidism in the developed world. It is caused by an immune defect in genetically susceptible individuals in whom the production of unique antibodies results in thyroid hormone excess and glandular hyperplasia. When unrecognized, Graves’ disease impacts negatively on quality of life and poses serious risks of psychosis, tachyarrhythmia and cardiac failure. Beyond the thyroid, Graves’ disease has diverse soft-tissue effects that reflect its systemic autoimmune nature. Thyroid eye disease is the most common of these manifestations and is important to recognise given its risk to vision and potential to deteriorate in response to radioactive iodine ablation. In this review we discuss the investigation and management of Graves’ disease, the recent controversy regarding the hepatotoxicity of propylthiouracil and the emergence of novel small-molecule thyroid-stimulating hormone (TSH) receptor ligands as potential targets in the treatment of Graves’ disease.

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TSI and TRAB antibodies

34) 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.

In conclusion, thyroid-stimulating antibodies in a bioassay or TSH-receptor antibodies detected with the h-TBII assay have the highest diagnostic power to differentiate Graves’ disease from toxic multinodular goitre.

 

34a)  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.

Graves’ disease is characterized by stimulating autoantibodies to the TSH-receptor (TRAb). The aim of this study was to compare the performance of a new TRAb assay based on competitive binding to recombinant human TSH-receptors (H-TRAb) with an assay employing purified porcine TSH-receptors (P-TRAb). Furthermore, to evaluate the applicability of the H-TRAb assay to discriminate between patients with hyperthyroidism due to Graves’ disease (GD) and multinodular toxic goitre (MNTG).

DESIGN AND MEASUREMENTS: H-TRAb and P-TRAb were measured in patients with newly diagnosed hyperthyroidism due to GD (n = 106) and MNTG (n = 94). For comparison, TRAb was measured in patients with primary autoimmune hypothyroidism, euthyroid subjects with an enlarged thyroid gland by ultrasound, and healthy controls (n = 100 for each group). Patients were consecutively included from a population survey.

RESULTS: If the cut-off values recommended by the manufacturer for TSH-receptor antibody positivity were used for evaluation, the sensitivity of the H-TRAb assay vs. the P-TRAb assay in diagnosing GD was: 95.3/67.9% (P < 0.001). Specificity was (H/P-TRAb): 99/99%. The sensitivity of P-TRAb was increased if the upper 97.5% limit of measurements in controls was used as cut-off (H-TRAb vs. P-TRAb: 95.3/80.2%, P < 0.001). Specificity (H/P-TRAb): 98/98%. The difference between assay performance may partly be due to a better technical performance of the H-TRAb assay with more reliable results in the low range of measurements. However, even in GD patients with clearly measurable TRAb, 25% had a P-TRAb < 50% of the value expected from the H-TRAb measurement. This suggests that a subgroup of patients produce TRAb with a higher affinity for the human than the porcine TSH receptor. A relatively high proportion of patients with MNTG were TRAb positive (H-TRAb/P-TRAb: 17/9%). Characteristics of H-TRAb positive and negative MNTG patients were compared. There was no difference between size of thyroid gland and number of nodules by ultrasonography. H-TRAb positive patients had significantly higher serum T4 and T3 and a greater number were TPO-Ab positive.

CONCLUSIONS: H-TRAb diagnosed Graves’ disease with a high sensitivity and specificity than P-TRAb. The high occurrence of TRAb in multinodular toxic goitre might in part reflect an overlap between Graves’ disease and multinodular toxic goitre in some patients.

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).

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

 

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.

Elevated TBIAb activity at the end of anti-thyroid drug treatment was found in 52.9% of Graves’ patients who subsequently relapsed, while in Graves’ patients in remission TBIAb was always negative.

 

 

SSKI Iodine in Graves

35) Robuschi, G., et al. “Effect of sodium ipodate and iodide on free T4 and free T3 concentrations in patients with Graves’ disease.” Journal of endocrinological investigation 9.4 (1986): 287-291.

Graves’ hyperthyroid patients were treated daily for 10 days with 1 g sodium ipodate, a cholecystographic agent which exerts a blocking effect on the peripheral conversion of T4 to T3, or with 12 drops of saturated solution of potassium iodide (SSKI). Serum concentrations of free T4 (FT4) and free T3 (FT3) were measured before, during and 5 and 10 days after the administration of each drug. Sodium ipodate treatment induced a rapid decrement of serum FT4 concentrations which declined from 48.9 +/- 6.6 pg/ml to 26.0 +/- 2.7 pg/ml. In these patients serum FT3 concentrations declined from 12.4 +/- 2.0 pg/ml to 2.5 +/- 0.4 pg/ml. Ten days after sodium ipodate withdrawal, serum FT4 and FT3 concentrations returned to baseline values. In patients treated with SSKI serum FT4 concentrations declined from 51.1 +/- 8.8 pg/ml to 11.3 +/- 1.4 pg/ml and FT3 from 15.7 +/- 2 pg/ml to 2.6 +/- 0.3 pg/ml. Moreover, after therapy interruption serum free thyroid hormone concentrations returned to baseline values in these patients. Serum FT4 pattern during the study was not different between the two groups of subjects whereas serum FT3 concentrations were significantly lower in patients treated with sodium ipodate. These findings indicate that SSKI and sodium ipodate are effective in inducing a rapid decrement of serum free thyroid hormone concentrations. Therefore the employment of these drugs may be useful in the treatment of patients with thyroid storm and those undergoing thyroidectomy

 

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Etiology Molecular Mimicry

Add here articles on H. Pyloiri see Diane Zlot emails

Graves case report  Graves Hyperthyroidism, Celiac, Gluten, Wheat, Yersinia Abs cross react with TSH Abs, Leaky Gut .  Clinical Case Report of  37 y/o female with Graves Hyperthyroidism and Celiac Dx who becomes euthyroid on Gluten Free Diet

36) Huang, Cindy, Amy Toscano-Zukor, and Xiangbing Wang. “Case Report: Hyperthyroidism, Iron-deficiency Anemia, and Celiac Disease.” Thyroid Science 4.3 (2009).

The objective was to report a case of a woman with celiac disease presenting with hyperthyroidism and iron-deficiency anemia. Methods. We report the clinical course of this patient and her laboratory findings. We highlight the important associations between hyperthyroidism, iron-deficiency anemia, and celiac disease. The literature is reviewed for the typical and atypical presentations of celiac disease in relation to hyperthyroidism and iron-deficiency anemia. Results. A 37-year-old woman presented with symptoms of hyperthyroidism and was found to have iron-deficiency anemia. During the work up for iron-deficiency anemia, she was diagnosed with celiac disease on small-bowel biopsy. After being placed on a gluten free diet, symptoms of hyperthyroidism improved without anti-thyroid medication.

Conclusion. Our case demonstrates that routine screening for celiac disease should be highly considered for patients with both hyperthyroidism and celiac

Graves and Yersinia 1986

37) Heyma, P. A. U. L. A., L. C. Harrison, and R. Robins-Browne. “Thyrotrophin (TSH) binding sites on Yersinia enterocolitica recognized by immunoglobulins from humans with Graves’ disease.” Clinical and experimental immunology 64.2 (1986): 249.                                                                                              Antibodies against the gram negative enteric bacterium Yersinia enterocolitica have been found in a high proportion of persons with autoimmune thyroid disorders, especially in those with Graves’ disease or hyperthyroidism (Shenkman & Bottone, 1981). There is strong evidence that Graves’ disease is caused by receptor autoantibodies which mimic the bioeffects of thyroid stimulating hormone (TSH) on the thyroid (Manley, Knight & Adams, 1982).

