The Autonomous Thyroid Nodule and Iodine Induced Hyperthyroidism Part Two

The Autonomous Thyroid Nodule and Iodine Induced Hyperthyroidism Part Two

Jeffrey Dach MD

Brenda is a 26 year old nurse seen my office for menstrual irregularities, and upon evaluation and testing was found to have a spot urine test indicating severe iodine deficiency.

Above header image: Autonomous Nodule in right thyroid lobe (red arrow) showing “hot” , avid update of radio-tracer, with suppression of remaining thyroid gland (blue dotted line) Outline of neck (blue dotted line). Courtesy of wikimedia commons.

Although Brenda had been in the US for twenty years, she was born and grew up in one of the Caribbean islands, noted for low iodine levels.  Because of the severe iodine deficiency, Brenda began iodine supplementation with iodized salt.  About a week later, Brenda experienced an episode of tachycardia, severe rapid heart rate, with a sustained pulse rate of 220 beats per minute.  Shortly after arriving at the local hospital Emergency Room, the tachycardia resolved spontaneously. The doctors had no explanation for the tachycardia, and Brenda was sent home with a Beta-Blocker Drug, called Atenolol to slow the heart rate should the tachycardia return.

What Caused Brenda’s Tachycardia?  The Autonomous Nodule.

Brenda’s tachycardia was a symptom of hyperthyroidism from an autonomous thyroid nodule.  When Brenda started taking iodized salt, the autonomous nodule converted the new iodine into excess thyroid hormone. This is an example of hyperthyroidism associated with dietary Iodine intake. The autonomous thyroid nodule manufactures thyroid hormone uncontrollably depending on iodine availability, outside of the normal control mechanism of TSH (thyroid stimulating hormone).  When these patients ingest dietary iodine, they become thyrotoxic, and new lab studies typically reveal a very low TSH, high Free T3 and high FreeT4. Despite the very low TSH, the autonomous nodule continues to take up iodine and produce large amounts of thyroid hormone. Yet, the low TSH suppresses iodine uptake in the surrounding normal thyroid tissue, thus explaining the “hot nodule” appearance of the autonomous nodule of the on the I-123 radio-nuclide scan (also called scintigram).

The Sonogram and Radio-Nuclide Thyroid Scan

Brenda was advised to stop the dietary Iodine and sent for diagnostic imaging.  Sure enough, Brenda’s thyroid sonogram showed a thyroid nodule in the right upper lobe, and her I-123 radio-nuclide scan showed the nodule avidly took up radio-tracer, a “Hot Nodule”, indicating an autonomous nodule. (25-29)

Thyroxine Suppression Test

In some cases, the nodule may not be hot enough to be visible on the radionuclide scan.  To make the nodule more visible, an additional step may be required. This is called a Thyroxine suppression test.  The scan is repeated after giving the patient Levothyoxine which suppresses uptake in the remaining normal thyroid tissue, yet does not affect the autonomous nodule, making the hot nodule stand out from the suppressed background thyroid tissue. (25-29)

Mutational Events Lead to Autonomy of Function

In 1998, Dr John Stanbury concluded the most common cause of iodine induced hyperthyroidism is the autonomous nodule, writing:

The biological basis for IIH (Iodine induced hyperthyroidism) 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. (21)

What is an Autonomous Nodule?

Since 1998, more recent medical research reveals that autonomous thyroid nodules are clones of cells that have a mutation in the TSH Receptor (Thyroid Stimulating Hormone Receptor). These mutations usually arise as a result of iodine deficiency in patients who spend their childhood in iodine deficient geographic regions.  Mutations in the gene for the TSH receptor make these nodules independent of TSH control.  Thus, based on the availability of Iodine, the autonomous nodule makes thyroid hormone uncontrollably. (9-13)(35)

What is the Etiology of Autonomous Nodules ?

What causes the autonomous nodule? Remember, iodine is needed for the production of thyroid hormone, and Iodine deficiency impairs this process causing hypothyroidism.  The pituitary responds to low thyroid hormone levels by secreting more TSH. Laboratory studies will show an  elevated TSH level.  The TSH travels in the blood stream to the thyroid gland and where it stimulates all steps in thyroid hormone production, including the generation of hydrogen peroxide. If the patient happens to have selenium deficiency, then their selenium-based antioxidants system will be deficient, with impaired degradation of the hydrogen peroxide. This excess hydrogen peroxide is toxic, oxidative and mutagenic to thyroid cells.  This oxidative damage to thyroid cells leads to mutations in the DNA, including mutations to the DNA for the TSH receptor. Such a mutation within a clone of thyroid cells creates the autonomous nodule. Note this is the same mechanism for carcinogenisis.  In 2007, Dr. Knut Krohn writes:

We reconstruct a line of events that could explain the predominant neoplastic character (i.e. originating from a single mutated cell) of thyroid nodular lesions. This process might be triggered by the oxidative nature of thyroid hormone synthesis or additional oxidative stress caused by iodine deficiency or smoking. If the antioxidant defense is not effective, this oxidative stress can cause DNA damage followed by an increase in the spontaneous mutation rate, which is a platform for tumor genesis. The hallmark of thyroid physiology—H2O2 [hydrogen peroxide] production during hormone synthesis—is therefore very likely to be the ultimate cause of frequent mutagenesis in the thyroid gland. DNA damage and mutagenesis could provide the basis for the frequent nodular transformation of endemic goiters. (51-53) Emphasis Mine.