 

Recently, saturable binding sites for TSH were demonstrated in Y. enterocolitica under non-physiological conditions (Weiss et al., 1983). We have characterized TSH binding sites on Y. enterocolitica under physiological conditions and studied their interaction with Graves’ immunoglobulins (Ig’s). Saturable and specific binding of receptor-purified 125I-TSH to lysozyme/EDTA-treated Y. enterocolitica (serotype 03) was demonstrated under both non-physiological and  physiological conditions. Scatchard binding plots were linear indicating a single class of binding site (Kd 1 X 10(-7) M, maximum of 30,000 binding sites  per cell). In the presence of Graves’ Ig’s the binding of 125I-TSH to Y. enterocolitica was significantly inhibited. Graves’ Ig’s also precipitated a  protein of relative molecular mass (Mr) 64,000 from Triton-solubilized, 125I-labelled Y. enterocolitica, similar in size to one of the proteins precipitated  by Graves’ Ig’s from human thyroid membranes.

These findings are consistent with the hypothesis that thyroid autoimmunity may be triggered by bacterial  infection via a mechanism involving crossreactivity at the level of the TSH receptor. They also suggest that elements of mammalian endocrine systems are  highly conserved and have a function in prokaryotes.

38) Petru, G., et al. “Antibodies to Yersinia enterocolitica in immunogenic thyroid diseases.” Acta Medica Austriaca 14.1 (1987): 11-14.

In 1976 Shenkman et al. revealed that in patients with thyroid disorders antibodies against Yersinia enterocolitica could be demonstrated in increased frequency. In 1983 Ingbar et al. first established that the gram-negative bacterium Yersinia enterocolitica shows on its surface saturable binding sites for thyrotropin (TSH). If such binding sites resemble immunologically human TSH receptors this would indicate that TSH receptor antibodies could be produced in selected individuals having been infected with bacteria showing TSH receptors. The aim of our study was to compare the incidence of antibodies against Yersinia enterocolitica in two groups of thyroid disorders which are either immunogenic (Graves’ disease and Hashimoto thyroiditis) or non-immunogenic (toxic adenomas, endemic goitre). In our series of 111 patients antibodies against Yersinia enterocolitica were demonstrated in a significantly higher percentage (36.3%) in patients suffering from immunogenic than in patients with non-immunogenic thyroid disorders (19.6%). The antibody titres were mainly directed towards Yersinia subtypes 8 and 3. It may, therefore, be assumed that the gram-negative bacterium Yersinia enterocolitica may have an active part in triggering immunogenic thyroid diseases such as Graves’ disease or Hashimoto thyroiditis.

1990

39) TAKUNO, HIROSHI, SHIGEKI SAKATA, and KIYOSHI MIURA. “Antibodies to Yersinia enterocolitica serotype 3 in autoimmune thyroid diseases.” Endocrinologia japonica 37.4 (1990): 489-500.

Abstract The prevalence of increased titres of antibodies to Yersinia enterocolitica (serotype 3) has been studied in sera from patients with various thyroid diseases. In contrast to the low prevalences of the antibodies in healty subject (24.3%), titres (greater than 10) of anti-Yersinia enterocolitica (anti-Yersinia) were found more frequently in patients with thyroidal disorders, especially in Graves’ disease (70.0%).

Furthermore, high titres of the antibodies (greater than or equal to 160) were found only in patients with Graves’ disease.

There was no significant correlation between the titers of anti -Yersinia antibodies and those of anti-TSH receptor antibodies in sera from patients with Graves’ disease. In seven individual samples of sera, the anti- Yersinia antibody titer was high before treatment, but the decrease in the anti-TSH receptor antibody titer following treatment was associated with a  simultaneous decline in anti-Yersinia antibodies in all of them. A highly positive and significant correlation between the titers of anti-TSH receptor antibodies and anti-Yersinia antibodies was obtained in each of them. These findings could be merely a reflection of the measurement of the cross-reaction of anti-Yersinia antibodies with anti-TSH receptor antibodies but the possibility of an association between Yersinia infection and the production of anti-TSH receptor antibodies in at least some patients with Graves’ disease cannot be ruled out.

40) Çorapçioğlu, Demet, et al. “Relationship between thyroid autoimmunity and Yersinia enterocolitica antibodies.” Thyroid 12.7 (2002): 613-617.

It has previously been proposed that subclinical Yersinia enterocolitica infection may play a role in autoimmune thyroid disease (AITD). In this study, we investigated the relationship between the thyroid autoantibodies and the antibodies that produced against different serotypes of Y. enterocolitica. A total of 215 subjects were included into the study (65 newly diagnosed Graves’ disease [GD], 57 Hashimoto’s thyroiditis [HT], 53 nontoxic diffuse goiter [NTDG], and 40 subjects for control group [CG]). Thyroid receptor antibodies (TRAb), thyroid and agglutinating antibodies against Y. enterocolitica serotype O:3, O:5, O:8, O:9 were measured in the blood samples. The highest incidence of Y. enterocolitica antibody positivity was measured in GD (53.8% for O:3, 29.2%  for O:5, 44.6% for O:8, and 40% for O:9) and followed by HT. In patients with GD, TRAb levels were also higher than in patients with HT, NTDG, and CG. There  was no difference between NTDG and CG in respect to the titer levels and the positivity of both TRAb and Y. enterocolitica antibodies. There was also a weak linear correlation between TRAb level and the titer of antibodies against Y. enterocolitica antigens. It can be concluded that Y. enterocolitica infection may play a role in etiology of GD in Turkey.

41) Brix, Thomas H., et al. “Too early to dismiss Yersinia enterocolitica infection in the aetiology of Graves’ disease: evidence from a twin case–control study.” Clinical Endocrinology 69.3 (2008): 491-496.

Yersinia enterocolitica (YE) infection has long been implicated in the pathogenesis of Graves’ disease (GD). The association between YE and GD could, however, also be due to common genetic or environmental factors affecting the development of both YE infection and GD. This potential confounding can be minimized by investigation of twin pairs discordant for GD.  We first conducted a classical case-control study of individuals with (61) and without (122) GD, and then a case-control study of twin pairs (36) discordant for GD.  Immunoglobulin (Ig)A and IgG antibodies to virulence-associated Yersinia outer membrane proteins (YOPs) were measured.  The prevalence of YOP IgA and IgG antibodies.

 

RESULTS: Subjects with GD had a higher prevalence of YOP IgA (49% vs. 34%, P = 0.054) and YPO IgG (51% vs. 35%, P = 0.043) than the external controls. The  frequency of chronic YE infection, reflected by the presence of both IgA and IgG YOP antibodies, was also higher among cases than controls (49%vs. 33%, P = 0.042). Similar results were found in twin pairs discordant for GD. In the case-control analysis, individuals with GD had an increased odds ratio (OR) of YE infection: IgA 1.84 (95% CI 0.99-3.45) and IgG 1.90 (95% CI 1.02-3.55). In the co-twin analysis, the twin with GD also had an increased OR of YE infection: IgA 5.5 (95% CI 1.21-24.81) and IgG 5.0 (95% CI 1.10-22.81).

 

CONCLUSION: The finding of an association between GD and YE in the case-control study and within twin pairs discordant for GD supports the notion that YE  infection plays an aetiological role in the occurrence of GD, or vice versa.

 

2011

 

42) Guarneri, Fabrizio, et al. “Bioinformatics support the possible triggering of autoimmune thyroid diseases by Yersinia enterocolitica outer membrane proteins homologous to the human thyrotropin receptor.” Thyroid 21.11 (2011): 1283-1285.

_______________________________

 

thyroid eye disease

 

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

radioiodine therapy for Graves’ disease can exacerbate ophthalmic disease;

44) 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.

45) 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.\

Our work demonstrates that TSHR protein expression in the orbit is confined to patients with TAO and is associated with elongated fibroblast-like cells.  In conclusion, until now our study is the largest study of TAO biopsies and it brings strong evidence that TSHR protein is present in the orbit and is specific for TAO. All the results corroborate the important and specific role of TSHR expression in the orbital tissues and of TRAB for the early process of TAO pathogenesis.

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

The development of the eye-muscle component of TAO can be best explained by T-cell targeting of an eye-muscle membrane antigen, whereas reactivity against TSH-r in the orbital fibroblast may be the key abnormality that leads to the congestive ophthalmopathy subtype, as well as other features of connective-tissue disorder in Graves’ disease.

autoimmunity against a thyroid-stimulating hormone receptor (TSH-r)–like protein in the orbital preadipocyte and, possibly, extraocular muscle fibre.

autoimmunity against TSH-r, expressed in fat and connective tissue, could explain the development of pretibial myxedema, acropachy and the OCT component of TAO

the eye-muscle and OCT–fat reactions are both autoimmune disorders that can occur alone or together in patients with thyroid autoimmunity, manifesting as 3 subtypes of TAO: ocular myopathy, congestive ophthalmopathy or mixed disease. In ocular myopathy, double vision, reduced eye movement and increased volumes of eye muscle (seen with orbital imaging techniques) result from damage to the eye muscles. In congestive ophthalmopathy, eye swelling, redness, chemosis and increased tearing are caused by inflammation in the periorbital tissues. Mixed disease is the most common manifestation of TAO. Chronic eyelid lag, occurring alone or with other features of TAO, may be a fourth subtype

 

full pdf

 

47) 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.

We propose that ocular myopathy and chronic eyelid retraction are due to autoimmunity against skeletal muscle calsequestrin in the extraocular and eyelid muscles, respectively. This may be initiated in the thyroid where calsequestrin expression is upregulated, possibly due to a stimulatory effect of TSH-r antibodies. We also propose that congestive ophthalmopathy results from a reaction against the TSH-r or collagen XIII in orbital fibroblast cell membranes.

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Zonulin and Leaky Gut

ful pdf

 

48) Fasano, Alessio.  Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer. Physiol Rev 91: 151–175, 2011;

 

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Lithium and Iodine Combination for Graves

49) Reversing hyperthyroidism by Jonathan Wright MD, Nutrition & Healing Newsletter Sept 8, 2011.

 

I have used that treatment for my patients with tremendous success ever since that study was released. In fact, every individual (except one) whom I’ve treated with iodine-iodide (in the form of Lugol’s Solution) and high dose lithium has had blood tests for thyroid hormone return to normal within two weeks. Their tests then stay normal as long as they use the Lugol’s solution and high dose lithium.

I have my patients use five drops of Lugol’s iodine three times a day for two or three days. Then I have them add 300 milligrams of lithium carbonate three times a day in addition to the Lugol’s.  (94 mg) Lugol’s Solution is available at any pharmacy, but you’ll have to get a prescription from your physician.

5% Lugol’s Solution 1 drop of 5% solution contains 6.25 mgs of iodine 2 drops of 5% solution contains 12.5 mgs of iodine

8 drops of 5% solution contains 50 mgs of iodine

16 drps = 100 mg

15 drops = 94 mg

Walter Reed Lithium and Iodine

50) Lithium and iodine combination therapy for thyrotoxicosis. Acta endocrinologica, 94(2), 174-183. Boehm, T. M., Burman, K. D., Barnes, S., & Wartofsky, L. (1980).  Walter Reed Army Hospital

 

In order to compare the relative therapeutic efficacy of iodine (I) and lithium (Li) in thyrotoxicosis, investigate possible additive effects of these agents, and examine their effect upon thyroidal release, 17 thyrotoxic patients were assigned to groups given either I (n = 9) or Li (n = 8) alone during an initial treatment period, with the alternate drug added as combination treatment during a second treatment period. Half of the patients received methimazole (MMI). Three additional thyrotoxic patients received I during both treatment periods to evaluate the possibility of cumulative I effect upon thyroidal release during the second treatment period. A double isotope technique was utilized as an index of thyroidal release, employing 125I as an intra-thyroidal label and [131I] T4 as a marker of T4 disposal. During the first treatment period either I or Li induced comparable, significant (P < 0.05) decreases in thyroidal release, as measured by slopes of ratios of serum PB125I: PB131I and by percentage inhibition of fractional T4 release rate. In response to Li, there was a 55% decrease in the slope of PB125I: PB131I with MMI and a 52% decrease without MMI. In response to I, there was a 70% decrease in the slope of PB125I: PB131I with MMI and a 57% decrease without MMI.

Further significant (P < 0.05) decreases in the slopes of these ratios during the second, combined treatment period (I + Li) occurred only in those patients who had initially received I. No further decreases in the second treatment period were seen in patients receiving I during both treatment periods. Thus, I and Li together display additive inhibition of thyroidal release only if I is administered initially, but the combination, if Li is used first, does not appear to be more effective than Li alone.

 

51)  BURMAN, KENNETH D., et al. “Sensitivity to lithium in treated Graves’ disease: effects on serum T4, T3 and reverse T3.” The Journal of Clinical Endocrinology & Metabolism 43.3 (1976): 606-613.

 

these observations support the thesis that the inhibitory effects of lithium and iodine upon thyroid hormone synthesis or secretion may involve a similar mechanism of action since increased thyroidal iodine content may be a consequence of therapy with either agent.


Combined Lithium – Methimazole

52) Wünsch, C., and H. J. Heberling. “Results of lithium treatment in severe hyperthyroidism.” Deutsche Zeitschrift fur Verdauungs-und Stoffwechselkrankheiten 44.1 (1984): 26-31.

Up to the present time lithium therapy is under discussion in patients with severe, particularly of contrast remedy induced hyperthyroidism. The aim of our presentation was to investigate if the short term combined methimazole-lithium therapy in the initial phase will be advantageous in contrast to the monotherapy of methimazole. The examination in our material showed a good effectiveness and tolerance of the combined therapy. At present the precise mechanism of action of lithium has not been elucidated. There is evidence that lithium inhibits the thyreoglobulin hydrolysis and the peripheral conversion of thyroxin to triiodothyronin. Other actions are under discussion. In our opinion only the combined methimazole-lithium therapy will be advantageous. Through this procedure an earlier drug effect could be expected and the increase of thyroid hormones after finishing lithium therapy will be suppressed. In the own material severe side effects are not demonstrable.

Lithium as Treatment for Thyrotoxicosis

similarity of inhibition of iodine release from the thyroid produced by Li(+) and iodides

53)   Temple, R. M. J. J., et al. “The use of lithium in the treatment of thyrotoxicosis.” The Journal of Clinical Investigation 51.10 (1972): 2746-2756.

Since lithium has been shown to inhibit release of iodine from the thyroid, we have investigated its therapeutic potential in thyrotoxicosis. Eight detailed (131)I kinetic studies were performed on seven thyrotoxic women and data was analyzed using a computer program. Lithium at serum levels of about 1 mEq liter decreased the loss of (131)I from the thyroid, led to a fall in serum (131)I levels and diminished urinary (131)I excretion. Computer simulation of the lithium effect required, in every case, that lithium inhibit hormonal and nonhormonal thyroid iodine release. In five cases a second lithium effect was required for a satisfactory fit of the model solution with observed data: namely, an inhibition of hormone disappearance from serum

NEITHER INHIBITION OF RELEASE NOR OF HORMONE DISAPPEARANCE SEEMED TO BE AFFECTED BY METHIMAZOLE (RELEASE: 52% decrease without methimazole, 60% with methimazole; hormone disappearance: approximately 60% decrease in both).

When Li(+) was discontinued, recovery of the iodine release rate and hormone disappearance rate over the observed time span was variable, ranging from no recovery to rates that exceeded pre-Li(+) values. When Li(+) is used alone its effect on serum hormone levels is diminished due to continued accumulation of iodide by the thyroid.

Thus, serum thyroxine-iodine levels fell 21-30% in 6-8 days in patients who did not receive methimazole and 15-67% in the methimazole-treated subjects. For prolonged therapy, therefore, a thiocarbamide drug must be used in conjunction with Li(+). The similarity of inhibition of iodine release from the thyroid produced by Li(+) and iodides is discussed.

 

54) Kristensen, O., H. Harrestrup Andersen, and G. Pallisgaard. “Lithium carbonate in the treatment of thyrotoxicosis: a controlled trial.” The Lancet 307.7960 (1976): 603-605.