The Autonomous Nodule Originates in an Iodine Deficient Region

In 1924, based on work of Drs. David Marine, and David Cowie, the United States began a program of iodine supplementation with iodized salt. This was done as a public health measure to reduce the health risks associated with iodine deficiency in the population. These health risks in newborn and young children include impaired growth, neurodevelopment and cognitive function in newborns, and goiter in young children. In 2020, Dr. Michael B Zimmerman writes:

Iodine deficiency has multiple adverse effects in humans due to inadequate thyroid hormone production… Iodine deficiency during pregnancy and infancy may impair growth and neurodevelopment of the offspring and increase infant mortality. Deficiency during childhood reduces somatic growth and cognitive and motor function… In most countries, the best strategy to control iodine deficiency in populations is carefully monitored iodization of salt.(72-75)

In 2015, Dr Michael Zimmermann writes in adults most thyroid disorders are related to iodine deficiency, such as goiter, autonomous nodules and toxic nodular goiter. The iodine deficiency causes hypothyroidism and elevated TSH which stimulates thyroid growth (goiter) and excess hydrogen peroxide production. In the event this damaging hydrogen peroxide production exceeds the capacity of the selenoprotein antioxidant system, this leads to mutagenicity leading to autonomous nodules and hyperthyroidism. A similar pathology, the toxic nodular goiter, contains multiple thyroid nodules, one or more of which is an autonomous nodule. Dr Michael Zimmermann writes:

iodine status is also a key determinant of thyroid disorders in adults. Severe iodine deficiency causes goitre and hypothyroidism …increased thyroid activity [from elevated TSH] can compensate for low iodine intake and maintain euthyroidism in most individuals, but at a price: chronic thyroid stimulation [from elevated TSH] results in an increase in the prevalence of toxic nodular goitre and hyperthyroidism in populations. This high prevalence of nodular autonomy usually results in a further increase in the prevalence of hyperthyroidism if iodine intake is subsequently increased by salt iodisation… Thus, optimisation of population iodine intake is an important component of preventive health care to reduce the prevalence of thyroid disorders. (72-75)

Iodized Salt Eliminates Autonomous Nodule

With the elimination of iodine deficiency after introduction of iodized salt in 1924, autonomous nodules became quite rare in the United States. Most of the cases we see now are patients migrating from iodine deficient geographic regions outside the United States.These people may harbor autonomous nodules, presenting with features of transient hyperthyroidism when supplemented with iodine in the diet. (1-13)

Hyperthyroidism After Iodized Salt Fortification

Even the small amounts of dietary iodine found in Iodized Salt can cause transient hyperthyroidism in patients with autonomous nodules. Public records show a transient increase in mortality from thyrotoxicosis in 1926-1928 after the introduction of Iodized Salt.  This was thought to be due to presence of pre-existing autonomous nodules in the population.  Likewise, in various other countries, Iodized salt and Iodized Bread programs were introduced, and again a transient increase in thyrotoxicosis was reported shortly afterwards. Again, these cases were thought to be autonomous nodules responding to dietary iodine supplements.  Note: some of these cases were toxic nodular goiter, with one or more autonomous nodules.(1-13)(20-23)

Thyrotoxicosis Caused by Iodine Containing Medications

In addition to iodized salt programs, thyrotoxicosis in the autonomous nodule patient may be caused by various iodine containing drugs such as amiodorone, and iodinated radiographic contrast. (76-77)

Iodine Induced Thyrotoxicosis in Normal thyroid Gland ?

In case reports of iodine causing hyperthyroidism in normal thyroid glands, one wonders if these so-called “normal thyroid glands” harbor autonomous nodules, or diffuse areas of autonomous tissue that may not be visible on imaging and are simply missed. Another possible etiology for iodine induced thyrotoxicosis in so called normal thyroid gland is painless thyroiditis, discussed below. (33-34)

Marine-Lenhart Syndrome

In Japan, as mentioned previously, potassium iodine is commonly used as a thyroid blocking drug in treatment of thyrotoxicosis caused by Grave’s disease. However, about 10-12 per cent of such cases do not respond or are made worse by iodine. Could some of these cases be explained by autonomous functioning thyroid tissue?   This is the Marine-Lenhart Syndrome (MLS) defined as Graves’ disease with thyroid nodular lesions, and clinical characteristics of both Graves’ disease and Plummer’s disease (toxic nodular goiter). In 2021, Dr. Hirosuke Danno found 0.26 per cent prevalence of MLS among Graves’ Disease patients in Japan. This is not high enough prevalence to explain the 10-12 per cent rate of iodine escape found in 2015 by Dr. Yoshihara when switching pregnant Graves’ disease patients from Methimazole to Iodine. However, the co-existence of Plummers’ with Graves’ is something to keep in mind when presented with a Graves’ Disease patient with atypical imaging and clinical features.  The imaging and clinical exam may reveal multiple nodules instead of the usual diffuse smooth enlargement indicating possible coexistance of toxic nodular goiter (Plummer’s Disease) with Graves’ Disease. Obviously, potassium iodide administration could not be expected to work in these atypical cases. (54-58)(64)

Over Expression of NIS in Autonomous Nodules

In 1999, Dr. Meller demonstrated over expression of the Na+/I- symporter (NIS) in autonomous nodules, providing an explanation for enhanced uptake and clearance of iodine on radionuclide scan. This high radio-iodine uptake allows differentiation from Painless Thyroiditis (PT) and Hashitoxicosis both of which have a very low radio-iodine uptake. (27)