Of 24 patients with newly diagnosed thyrotoxicosis, 13 were randomly selected for treatment with methimazole 40 mg per day, and 11 for treatment with lithium carbonate in such doses that the serum lithium lay between 0-5 and 1-3 meq. per litre. The lithium treatment brought about a fall in serum-thyroxine iodine (T4I) of 27.0%, and in the free-thyroxine index (F.T.I.) of 38.1% after 10 days. A comparison of the two patient groups with regard to the fall in F.T.I. after 3 and 10 days showed no statistically significant difference; similarly the calculated confidence limits appeared to exclude any difference of clinical importance. 8 of the 11 patients subjected to lithium treatment had side-effects, so that the general condition, which was already affected by the hyperthyroidism, was worsened. It is concluded that lithium cannot be considered superior to thiocarbamides for the rapid control of thyrotoxicosis.

 

55) Benbassat, Carlos A., and Mark E. Molitch. “The Use of Lithium in the Treatment of Hyperthyroidism.” The Endocrinologist 8.5 (1998): 383-388.

We describe four patients treated with lithium for the control of hyperthyroidism. Conventional therapy with propylthiouracil and/or methimazole was tried initially, but the patients were either unresponsive or developed side effects during the drug administration. Within several days of reaching therapeutic levels of lithium, a euthyroid state was achieved in three of the four cases. Our observations support the use of lithium as an alternative antithyroid drug in the treatment of hyperthyroidism in certain defined indications, a clinical use that is not widely known.

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Medical treatment of Graves state of the art

Fumarola, A., Di Fiore, A., Dainelli, M., Grani, G., & Calvanese, A. (2010). Medical treatment of hyperthyroidism: state of the art. Experimental and clinical endocrinology & diabetes, 118(10), 678.

honda, A., et al. “RELATIONSHIP BETWEEN THE EFFECTIVENESS OF INORGANIC IODINE AND THE SEVERITY OF GRAVES’THYROTOXICOSIS: A RETROSPECTIVE STUDY.” Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists (2017).

iodine combined with methimazole was required to ultimately restore euthyroidism. Case report.

Boehm, T. M., et al. “Iodine treatment of iodine-induced thyrotoxicosis.” Journal of Endocrinological Investigation 3.4 (1980): 419-424.

A 62-year-old female who had received prolonged iodine therapy for asthma presented with severe thyrotoxicosis and severe asthma. Her history, elevated serum thyroxine and triiodothyronine, low 131I uptake, and elevated intrathyroidal iodine content by fluorescent scan were most consistent wiht a diagnosis of iodine-induced thyrotoxicosis (IITT). The clinical course of her thyrotoxicosis was protracted, and in spite of its etiologic role in the precipitaton of thyrotoxicosos, iodine was therapeutically efficacious, although combined treatment with methimazole was required to ultimately restore euthyroidism. Therapy with lithium was also employed but appeared to be only transiently effective and combined no additional decrement in serum T4 than that seen with iodine alone. The case exemplifies the heterogeneity of what is considered “iodine-induced” thyrotoxicosis, the complexities inherent in establishing a diagnosis of IITT, and the use of other rapid acting pharmacologic agents in IITT when beta blockade is contraindicated by asthma.

 

2020 More Recent:  Iodine for Graves Hyperthyroidism

64) Suzuki, Nami, et al. “Therapeutic efficacy and limitations of potassium iodide for patients newly diagnosed with Graves’ disease.” Endocrine Journal (2020): EJ19-0379.

KI therapy appears to offer an effective and potentially safer therapy for about 60% of female patients with mild GD, and thus could represent a third drug option for these patients.

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Long term Iodine compared to MMI in Graves over 12 months

65) Uchida, Toyoyoshi, et al. “Therapeutic effectiveness of potassium iodine in drug-naïve patients with Graves’ disease: a single-center experience.” Endocrine 47.2 (2014): 506-511.

Patients who continued the initial treatment showed significant and comparable reductions in FT4, FT3 and TRAb by MMI as well as by KI at the end of 12-month treatment. Although patients were limited to mild untreated Graves’ disease thyrotoxicosis, KI offers a possible alternative initial treatment for this condition.

Iodine is beneficial against Graves’ thyrotoxicosis, though its effects are short-lived. However, its long-term effectiveness as an initial therapy has not been fully elucidated. Here, we compared the effects of potassium iodine (KI) and methimazole (MMI) in Graves’ thyrotoxicosis and on thyrotropin receptor antibody (TRAb) levels. Between 2008 and 2011, 293 patients with untreated Graves’ disease visited the outpatient clinic of Juntendo University. Of these, 227 patients were treated with MMI and 30 treated with KI as the initial therapy. To compare the effects of KI and MMI, we identified patients with similar probabilities of receiving MMI or KI using propensity score (PS) analysis based on the observed clinical features. PS matching created 20 matched pairs of patients with Graves’ disease treated with MMI and KI. The baseline characteristics of post-matched patients treated with MMI were comparable to those treated with KI (FT3; 7.16 ± 2.30, 6.56 ± 1.85 pg/ml, FT4; 2.57 ± 0.79, 2.49 ± 0.70 ng/dl, respectively). The initial dose of MMI was 14.0 ± 8.2 mg/day and that of KI was 53.6 ± 11.7 mg/day. Three patients of the KI group did not respond to the monotherapy, requiring the inclusion of antithyroid drugs. One patient on MMI developed moderate skin eruption, but continued the treatment. Patients who continued the initial treatment showed significant and comparable reductions in FT4, FT3 and TRAb by MMI as well as by KI at the end of 12-month treatment. Although patients were limited to mild untreated Graves’ disease thyrotoxicosis, KI offers a possible alternative initial treatment for this condition.

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Combined Iodine and Methimazole for Graves 2015 Initial Therapy  Sato

Initial Therapy

Sato, Shotaro, et al. “Comparison of efficacy and adverse effects between methimazole 15 mg+ inorganic iodine 38 mg/day and methimazole 30 mg/day as initial therapy for Graves’ disease patients with moderate to severe hyperthyroidism.” Thyroid 25.1 (2015): 43-50.

Background: Methimazole (MMI) is usually used at an initial dose of 30 mg/day for severe Graves’ disease (GD) hyperthyroidism, but adverse effects are more frequent at this dose than at MMI 15 mg/day.

Objectives: We designed a regimen to address the lack of a primary therapeutic effect of the MMI 15 mg/day by combining it with inorganic iodine at 38.2 mg/day. Our aim was to compare the two regimens (MMI 15 mg+inorganic iodine at 38.2 mg/day (M15+I) vs. MMI 30 mg/day (M30)) in terms of therapeutic effect, adverse effects, and remission rate.

Design and patients: In a prospective study, 310 patients with untreated GD (serum free thyroxine (fT4) ≥5 ng/dL) were assigned to one of the two regimens. Potassium iodide was discontinued in the M15+I group as soon as the serum fT4 level was within the reference range (0.8-1.6 ng/dL).

Results: Percentages of patients achieving an fT4 level within reference range in ≤30, ≤60, or 90 days on the study treatment regimens were 45.3%, 73.9%, and 82.0% respectively for the M15+I group, and 24.8%, 63.1%, and 75.2% respectively for the M30 group. Hence, the proportions of patients achieving this goal in ≤30 or ≤60 days were significantly larger in the M15+I group.

Adverse effects that required discontinuation of MMI were more frequent in the M30-treated than in the M15+I-treated group (14.8% vs. 7.5%; p=0.0387).

The remission rates in the M15+I and M30 groups were 19.9% and 14.8%-higher in the former, but the difference did not reach statistical significance.Conclusion: The results of this study raise the possibility that M15+I is superior to M30 as a primary treatment for moderate to severe hyperthyroidism caused by GD.

Substituting Iodine for MMI in pregnancy Sometimes an ATD is added to the iodine

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.

Background: To control hyperthyroidism due to Graves’ disease, antithyroid drugs should be administered. Several studies have shown that exposure to methimazole (MMI) during the first trimester of pregnancy increases the incidence of specific congenital anomalies that are collectively referred to as MMI embryopathy. Congenital anomalies associated with exposure to propylthiouracil (PTU) have also recently been reported.

Methods: This study investigated whether substituting potassium iodide (KI) for MMI in the first trimester would result in a lower incidence of major congenital anomalies than continuing treatment with MMI alone. The cases of 283 women with Graves’ disease (GD) were reviewed whose treatment was switched from MMI to KI in the first trimester (iodine group), as well as the cases of 1333 patients treated with MMI alone (MMI group) for comparison. Another major outcome of interest was the incidence of neonatal thyroid dysfunction. The subjects of the analysis of major congenital anomalies and neonatal thyroid dysfunction were live-born infants.

Results: The incidence of major anomalies was 4/260 (1.53%) in the iodine group, which was significantly lower than the incidence of 47/1134 (4.14%) in the MMI group. Two neonates in the iodine group had anomalies consistent with MMI embryopathy (0.8%), as opposed to 18 neonates in the MMI group (1.6%). None of the neonates exposed to KI had thyroid dysfunction or goiter.

Conclusions: Substituting KI for MMI as a means of controlling hyperthyroidism in GD patients during the first trimester may reduce the incidence of congenital anomalies, at least in iodine-sufficient regions.

Their thyroid hormone levels were measured again two to four weeks after the switch to iodine. KI was prescribed as an inorganic iodine dose of 10–30 mg/day in the form of a solution (10 mg of KI per drop of the infusion) or KI tablets (38 mg of KI per tablet). When the fT4 level after the substitution was within the reference range, the KI dose was tapered, and when the fT4 level had risen, the KI dose was increased during the first trimester. When a patient being treated with KI was still hyperthyroid in the second trimester, an ATD was added to KI, or an ATD was substituted for KI.

 

See 25) Calissendorff, Jan, and Henrik Falhammar. “Lugol’s solution and other iodide preparations: perspectives and research directions in Graves’ disease.” Endocrine 58 (2017): 467-473.

However, in the investigation by Takata et al. a combination of iodide solution was used together with methimazole for up to 8 weeks [33]. 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 Lugols (50–100 mg daily), control of hyperthyroidism after 12 months was comparable with that seen in patients receiving low-dose methimazole treatment [34].

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 [35].

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 [36]. Reactivation of thyrotoxicosis could to some extent be explained by a stimulation of the immune system as elevation of TSH receptor antibodies has been noted in euthyroid patients preoperatively with 60 mg iodide twice daily for 10 days [37]. However, in long-term treatment with iodide these antibodies has been reported to decline [35].

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Short term Iodine plus MMI  Takata

See (32)

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.

Objective: Combined treatment with anti-thyroid drugs (ATDs) and potassium iodide (KI) has been used only for severe thyrotoxicosis or as a pretreatment before urgent thyroidectomy in patients with Graves’ disease. We compared methimazole (MMI) treatment with MMI + KI treatment in terms of rapid normalization of thyroid hormones during the early phase and examined the later induction of disease remission.

Design and patients: A total of 134 untreated patients with Graves’ disease were randomly assigned to one of four regimens: \\

Group 1, MMI 30 mg;

Group 2, MMI 30 mg + KI;

Group 3, MMI 15 mg and

Group 4, MMI 15 mg + KI.

For easy handling, KI tablets were used instead of saturated solution of KI. KI was discontinued when patients showed normal free thyroxine (FT4) levels but MMI was continued with a tapering dosage until remission. Remission rate was examined during a 4- to 5-year observation.

Measurements: Serum FT4, FT3 and TSH were measured by chemiluminescent immunoassays. TSH receptor antibody (TRAb) was assayed with TRAb-ELISA. Goitre size was estimated by ultrasonography.

Results: After 2 weeks of treatment, normal FT4 was observed in 29% of patients in Group 1 and 59% (P < 0.05) of patients in Group 2. Furthermore, normal FT4 after 2 weeks of treatment was observed in 27% of patients in Group 3 and 54% (P < 0.05) of patients in Group 4. Similarly, FT3 normalized more rapidly in Groups 2 and 4 than in Groups 1 and 3. None of the patients showed an increase in thyroid hormones or aggravation of disease during combined treatment with MMI and KI. The remission rates in Groups 1, 2, 3 and 4 were 34%, 44%, 33% and 51%, respectively, and were higher in the groups receiving combined therapy but differences among four groups did not reach significance.

Conclusions: Combined treatment with MMI and KI improved the short-term control of Graves’ hyperthyroidism and was not associated with worsening hyperthyroidism or induction of thionamide resistance.

iodide is primarily used in conjugation with ATDs to prepare patients for thyroidectomy.15 Iodide administration in combination with ATDs has been reported to reduce the efficacy of ATDs in vitro.

16–18 Roti et al. reported that the combination of ATDs with Lugol’s Iodine was no more effective than ATDs alone in restoring serum thyroid hormone concentrations to normal. However, sodium ipodate added to ATDs did reduce serum T3 and control heart rate more rapidly.7 Martino et al. reported that monotherapy of Graves disease with iodide produced only short term control of thyrotoxicosis and that its use impaired the efficacy of subsequent treatment with ATDs.19  In this study, however, we clearly observed the rapid reduction of thyroid hormones by combination therapy with MMI and KI and hormone reduction is more effective than with MMI monotherapy.

In Japan, Kasai et al.22 used propylthiouracil (PTU) (300 mg/day) combined with small doses of iodide (3 or 6 mg/day) for <3 weeks and they found that combined therapy was much more effective than PTU or iodide alone in the early phase of treating hyperthyroidism, although they did not examine the long term effect. Their data and our results in this study clearly show the effectiveness of combined therapy with ATDs and KI in the early normalization of thyroid hormones.

Although it is well known that use of iodide as monotherapy may result in escape from control of thyrotoxicosis,23 our study shows that this does not occur when iodide is administered contemporaneously with ATDs. Nor did we observe a reduction in the effectiveness of ATDs when iodide was administered In this study, however, the remission rate was higher in the group receiving combination therapy than that in the group receiving MMI alone, although the difference did not reach significance.

The remission rate after 2–3 years of treatment with ATDs is around 40% in Japan 25 and our study does not indicate an adverse effect of iodide on remission rate.

. In combined therapy with MMI 15 mg and KI, normal FT4 was obtained in 73% of patients after 4 weeks of treatment, although the duration of KI usage was slightly longer than that of those receiving MMI 30 mg + KI treatment. If iodine is to be used in combination with ATDs for treatment of  thyrotoxicosis due to Graves disease, then our study suggests that 15 mg of methimazole is adequate.

 

Jeong, Kyung Uk, Hae Sang Lee, and Jin Soon Hwang. “Effects of short-term potassium iodide treatment for thyrotoxicosis due to Graves disease in children and adolescents.” Annals of Pediatric Endocrinology & Metabolism 19.4 (2014): 197-201.

The use of potassium iodide in combination with antithyroid drug is effective for more rapid normalization of thyroid hormones in the early phase treatment of childhood thyrotoxicosis, but larger studies with adequate power are needed in future.

Combination Methimazole and Iodine  – Aggravation when Iodine discontinued

Tachibana, Seigo, et al. “An Analysis for Aggravation of Thyroid Function After Discontinuing Potassium Iodine in Graves’ Patients Treated With Methimazole and Potassium Iodine.” Journal of Endocrinology and Metabolism 3.6 (2014): 132-137.