Toxic Multinodular Goiter

Toxic Multinodular Goiter is caused by chronic iodine deficiency, usually by growing up in an iodine deficient country or region, and is clinically similar to autonomous thyroid nodule. A nodular goiter becomes “toxic” when one of the nodules within the thyroid is, in fact, an autonomous nodule. Typically, this will cause thyrotoxicosis whenever the patient consumes dietary iodine. A number of case reports in the medical literature report thyrotoxicosis after iodine consumption. Typically, these cases describe a multinodular goiter which harbor at least one autonomous nodule.(65-66)

Treatment of Toxic Adenoma and Toxic Multinodular Goiter

Treatment of thyrotoxicosis caused by autonomous thyroid nodule or toxic nodular goiter consists of the following: (38-48)(59-63)

1) Thyroid Blocking Drugs: also called medical treatment. The most commonly used drug is Methimazole, 15-30 mg per day. Lithium Carbonate 300 mg TID has also been found useful as a thyroid blocking drug, and may be given prior to radioactive iodine (I-131) therapy to enhance retention of Iodine in the autonomous nodule within the thyroid gland. To slow the heart rate, Beta Blockers (atenolol 25-50 mg/day) are commonly prescribed for relief of tachycardia. (44-48)

2) Thyroid Ablation with Radiation: Radioactive Iodine (I-131) therapy for autonomous nodule is a form of radiation therapy which ablates the nodule, and is quite successful for this entity. Autonomous nodules are highly active and soak up most of the radioactive iodine, sparing the remaining normal gland. (45-47)

3) Surgical Ablation: Surgical removal of the nodule with thyroid lobectomy procedure. (63)

4) Percutaneous Injection: Percutaneous ethanol injection into the autonomous thyroid nodule under ultrasound control. (38-40)

I apologize for not mentioning the many other forms of treatment in the medical literature.

Iodine Induced Toxic Effects in Healthy Humans: A Myth

Normal healthy people are able to consume large amounts of iodine obtained from diet, supplements or medication, without adverse effects.  This is due to normal autoregulatory function of the thyroid, called the “escape from the Wolf Chaikoff Effect”.  The thyroid gland compensates for the high dietary iodine intake by downregulating the NIS sodium iodide symporter and inhibiting organification. Let us review a number of facts.

1) For many years from 1890 to 1930, physicians commonly prescribed high dose iodine for many disorders in the form of Lugol’s Solution.

2) The Japanese diet is very high in iodine averaging 12 mg per day.

3) Iodine containing medications such as SSKI, Amiodorone, and radiographic contrast agents are routinely prescribed by physicians, without concerns for iodine induced thyrotoxicosis.

4) Government protocol provides 65 mg potassium iodide capsules to populations surrounding nuclear power plant accidents to prevent thyroid cancer from radioactive iodine uptake.

As you can see from above, large segments of the population have been routinely exposed to high doses of iodine from various sources over the past 100 years, and we are still here !

Iodine Toxic Effects in the Iodine Deficient State – Painless Thyroiditis

However, iodine may induce toxic effects under conditions of iodine deficiency. These toxic effects are mediated by hydrogen peroxide generation. If not neutralized by the seleno-protein antioxidant system causes inflammation and thyroiditis, remarkably similar to Painless Thyroiditis. This mechanism was described in  2000 by Dr. Bernard Corvilain who found that acute iodine administration to iodine depleted dogs and mice increased hydrogen peroxide generation, rather than inhibited it. This toxicity was aggravated by selenium deficiency, causing insufficent gluathione peroxidase for neutralization of the hydrogen peroxide.

I would suggest this same mechanism could be at play in the Painless Thyroiditis cases described by Dr. Okamura in his Graves’ Disease patients.  Although Dr. Okamura’s patients were not iodine deficient, thyroid hyper-stimulation in Graves’ Disease resembles an iodine deficiency state with hyperfunction and high radio-iodine uptake. Similarly, studies in man and animals show acute iodine depletion causes thyroid hyper-function and increased radio-iodine uptake, also characteristic features of Graves’ hyperthyroidism. Chronic excess dietary iodine intake has the opposite effect in animal and human studies showing decreased radio-iodine uptake (Wolf-Chaikoff Effect).

In human and animal studies, a state of chronic iodine deficiency severely reduces output of thyroid hormones producing low levels of Free T3 and Free T4.  This is a hypothyroid state which triggers TSH elevation by the pituitary. TSH stimulates all steps in thyroid hormone production including upregulation of NIS, and damaging hydrogen peroxide generation. As mentioned in a previous chapter on Preduction of Thyroid Hormones, the Graves’ Disease patient is spared the damaging stimulation of excess hydrogen peroxide generation because, unlike TSH itself,  TSH receptor antibodies do not stimulate hydrogen peroxide generation. (82)(85-88)

Dr. Bernard Corvilain writes:

the increase in H2O2 [hydrogen peroxide] synthesis induced by iodide in iodine-depleted thyroid may have a toxic role in the cell. A necrosis of follicular cells was already described after administration of iodide to iodine-deficient dogs but not to control dogs. A necrotizing effect of iodide was also described in iodine-deficient rats and mice. The toxicity of iodide was aggravated in cases of selenium deficiency, a circumstance in which defenses against H2O2 are reduced due to a decreased activity of glutathione peroxidase. Our data are in keeping with the hypothesis that some of these toxic effects induced by iodide in iodide-deficient thyroids may be partly related to the toxicity of H2O2. (69-71)

Painless Thyoiditis  – Iodine induced Hyperthyroidism in Normal Thyroid Gland

Thyroiditis is an inflammatory condition with rupture of the follicles with release of preformed thyroid hormone, causing thyrotoxicosis. Painless Thyroiditis resembles Hashitoxicosis as they both have very low radio-iodine uptake, usually less than one per cent which differentiates both entities from Graves’ thyrotoxicosis which has very high radio-iodine uptake. Thyroid blocking drugs, useful in Graves’ disease are not effective in Painless Thyroiditis and Hashitoxicosis as they cannot prevent the rupture of follicles with release of preformed thyroid hormone.

Severe Recurrent Painless Thyroiditis Case Report

in 2013, Dr Hiroaki Ishii reported a case of recurrent Painless Thyroiditis that was so severe, it requiring thyroidectomy. Initially, the doctors thought the patient’s diagnosis was TRAb negative Grave’s disease and treated with medthimazzole for a short time. The diagnosis was then changed to Painless Thyroiditis when a low radio-iodine uptake was obtained:

The treatment of painless thyroiditis is typically limited to observation, given the transient and mild nature of the thyroid dysfunction. Beta-Adrenergic blockade is effective for the treatment of symptoms related to thyrotoxicosis. Antithyroid medication and iodide intake are not effective in preventing hormone release from the affected gland. At the beginning of management of this case, we treated with anti-thyroid drugs for a few weeks due to an initial diagnosis of Graves’ disease, although TRAb was negative…The diagnosis of painless thyroiditis was based on the presence of thyrotoxicosis with low radioactive iodine uptake and negative TSH receptor antibodies.(83)

Case Report Iodine Deficient Male – Iodine  Induced Hyperthroidism

Graves Disease, Autonomous Nodule or Painless Thyroiditis ?

in 2020, Dr. Itivrita Goyal reported a case of iodine induced thyrotoxicosis in a young male who initially presented severely hypothyroid with severe iodine deficiency. This scenario replicates the iodine depleted animal studies mentioned above by Dr. Bernard Corvilain.

In Dr. Itivrita Goyal’s case report, the initial clinical presentation was that of iodine deficiency with hypothyroidism and elevated TSH.  The patient had a diffusely enlarged thyroid without nodules, the TSH was elevated, 24.4 mIU/L,  and the free thyroxine level (FT4) was below <0.4 ng/dL. In other words, the lab pattern showed severe hypothyroidism. Thinking the patient hypothyroid, the primary care physician ordered Levothyroxine, but the patient never took it.

Very High Radio-Iodine Uptake

The patient’s radio-iodine uptake was very high at 91 per cent uptake. In my opinion, a smooth diffusely enlarged thyroid gland with increased uptake of 91 per cent is suggestive for Graves’ Disease.  The patient was given a multivitamin containing the RDA [recommended daily allowance] for iodine.  Following this increases iodine intake, the patient became hyperthyroid.

Perhaps this patient had Graves’ disease from the onset, which became apparent after iodine repletion. However, the TRAb and TSI antibody tests were not done, so we do not have confirmation of Graves’ disease. However, rarely a GD patient will have negative TRAb and TSI antibodies.

Thyroid Nodule on Ultrasound

The second thyroid ultrasound showed a nodule which raises the question of autonomous functioning nodule as the etiology of the hyperthyroidism after iodine repletion. However, the radionuclide thyroid scan failed to show a “hot nodule”, meaning there was diffuse uptake, not the focal increased radio-iodine uptake within the nodule one would expect for an autonomous nodule.  There was no suppression of radionuclide uptake in the surrounding diffusely enlarged gland. Again this clinical pattern is more suggestive for Graves’ disease which was made obvious upon iodine repletion.  This scenario of Graves’ disease unmasked by iodine repletion was described in 1998 by Dr. Stanbury who writes:

IIH [Iodine Induced Hyperthyroidism] may also occur with an increase in iodine intake in those whose hyperthyroidism (Graves’ disease) is not expressed because of iodine deficiency. (84)

To get back to Dr. Bernard Corvilain and his iodine depleted animal studies, perhaps this patient’s thyrotoxicosis upon iodine repletion canbe explained as Painless Thyroiditis. This was described in 2022 by Dr. Okamura who reported Painless Thyroiditis mimicking a relapse of hyperthyroidism after potassium iodide administration for treatment of Graves’ thyrotoxicosis.  Granted, this patient had a very small iodine dose (150 mcg) compared to the larger amounts (50-100 mg) in Dr. Okamura’s patients. (82)

Indeed, clinical features resembles Graves’ disease with a radio-iodine scan showing very high iodine uptake, and a diffusely enlarged thyroid gland with increased blood flow. Upon giving the patient iodine (150 mcg/day), the patient attained a euthyroid state for 6 months, and then became thyrotoxic. Was the thyrotoxicosis secondary to underlying Graves’ Disease or Painless Thyroiditis?  The authors raise this same question, writing:

Ultrasound (US) of the neck showed enlarged thyroid gland without nodules. Laboratory workup revealed thyroid-stimulating hormone (TSH) was increased to 24.4 mIU/L (reference range is 0.4 to 5.0 mIU/L), free thyroxine level (FT4) was <0.4 ng/dL (reference range is 0.8 to 1.8 ng/dL), slightly increased thyroid peroxidase antibody of 43 IU/mL (reference range is <35 IU/mL), and negative thyroglobulin antibody. He was started on levothyroxine supplementation by his primary care physician but never took it. Three months later, his TSH was 6.1 mIU/L, thyroid peroxidase antibody was negative, and total triiodothyronine was within normal limits. FT4 test was not ordered at this time…The nontoxic goiter associated with primary hypothyroidism was thought to be secondary to severe iodine deficiency given the patient’s low intake of dietary iodine for many years...Urine testing showed a very low spot urine iodine level of 4 μg/L (reference range is 28 to 544 μg/L)…The patient was started on a multivitamin supplement containing 150 μg of iodine daily and was advised to consume iodine-rich foods. On follow up in the clinic 3 months later, the spot urine iodine levels had improved to 91 μg/L (performed by LabCorp; reference range is 28 to 544 μg/L). Thyroid function tests had normalized with TSH within normal range (0.655 mIU/L) and FT4 normalized to 1.24 ng/dL…He was evaluated in the clinic 6 months later with repeat thyroid function tests and US of the thyroid gland. He complained of weight loss, palpitations, and pedal edema. Laboratory data suggested primary hyperthyroidism with
TSH <0.002 mIU/L, FT4 elevated to 2.8 ng/dL (reference
range is 0.7 to 1.9 ng/dL), and total triiodothyronine elevated to 326 ng/dL (reference range is 80 to 180 ng/dL). At this time, 24-hour urine iodine level was normal at 145 μg/24 hours (performed by Quest Diagnostics, Secaucus, NJ; reference range is 70 to 500 μg/24 hours). US showed enlargement of both thyroid lobes with increased blood flow and a 1.2-cm nodule in the posteroinferior aspect of the left lobe. Hyperthyroidism was likely secondary to increased uptake of iodine or an underlying autoimmune state leading to increased hormone production and secretion. [Graves’s Disease?].(68)

Thyrotoxicosis Attributable to Excess Iodine

Amiodorone (Iodine) Induced Thyrotoxicosis

In 2008, Dr. Erik Mittra reported on iodine induced thyrotoxicosis, most commonly autonomous nodule and toxic nodular goiter, and less common amiodoroane induced thyrotoxicosis. Amiodorone is used to treat cardiac arrythmias. Its chemical structure is remarkably similar to thyroxine, and contains a hefty dose of iodine, 75 mg. in each 200 mg tablet.  The effects of amiodorone are due either to the excess iodine released by the drug, or due to the toxic effect of the drug itself. Dr. Erik Mittra writes:

the iodine content is 75 mg in a 200-mg tablet of amiodarone and 18.7 mg/ml in the intravenous solution. Approximately 10% of the iodine content of oral amiodarone is released into the circulatory system. (89)

I am including this discussion of amiodorone because it encapsulates the main concepts of how the thyroid gland may react to excess iodine. Amiodorone is widely used by cardiologists even though adverse effects may occur, such as hypo-thyroidism or hyper-thyroidism induced by the drug.

In 2019, Dr. Richard Trohman estimated the incidence of Amiodarone induced hyothyroidism (5–10%), and hyperthyroidism (0.9–10%), writing:

Older estimates have suggested that the overall incidence of amiodarone-induced thyroid dysfunction ranges from 2 to 24% . More recent reviews of the literature noted that hypothyroidism occurs in 5–10% and hyperthyroidism afflicts approximately 0.9–10% of amiodarone recipients. These differences may reflect the evolution of more conservative dosing regimens employed over time. A meta-analysis suggested that when lower amiodarone doses (152–330 mg daily) were used, the incidence of thyroid dysfunction was 3.7%. (93)

One may raise the question of why mainstream medicine uses Amiodarone freely without concern for inducing thyrotoxicosis in 0.9-10% of recipients.  When this happens the cardiologist calls the endocrinologist to manage the patient. Yet, this is reversed for Potassium Iodide treatment of Graves’ Disease where concern for escape or worsening thyrotoxicosis in a subset of 9-12 per cent of patients has been the objection endocrinologists to its use in the United States.

Amiodarone Induced Hypothyroidism

Regarding Amiodarone induced hypothyroidism, this is merely same failure to escape from the “Wolf Chaikoff Effect” in patients with underlying autoimmune thyroid disease and high dose dietary iodine intake. This was previously discussed.

Amiodarone Induced Thyrotoxicosis – Two Types

Amiodarone induced thyrotoxicosis consists of two types. Type one is due to autonomous thyroid tissue within either a single nodule or a multi-nodular goiter which uncontrollably converts the iodine released by amiodorone into thyroid hormone.

Type Two Destructive Thyroiditis

Type two is a form of destructive thyroiditis with rupture of follicles and release of preformed thyroid hormone, a mechanism identical to Painless thyroiditis with low radio-iodine uptake. The Amiodarone molecule carries its own toxic effect upon the thyroid which accounts for the thyroiditis in the type II version. This is a form of severe destructive inflammatory thyroiditis, in excess of the relatively milder toxic effect of iodine itself. Amiodarone is fat soluble and has a long half life is lipid, making treatment much more challenging in the throtoxic patient. Dr. Mittra  writes:

Iodine-induced thyrotoxicosis is also called Jod Basedow disease. Jod Basedow is derived from jod, the German for iodine, and Basedow from Von Basedow who described in German what the English-speaking medical world knows as Graves’ disease (151). Iodine-induced thyrotoxicosis is usually not Graves’ or Basedow’s disease but toxic nodular goiter. It is more likely to occur in regions of iodine deficiency in people with nodular goiters who are
then exposed to an excess of iodine. The autoregulatory controls of the thyroid must fail for this to occur. Usually an increase in plasma inorganic iodine causes reduced trapping of iodine, organification (Wolff–Chaikoff effect) and reduced release of preformed thyroid hormones. Thus, an autonomously functioning nodular goiter is at most risk. The source of iodine is usually apparent, such as the addition of iodine to salt. There are many reports of this occurring in regions of low iodine intake soon after iodine is added to the diet. The extensive review by Stanbury et al. discusses the history, etiology and epidemiology of this (154). This is rare in the population born and raised in the United States but is found in immigrants from regions of low dietary iodine who come to the United States …In regions of iodine deficiency  amiodarone is more likely to cause thyrotoxicosis, and in iodine-sufficient regions hypothyroidism is more likely. This difference is attributed to nodular goiter [toxic goiter] being more prevalent in iodine-deficient regions. The excess iodine from amiodarone provides the raw material for the nodules to produce excess thyroid hormones. This has been designated type 1 amiodarone–induced thyrotoxicosis. It contrasts with type 2, which is attributable to destruction of follicles producing a thyroiditis-like picture. Type 2 is more common in the United States. Some patients have an overlap of these patterns. In the United States, most patients have a low uptake of 123-I [radioiodine]. In contrast in regions of low iodine intake the uptake values in type 1 amiodarone–induced thyrotoxicosis can be normal or high…Ultrasound with color flow Doppler shows increased vascularity in type 1 and reduced vascularity in type 2 AIT. Treatment is difficult because amiodarone is often the most effective antiarrhythmic in the patient and there is reluctance to stop it. In addition, because of the long half-life its effects persist for months to years. The low uptake of radioiodine makes 131-I useless [thyroid ablation with radio-iodine]. Antithyroid medication such as methimazole 30–40 mg daily has been effective and the patient should be educated about side effects, including skin rash and agranulocytosis. Potassium perchlorate has been used as a competitive inhibitor of trapping iodine by the sodium–iodide symporter. Reports from Europe indicate a combination of methimazole and potassium perchlorate is successful. Potassium perchlorate is not available in the United States. Corticosteroids such as prednisone at 30–60 mg/d are effective in the destructive type 2 syndrome. Thyroidectomy can be undertaken when antithyroid therapy is ineffective, but these patients are often poor operative candidates because of the underlying cardiac disease. (90-91)

Elevated Iodine Content in Thyroid

In 1983, Dr. Aubene Leger measured thyroid iodine content with x-ray flourescence in ten patients with Amiodarone Thyrotoxicosis compared to six patients euthyroid on Amiodarone. The authors felt the thyrotoxicos was a  result of autonomous thyroid tissue with loss of autoregulation and failure to inhibit organification iodine which is converted to thyroid hormone uncontrollably (Type I). The iodine content of the thyroid glands was high, yet the 24 hr radio-iodone uptake was only 2.7 %.The low uptake suggests thyroiditis (Type II). This was back in 1983, so it is unclear which patients were type I or type II. Later studies clarifed the two Types. Dr. Aubene Leger writes:

The results show that during treatment by amiodarone the thyroid iodine content of euthyroid patients was close to that of control
values, whereas that of patients with thyrotoxicosis was significantly increased, suggesting an abnormality in the autoregulation of thyroid iodine content…The mean 1-131 24-hr uptake was 2.7 %±I.4% (normal range 20-45%)…When thyrotoxicosis occurs in amiodarone-treated patients, comparison of their thyroid iodine content with that of amiodarone-treated euthyroid patients suggests that thyrotoxicosis is the consequence of a failure of inhibition of iodine organification, leading to an excess of organified iodine. The thyrotoxicosis corresponds to the discharge of the hormonal stores into the circulation [from thyroiditis ?]. The progressive decrease of total iodine content corresponds to the diminution of the stores of organified iodine…Thus it seems unlikely that autonomous thyroid tissue
was present in our cases, as it has been suggested in other

Direct Toxic Effect on Thyroid Gland

In 2019, Dr. Richard Trohman studied thyroid physiology, pathophysiology, diagnosis and management of Amiodarone thyrotoxicosis, writing that the drug has a direct toxic effect on the thyroid distinct from iodine:

Amiodarone has direct, dose-dependent cytotoxic effects on the thyroid in a variety of animal models. These findings have been confirmed in human post-operative pathologic specimens. DEA [amiodorane metabolite] is even more cytotoxic for thyroid cells than the parent drug. Although iodide excess may induce apoptosis, amiodarone administration is associated with ultrastructural changes indicative of thyroid cytotoxicity distinct from those induced by excess iodine alone. These changes include marked distortion of thyroid architecture, apoptosis, necrosis, inclusion bodies, lipofuscinogenesis, macrophage infiltration, and markedly dilated endoplasmic reticulum (ER)…Amiodarone-induced hyperthyroidism is a much more complex entity than AIH [Amiodorone induced Hypothyroidism]. There are two main forms of amiodarone-induced thyrotoxicosis (AIT). Type I AIT usually occurs in abnormal thyroid glands and is the result of excessive iodine-induced hormone synthesis and release. Autoregulatory mechanisms modulate the thyroid gland’s iodine handling according to its iodine content . Disruption of these autoregulatory mechanisms is suggested by the high glandular iodine content associated with AIT compared with euthyroid amiodarone recipients and by return of iodine content to normal during resolution of thyrotoxicosis. Toxic nodular goiter and Graves’ disease are the most common causes of Type I AIT in patients with preexisting or “latent” thyroid disease…Type II AIT is a destructive thyroiditis leading to release of preformed (stored) thyroid hormones from damaged thyroid follicular cells. Type II AIT typically occurs in patients without underlying thyroid disease… Type II AIT persists for 1–3 months, until thyroid hormone stores are depleted, but resolves more quickly after glucocorticoid therapy.(93-94)