In fact, the frequency of agranulocytosis by MMI at a dose of 15 mg per day was significantly lower than that by MMI at a dose of 30 mg per day. Thus, one way to reduce the risk of agranulocytosis by MMI is the combination therapy of a relatively small dose of MMI and potassium iodine (KI) in the initiation therapy. Actually, the administration of KI for GD patients has been shown to be one useful therapeutic choice, which can correct thyroid function very rapidly. It is well known that adequate dose of KI suppresses the release and synthesis of thyroid hormone in the thyroid of GD patients [4, 5]. In situations that a rapid correction of thyroid function is required, such as severe thyrotoxicosis containing thyroid storm and preparation for urgent thyroidectomy, KI treatment has also been reported to be definitely advantageous [6-9].  Takata et al reported that initial therapy using MMI combined with KI is useful to correct thyroid function in GD patients in Japan [10]. In their report, when free T4 (FT4) was corrected to the normal range, KI was discontinued. After cessation of KI, transient aggravation of thyroid function was observed in 8.1-9.4% of patients

Between April 2010 and December 2012, 565 GD patients visited Yamashita Thyroid and Parathyroid Clinic. Of these, 87 patients received MMI combined with KI therapy as an initial treatment, because their concentrations of thyroid hormone were extremely high, or their clinical manifestations associated with thyrotoxicosis were remarkable.

Both MMI (daily dose of 10 – 20 mg) and KI (daily dose of 50 mg) were prescribed to these subjects.

When the KI dose was judged to be proper, 50 mg of KI medication was continued for a while and stopped or tapered. In the tapering of KI, the dose was reduced to 25 mg per day, continued for a while and finally stopped. MMI was tapered every 5 mg at the reduction of MMI.

In conclusion, our study suggested that the methods of drug adjustment and “the duration from initiation of medication to normalization of thyroid hormone” may be significant factors of transient aggravation after cessation of KI in patients with GD treated with MMI combined with KI. It may be better not to reduce both drugs simultaneously, especially in patients who show the relatively shorter duration of normalization of thyroid function.

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Methimazole resistance case report

LI, HUA, et al. “A Hyperthyroid Patient with Graves’ Disease Who Was Strongly Resistant to Methimazole Investigation on Possible Mechanisms of the Resistance.” Endocrine Journal 42.5 (1995): 697-704.

Patient A was hospitalized  on May 14, 1993. Since June 7th, she had been kept normal serum T3 and T4 levels with 150 mg of MMI and an additional 450 mg dose of PTU followed by 15 drops of Lugol’s solution per day. Subtotal thyroidectomy was performed on July 8th.

Mechanisms

Raby, C., et al. “The mechanism of action of synthetic antithyroid drugs: iodine complexation during oxidation of iodide.” Endocrinology 126.3 (1990): 1683-1691.

These results suggest that synthetic antithyroid agents may act either on peroxidase and/or the molecular iodine which may be produced by oxidation of iodides (21- →I2 → 2I+). It has been shown that oxidation of I- can occur in the absence of thyroglobulin. In the absence of a suitable receptor, significant amounts of I2 may, thus, accumulate. The action of such drugs on molecular iodine may have considerable pharmacological significance. (Endocrinology126: 1683–1691, 1990)

Lagorce, J. F., et al. “Formation of molecular iodine during oxidation of iodide by the peroxidase/H2O2 system. Implications for antithyroid therapy.” Biochemical pharmacology 42 (1991): S89-S92.

 

 

Remission rate with Methimazole

van Lieshout, Jelmer M., et al. “Methimazole-induced remission rates in pediatric Graves’ disease: a systematic review.” European Journal of Endocrinology 185.2 (2021): 219-229.

Conclusions: Using a standardized calculation, the overall remission rate in methimazole-treated pediatric GD is 28.8%. A few small studies indicate that longer treatment increases the remission rate.

 

Choo, Young Kwang, et al. “Hypothyroidism during antithyroid drug treatment with methimazole is a favorable prognostic indicator in patients with Graves’ disease.” Thyroid 20.9 (2010): 949-954.

Background: A major problem with antithyroid drug (ATD) therapy in Graves’ disease is the high relapse rate. Therefore, clinicians have sought prognostic indicators of permanent remission. Suppression of serum thyrotropin (TSH) when ATD therapy is stopped carries a poor prognosis, but little is known regarding the significance of elevated serum TSH concentrations in the course of ATD therapy. The objective of this study was to determine if elevated serum TSH concentrations during methimazole (MMI) therapy is associated with a favorable long-term prognosis.

Methods: We retrospectively studied patients with Graves’ disease who were initially on MMI, in whom this drug was stopped because they had undetectable thyroid-stimulating antibodies (TSAbs) or were euthyroid after at least 24 months on MMI treatment. A strategy of high MMI doses plus T4 was not used in these patients. We identified 40 patients with elevated serum TSH concentration (>10 microIU/mL) during MMI therapy (H-TSH group). Eighty-five percent of the H-TSH group had negative tests for TSAb. The H-TSH group was sex- and age-matched with 37 patients who had similar selection criteria, but did not have elevated serum TSH concentration during MMI therapy (N-TSH group). The H-TSH and N-TSH groups were similar in gross thyroid size, percentage of patients with exophthalmos, serum free thyroxine, duration of MMI treatment, TSAb status, duration that their TSAb tests remained negative, and thyroid peroxidase antibody titers. The patients were followed for 24 months after stopping MMI.

Results: In the H-TSH group, MMI-associated hypothyroidism typically occurred after 7-8 months of treatment with daily doses of 10-15 mg MMI. No patient had severe symptoms of hypothyroidism. The percentage of patients in remission at 6, 12, and 24 months after discontinuation of MMI was 90.0, 87.5, and 85.0, respectively, in the H-TSH group and 70.3, 67.6, and 54.1, respectively, in the N-TSH group (p < 0.05 for the comparison of groups at 6 and 12 months and p < 0.001 for comparison of the groups at 24 months).

Conclusions: In patients with Graves’ disease who are treated with MMI for at least 2 years and become euthyroid, the occurrence of elevated serum TSH concentrations during MMI treatment is a favorable indicator for long-term remission and is independent of multiple other factors including TSAb status, duration of MMI treatment, and gross parameters of goiter size.

 

Iodine for Graves 1975

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.

Serum thyroxine (T4) and triiodothyronine (T3) concentrations were measured at frequent intervals in 9 hyperthyroid patients treated with iodide alone. Serum T4 and T3 levels fell initially in all patients. In 6 patients, after a mean fall in serum T4 of 46% and in serum T3 of 47% after 4 to 11 days of therapy, thyroid hormone levels began to rise. In the 3 remaining patients a rise in thyroid hormone levels was not seen following the initial fall. However, in one of this group T4 and T3 levels did not reach the normal range despite 60 days of therapy. These data support the concept that iodide alone is not an ideal agent for the treatment of hyperthyroidism.

Lithium for Graves

Spaulding, S. W., et al. “The inhibitory effect of lithium on thyroid hormone release in both euthyroid and thyrotoxic patients.” The Journal of Clinical Endocrinology & Metabolism 35.6 (1972): 905-911.

The findings presumably reflect the fact that lithium blocks the release of hormone from the thyroid gland in both normal and hyperthyroid patients, although the latter seem more sensitive to this effect.

 

 

Temple, R., et al. “The use of lithium in the treatment of thyrotoxicosis.” The Journal of Clinical Investigation 51.10 (1972): 2746-2756.

Neither inhibition of release nor of hormone disappearance seemed to be affected by methimazole (release: 52% decrease without methimazole, 60% with methimazole; hormone disappearance: ∼60% decrease in both). When Li+ was discontinued, recovery of the iodine release rate and hormone disappearance rate over the observed time span was variable, ranging from no recovery to rates that exceeded pre-Li+ values.

Preparation for thyroidectomy

Langley, Roy W., and Henry B. Burch. “Perioperative management of the thyrotoxic patient.” Endocrinology and Metabolism Clinics 32.2 (2003): 519-534.

When Li+ is used alone its effect on serum hormone levels is diminished due to continued accumulation of iodide by the thyroid. Thus, serum thyroxine-iodine levels fell 21-30% in 6-8 days in patients who did not receive methimazole and 15-67% in the methimazole-treated subjects. For prolonged therapy, therefore, a thiocarbamide drug must be used in conjunction with Li+. The similarity of inhibition of iodine release from the thyroid produced by Li+ and iodides is discussed.

Giving Iodine to Normal Healthy People – parameters stay WNL

Vagenakis, Apostolos G., et al. “Control of thyroid hormone secretion in normal subjects receiving iodides.” The Journal of Clinical Investigation 52.2 (1973): 528-532.

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Long-term ATD

El Kawkgi, Omar M., Douglas S. Ross, and Marius N. Stan. “Comparison of long‐term antithyroid drugs versus radioactive iodine or surgery for Graves’ disease: a review of the literature.” Clinical Endocrinology 95.1 (2021): 3-12.

Long-term ATD is a viable alternative to ablative therapies in the management of GD offering advantages across multiple patient centred outcomes.

 

Song, Ari, et al. “Long-Term Antithyroid Drug Treatment of Graves’ Disease in Children and Adolescents: A 20-Year Single-Center Experience.” Frontiers in endocrinology 12 (2021): 721.

The cumulative remission rates were 3.3%, 19.6%, 34.1%, 43.5%, and 50.6% within 1, 3, 5, 7, and 10 years of starting ATD, respectively.

Background/purpose: Graves’ disease (GD) is the most common cause of thyrotoxicosis in children and adolescents. There is some debate regarding the optimal treatment and predicting factors of remission or relapse in children and adolescents with GD. In this study, we report a retrospective study of 195 children and adolescents with GD treated at a single tertiary institution in Korea.

Methods: This study included children and adolescents with GD diagnosed before 19 years of age from January of 2000 to October of 2020. The diagnosis of GD was based on clinical features, high thyroxine (FT4), suppressed thyroid-stimulating hormone, and a positive titer of thyrotropin receptor antibodies. Remission was defined as maintenance of euthyroid status for more than six months after discontinuing antithyroid drug (ATD).

Results: A total of 195 patients with GD were included in this study. The mean age at diagnosis was 12.9 ± 3.2 years, and 162 patients (83.1%) were female. Among all 195 patients, five underwent thyroidectomy and three underwent radioactive iodine therapy. The mean duration of follow-up and ATD treatment were 5.9 ± 3.8 years and 4.7 ± 3.4 years, respectively. The cumulative remission rates were 3.3%, 19.6%, 34.1%, 43.5%, and 50.6% within 1, 3, 5, 7, and 10 years of starting ATD, respectively. FT4 level at diagnosis (P = 0.001) was predicting factors for remission [HR, 0.717 (95% CI, 0.591 – 0.870), P = 0.001]. Methimazole (MMI)-related adverse events (AEs) occurred in 11.3% of patients, the most common of which were rash and hematologic abnormalities. Of a total of 26 AEs, 19 (73.1%) occurred within the first month of taking MMI.

Conclusions: In this study, the cumulative remission rate increased according to the ATD treatment duration. Long-term MMI treatment is a useful treatment option before definite treatment in children and adolescents with GD.

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LOW IODINE DIET Worsens Outcome of MMI for Graves

Pearce, Elizabeth N. “A low-iodine diet during Methimazole treatment worsens graves’ disease outcomes.” Clinical Thyroidology 30.2 (2018): 66-68.

 

 

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).

Interestingly, anti-TPO Ab and anti-TG Ab can be detected in up to 70% of patients with GD, in addition to TBII and TSIG antibodies at the time of diagnosis [19].

We believe this report is important as not only is it the first to report thyrotoxicosis due to GD, then due to Hashitoxicosis, and then due to GD in the same individuals, but also the cooccurrence of these 2 autoimmune processes highlights the concept that these are not separate processes but parts of the same autoimmune spectrum.

Note: High 24 hr I-123 uptake for GD
Low 24 hr I-123  for Hashitoxicosis

Pt 1 during GD thyrotoxicosis: I123 thyroid uptake and scan revealed increased 4-hour uptake at 34% (5–15%) and 24-hour uptake at 62% (15–35%).

Pt 1 during Hashitoxicosis:  Repeat I-123 thyroid uptake and scan revealed low 4-hour uptake of 2.5% and low 24-hour I123 uptake of 2.3%.

Pt 2 I123 thyroid uptake and scan demonstrated low 4-hour uptake of 3% and 24-hour uptake of 5%. Hashitoxicosis was then diagnosed but did not require treatment.

Pt 3    I 123 thyroid uptake and scan revealed low 4-hour uptake of 2.9% (5–15) and low 24-hour uptake of 4.7% (10–35), suggestive of Hashitoxicosis.

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2021 Gorini

Gorini, Francesca, et al. “Selenium: an element of life essential for thyroid function.” Molecules 26.23 (2021): 7084.

Patients with newly diagnosed GD presented low Se levels. In addition, GD disease remission (in subjects followed for 20.1 months) was associated with higher serum Se levels (>120 µg/L) that inversely correlated with TSH receptor autoantibodies (TRAb), suggesting beneficial effects of Se on the thyroidal autoimmune process and GD outcomes [68,69]   Pedersen, I.B.; Knudsen, N.; Carlé, A.; Schomburg, L.; Köhrle, J.; Jørgensen, T.; Rasmussen, L.B.; Ovesen, L.; Laurberg, P. Serum selenium is low in newly diagnosed Graves’ disease: A population-based study. Clin. Endocrinol. 2013, 79, 584–590.

  1. Wertenbruch, T.; Willenberg, H.S.; Sagert, C.; Nguyen, T.B.; Bahlo, M.; Feldkamp, J.; Groeger, C.; Hermsen, D.; Scherbaum,W.A.; Schott, M. Serum selenium levels in patients with remission and relapse of graves’ disease. Med. Chem. 2007, 3, 281–284.\

Nordio, Maurizio, and Sabrina Basciani. “Treatment with myo-inositol and selenium ensures euthyroidism in patients with autoimmune thyroiditis.” International Journal of Endocrinology 2017 (2017).

Ferrari, S. M., et al. “Myo-inositol and selenium reduce the risk of developing overt hypothyroidism in patients with autoimmune thyroiditis.” Eur Rev Med Pharmacol Sci 21.2 Suppl (2017): 36-42.

Danailova, Yana, et al. “Nutritional Management of Thyroiditis of Hashimoto.” International Journal of Molecular Sciences 23.9 (2022): 5144.

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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.

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Bagchi

 

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.

Iodine in excess is known to acutely inhibit thyroidal secretion. In the present study we have characterized the time course of the iodine effect in vitro and investigated the underlying mechanisms. Labelled thyroid glands were cultured in vitro in medium containing mononitrotyrosine, an inhibitor of iodotyrosine deiodinase. The rate of hydrolysis of labelled thyroglobulin was measured as the proportion of labelled iodotyrosines and iodothyronines recovered at the end of culture and was used as an index of thyroidal secretion.

Thyrotrophin (TSH) administered in vivo acutely stimulated the rate of thyroglobulin hydrolysis. Addition of NaI 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.

Iodide abolished the dibutyryl cAMP induced stimulation of thyroglobulin hydrolysis. Iodide required organic binding of iodine for its effect but new protein or RNA synthesis was not necessary. The inhibitory effects of iodide and lysosomotrophic agents such as NH4Cl and chloroquin on thyroglobulin hydrolysis were additive suggesting different sites of action. Iodide added in vitro altered the distribution of label in prelabelled thyroglobulin in a way that suggested increased coupling in the thyroglobulin molecule. These data indicate that 1) the iodide effect occurs progressively over a 6 h period, 2) continued presence of iodide is not necessary once the inhibition is established, 3) iodide exerts its action primarily at a post cAMP, prelysosomal site and 4) the effect requires organic binding of iodine, but not new RNA or protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

 

 

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

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. The Wolff-Chaikoff effect was also overcome by the presence of a hydrogen peroxide-generating system, such as glucose-glucoseoxidase or tyramine. TSH and hydrogen peroxide enhanced the synthesis of both iodotyrosines and iodothyronines. The enhanced organification of iodine in the presence of TSH or hydrogen peroxide was not due to an abrupt synthesis of organic iodine during the early phase of incubation before intrathyroidal iodide concentrations had reached the inhibitory levels. 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.

 

 

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. The Wolff-Chaikoff effect was also overcome by the presence of a hydrogen peroxide-generating system, such as glucose-glucoseoxidase or tyramine. TSH and hydrogen peroxide enhanced the synthesis of both iodotyrosines and iodothyronines. The enhanced organification of iodine in the presence of TSH or hydrogen peroxide was not due to an abrupt synthesis of organic iodine during the early phase of incubation before intrathyroidal iodide concentrations had reached the inhibitory levels. 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.

Samuels, Mary H. “Most Patients with Graves’ Disease Treated with Antithyroid Drugs Eventually Require Additional Therapies.” Clinical Thyroidology 32.1 (2020): 9-11.

Hurtado, Carolina, Michael W. Yeh, and Masha J. Livhits. “Antithyroid medications are the most common treatment for graves’ disease in the united states despite high rates of treatment failure.” Clinical Thyroidology 32.4 (2020): 162-165.

 

Cooper, David S. “Long-term Antithyroid drug treatment of patients with graves’ disease.” Clinical Thyroidology 31.6 (2019): 230-233.

However, in older patients (e.g., those >60 years of age), definitive therapy should be more strongly considered at the time of initial diagnosis or if TRAb titers persist for more than 1 to 2 years of antithyroid drug therapy (3). This is because the effects of persistent or recurrent hyperthyroidism that could develop are potentially life-threatening (e.g., atrial fibrillation or other adverse cardiovascular outcome (12)) or clinically significant (e.g., osteoporosis). While it is true that older patients are more likely to achieve remission (7), the worry that remissions are not necessarily lifelong makes definitive treatment more reasonable (3). However, in young and middle-aged patients, long-term therapy with methimazole may become a more widely accepted strategy, especially given recent data on the adverse effects of radioiodine therapy on quality of life (13). Failure to attain normal TRAb levels after 12 to 18 months of methimazole therapy does not rule out the possibility of remission occurring over a longer time horizon of 5 to 10 years.

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Honda, Akira, et al. “Relationship between the effectiveness of inorganic iodine and the severity of Graves thyrotoxicosis: a retrospective study.” Endocrine Practice 23.12 (2017): 1408-1413.

Suzuki, Nami, et al. “Therapeutic efficacy and limitations of potassium iodide for patients newly diagnosed with Graves’ disease.” Endocrine Journal (2020): EJ19-0379.

Compared to these previous reports [10-12], the present study confirmed that KI therapy is effective for GD in patients with FT4 values <5.0 ng/dL .  ATDs are known to induce morphological changes in thyroid tissue, such as increased cellularity and diminished amounts of colloid [13]. Considering this fact, thyroid tissues from subjects analyzed in previous reports [10-12] were likely to have been affected by ATDs, and such degeneration might have impacted the efficacy of KI. Although, similarities were present between this and previous studies, such as the factors related to KI responsiveness, our study was designed as a prospective study, and all subjects were treated using KI alone, meaning that our study provides more accurate data on the effects of KI

ATDs are known to sometimes cause lifethreatening problems, such as drug-induced liver injury and agranulocytosis. KI monotherapy appears potentially safer as a treatment for patients with GD.

In the present study, males displayed a 3.6-fold higher risk of KI non-responsiveness than females.

Some studies have indicated thyroid enlargement is induced by oral intake of iodine. Namba et al. observed reversible thyroid enlargement in healthy euthyroid volunteers after administration of iodine [21]. Likewise, Yabuta et al. noted that thyroid volume in patients with GD increased after preoperative administration of KI, even with durations less than a month [22]. In the present study, thyroid volume for the total subject group was significantly increased after one year, compared with baseline volume, and thyroid volume changes were larger in the KI non-responder group.

Even so, signifi‐cant enlargement of the thyroid was recognized in the KI non-responder group, suggesting that patients displaying an increase in thyroid volume during the clinical course might have a greater risk of KI non-responder status.

KI therapy appears to offer an effective and potentially safer therapy for about 60% of female patients with mild

GD, and thus could represent a third drug option for these patients

 

 

Huang, Huibin, et al. “Optimal iodine supplementation during antithyroid drug therapy for Graves’ disease is associated with lower recurrence rates than iodine restriction.” Clinical Endocrinology 88.3 (2018): 473-478.

Conclusion: Optimal dietary iodine supplementation during antithyroid drug therapy for GD is associated with lower recurrence rates than iodine restriction, and therefore, diet control with strict iodine restriction might be an adverse factor in the management of GD.

 

Yabuta, Tomonori, et al. “Preoperative administration of excess iodide increases thyroid volume of patients with Graves’ disease.” Endocrine journal 56.3 (2009): 371-375.

 

Roti, E., et al. “Effects of chronic iodine administration on thyroid status in euthyroid subjects previously treated with antithyroid drugs for Graves’ hyperthyroidism.” The Journal of Clinical Endocrinology & Metabolism 76.4 (1993): 928-932.

In the two EG patients who developed hyperthyroidism after SSKI was discontinued, serum TSH-RAb were not present before, during, and after iodine administration. This finding does not exclude the diagnosis of recurrent Graves’ disease, since it has been reported that not all patients with Graves’ disease have TSH-RAb (21). It is unlikely that these two EG patients had autonomous thyroid function before and during SSKI administration, since basal and TRH-stimulated serum TSH concentrations were normal. Others have observed focal inflammatory lesions in the thyroids from patients with iodine-induced hyperthyroidism, suggesting a destructive process with leakage of thyroid hormones into the blood (22). We did not observe any signs or symptoms suggesting subacute thyroiditis in the two EG patients who developed hyperthyroidism after iodine withdrawal. Thus, in the two EG subjects who developed hyperthyroidism after iodine was discontinued, the onset of hyperthyroidism may  have been due to increased synthesis of thyroid hormone and partial inhibition of hormone release during iodine administration, with a subsequent release of stored hormone after iodine withdrawal. It is also possible that these two patients might have developed spontaneous recurrent hyperthyroidism regardless of iodine administration.

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

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 (15) and its synthesis due to a decrease in TPO mRNA (12).

In contrast, KI has a cytotoxic effect on only human thyroid follicles that is abolished by MMI. Furthermore, Xu et al. (19) showed a cytotoxic effect due to KI by demonstrating that excess iodine contributes to autophagy suppression and apoptosis of thyroid follicular cells using a cell line of human thyroid follicular epithelial cells. The pathogenesis of KI-induced PT is unclear but may be related to this cytotoxic effect of KI. In addition, because 10 of the 11 patients in our current study with KI-induced PT were positive for TgAb and/or TPOAb, an autoimmune mechanism may be involved in this process. Finally, we emphasize that clinicians who manage GD patients who received KI after discontinuing ATD due to side effects., should be alert for KI-induce PT.

Katoh, Daisuke, et al. “Successful treatment of amiodarone-induced thyrotoxicosis type 1 in combination with methimazole and potassium iodide in a patient with Hashimoto’s thyroiditis.” Internal Medicine 59.3 (2020): 383-388.

Second, potassium iodide in combination with antithyroid drugs might be an effective treatment for AIT type 1 in countries where sodium perchlorate is not available.

Roti, Elio, and Ettore Degli Uberti. “Iodine excess and hyperthyroidism.” Thyroid 11.5 (2001): 493-500.

 

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

The 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%.

Leung, Angela M., and Lewis E. Braverman. “Iodine-induced thyroid dysfunction.” Current opinion in endocrinology, diabetes, and obesity 19.5 (2012): 414.

Wartofsky, Leonard, Bernard J. Ransii, and Sidney H. Ingbar. “Inhibition by iodine of the release of thyroxine from the thyroid glands of patients with thyrotoxicosis.” The Journal of clinical investigation 49.1 (1970): 78-86.

it is concluded that the rapid decrease in T4 secretion induced by iodine is not the result of an acute, sustained inhibition of T4 synthesis, but rather results from an abrupt decrease in the fractional rate of thyroidal T4 release.

 

 

Last updated on by Jeffrey Dach MD

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