In 2007, Dr Kazuko Yamazaki studied the effect of Amiodarone on cultured thyroid follicles in-vitro finding no cytotoxic effect at therapeutic concentrations. However at supraphysiologic concentrations there were cytotoxic effects, thought to be due to “exceeding endogenous antioxidant capacity”, i.e referring to the selenoprotein glutathione peroxidase, writing:

When thyroid follicles obtained from a patient with Graves’ disease who had been treated with amiodarone were cultured in amiodarone-free medium, TSH-induced thyroid function was intact, suggesting that amiodarone at a maintenance dose did not elicit any cytotoxic effect on thyrocytes... Conclusion: These in vitro and ex vivo findings suggest that patients taking maintenance doses of amiodarone usually remain euthyroid, probably due to escape from the Wolff-Chaikoff effect mediated by decreased expression of NIS mRNA [sodium iodide symporter messenger RNA]. Further, amiodarone is not cytotoxic for thyrocytes at therapeutic concentrations but elicits cytotoxicity through oxidant activity at supraphysiological concentrations. We speculate that when amiodarone-induced prooxidant activity somehow exceeds the endogenous antioxidant capacity, the thyroid follicles will be destroyed and amiodarone-induced destructive thyrotoxicosis may develop.(95)

Note: the antioxidant capacity above refers to the seleno-protein anti-oxidant system, glutathione peroxidase. Notice this is the same mechanism for destructive thyroiditis seen in endemic myxedematous cretinism in Zaire, Africa, Hashitoxicosis and Painless Thyroiditis.(96)

Pathogenesis of Amiodarone Induced Thyrotoxicosis

In 2009, Dr. Silvia Eskes and Wilmar M. Wiersinga described the pathogenesis of AIT [Amiodarone induced Thyrotoxicosis] type 2 as similar to that of subacute thyroiditis (SAT), in which thyrotoxicosis is due release of preformed thyroid hormone from from damaged thyroid follicles, writing:

The pathogenesis of AIT [Amiodarone induced thyrotoxicosis] type 2 is similar to that of subacute thyroiditis (SAT), in which thyrotoxicosis is due to the release of preformed thyroid hormone into the bloodstream from damaged thyroid follicular epithelium. AM [Amiodarone] and DEA have (independently from iodine) a direct cytotoxic effect on cultured human thyrocytes. AM disrupts the architecture of the thyroid at a cellular and subcellular level in an experimental animal model changes akin to the severe follicular damage and disruption observed in thyroids of SAT [subacute thyroiditis] and AIT type 2 whereas AM-treated euthyroid patients show minimal or no thyroid follicular damage. The ultrastructural changes include an increased number of secondary lysosomes, exhibiting marked lipofuscinogenesis and dilation of the endoplasmic reticulum, with sparing of the mitochondria. Similar changes have been observed in other tissues damaged during AM treatment, and disruption of subcellular organelle function seems to explain the toxic effects of AM. Toxicity increases with exposure time to AM in clinical studies and, at times, is related to the cumulative dose of AM. Other similarities of AIT type 2 with SAT, supporting the view of AIT type 2 as a drug-induced destructive thyroiditis, are (a) the sudden onset, (b) sometimes the presence of a small painful goitre, (c) low or absent thyroidal radioiodine uptake, (d) frequently a self-limiting course and (d) high incidence of a subsequent subclinical hypothyroid stage.(97)

Treatment of Amiodarone Associated Thyrotoxicosis

In 2018, Dr Virginia Li Volsi Discusses the treatment of Amiodarone inuced thyrotoxicosis is different for each type. Type I is treated with thyroid blocking ducgs, such as Methimazole. Type II is treted with glucocorticoids, or thyroidectomy if severe.

Amiodarone induced thyrotoxicosis (AIT) is classified as type I and type II, the former occurs in patients with underlying thyroid disease such as nodular goiter, autonomous nodular goiter or Graves’ disease, whereas, Type II is caused by iodine-led destruction of the thyroid follicular epithelium in a normal thyroid gland. Because amiodarone is vital to control the cardiac problems, it is often not possible to wean the patient from the medication or to change to another drug. The first line of therapy in amiodarone induced thyrotoxicosis is treatment with Thionamides [Methimazole] in AIT I and glucocorticoids in AIT II. Thyroid excision is undertaken in patients who do not respond to medical therapy in order to treat the hyperthyroidism which often worsens cardiac symptoms.(98-99)

Serum Thyroglobulin as Sensitive Marker of Thyroiditis

In various inflammatory conditions of the thyroid, the ruptured follicles release thyroglobulin into the blood stream, and measurement of thyroglobulin may indicate severity of thyroiditis.  In 1978, Dr. Izumi wrties:

Serum Tg appears to be a sensitive indicator of acute thyroidal damage due to surgical, radiation, or inflammatory trauma. (100-102)

Thyroiditis, Thyroidal Iodine Content Decreases by 2/3, Serum Thyroglobulin Increases

In 1986, Dr. Robert Smallridge studied thyroid iodine content with flourescent scanning and serum thyroglobulin for clues to the natural history of destruction-induced thyroiditis, finding low iodine content early on in the disease, most likely caused by the low iodine uptake.  There was also low thyroglobulin from rupture of follicles, writing:

Twenty-eight patients with destructive thyroiditis were followed to study the natural history of healing of thyroid gland injury. All had sequential measurements of thyroidal iodine [127-I] content by fluorescent scanning (normal mean, 10.1 mg), 17 had serial serum thyroglobulin (Tg) measurements (normal, less than 21 ng/ml), and 13 had perchlorate discharge studies during the recovery phase. Seventeen patients had painful subacute thyroiditis (SAT), 9 had painless thyroiditis with thyrotoxicosis (PTT), and 2 had postpartum thyroiditis with thyrotoxicosis (PPT). Thyroidal iodine content decreased from a mean of 9.8 to a nadir of 3.8 mg in patients with SAT and from 8.5 to a nadir of 3.5 mg in patients with PTT. Mean serum Tg concentrations were highest (approximately 165 ng/ml) in both groups 1-3 months after the onset of symptoms. Abnormalities in both 127-I content and Tg levels persisted for 2 or more yr in some individuals… Three patients had positive perchlorate discharge tests (2 of 8 with Permanent hypothyroidism occurred in 3 patients (2 with PTT; 1 with SAT and positive antibodies)…These data indicate that several years may be necessary for complete resolution of destructive thyroiditis; many patients have evidence of thyroid injury persisting long after serum thyroid hormone and TSH levels become normal. (103)

Conclusion: The autonomous nodule and toxic nodular goiter are the two most common causes of iodine induced hyperthyroidism in the U.S.  Unlike Graves’ Disease in which iodine may serve as a thyroid blocking agent, iodine is contraindicated for the autonomous nodule and toxic nodular goiter patient, as in these cases, iodine causes thyrotoxicosis, which may represent a life-threatening medical emergency.

Another important cause of thyrotoxicosis is the cardiology drug Amiodarone which causes a destructive thyroiditis strikingly similar to two other forms of thyroiditis, Painless Thyroiditis, and Hashitoxicosis, all three characterized by low radio-iodine uptake.


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Hyperthyroidism from Multinodular Goiter

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Painless Thyroiditis

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

It is very important to diagnose correctly the etiology of thyrotoxicosis, because the course and treatment of thyrotoxicosis with low radioactive iodine uptake differ significantly from that of hyperthyroidism due to Graves’ disease or toxic nodular goiter. Many causes of subacute thyroiditis have been identified producing a characteristic course of transient hyperthyroidism, followed by hypothyroidism, and usually recovery. Ectopic hyperthyroidism includes factitious thyroid hormone ingestion, struma ovarii, and, rarely, large deposits of functioning thyroid cancer metastases. Iodine-induced hyperthyroidism may be associated with low radioiodine uptakes. Amiodarone-associated hyperthyroidism may be the result of subacute thyroiditis or iodine-induced hyperthyroidism; assessment and treatment can be quite challenging

Thyrotoxicosis is most commonly caused by the excessive production of thyroid hormone by the thyroid gland. In Graves’ disease, hyperthyroidism results from stimulation of the thyrotropin receptor by a specific immunoglobulin, whereas in patients with toxic adenoma and toxic multinodular goiter, autonomous production of hormone is the mechanism of hyperthyroidism. These and other additional causes of hyperthyroidism (Table 1) are associated with a high 24-hour radioiodine uptake, reflecting the ongoing organification of iodine into thyroglobulin during the process of thyroid hormone synthesis.

In contrast, several important causes of thyrotoxicosis are associated with a low 24-hour radioiodine uptake (see Table 1). These disorders can be divided into three groups. 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%.

Ectopic thyrotoxicosis refers to those disorders in which the source of thyroid hormone is extrathyroidal, and the radioiodine uptake measured over the thyroid gland is usually less than 1%.

Iodine-induced hyperthyroidism may be associated with a low radioiodine uptake, because the exogenous iodine intake dilutes the radioiodine tracer used to determine the uptake. In contrast to other causes of thyrotoxicosis with low radioiodine uptake, iodine-induced hyperthyroidism is associated with intrathyroidal production of thyroid hormone, and the 24-hour radioiodine uptake is low but frequently greater than 1%.

79) Gluck, Franklin B., Martin L. Nusynowitz, and Stephen Plymate. “Chronic lymphocytic thyroiditis, thyrotoxicosis, and low radioactive iodine uptake: report of four cases.” New England Journal of Medicine 293.13 (1975): 624-628.

To characterize four patients with thyrotoxicosis and a low radioactive iodine uptake, thyroid biopsies were performed, and iodine metabolism was studied. Histologic examination showed the presence of chronic lymphocytic thyroiditis, with no features of Graves’s disease, in all. Detailed studies in one patient revealed insufficient metabolism of iodine to account for the clinical and chemical features of thyrotoxicosis, which implies that release of stored hormone by the inflammatory process causes the thyrotoxic state. The thyrotoxicosis in this entity subsides spontaneously. Thus, this form of thyrotoxicosis differs from the usual form found in Graves’s disease in that histologie features of Graves’s disease are absent, the radioactive iodine uptake is low, and specific antithyroid therapy is contraindicated. The observations further demonstrate that the radioactive iodine uptake remains a valuable tool in the diagnosis of thyrotoxicosis and the differentiation of its various forms.

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

Two male patients aged 36 and 52 years with thyrotoxicosis revealed a serum T3 of 2.8 and 6.5 nmol/l and a serum T4 of 166 and 238 nmol/l, respectively. Both had been exposed to iodine (2-10 mg daily) for 2-12 months before thyrotoxicosis was diagnosed. Urinary iodine excretion was high, 5000 and 10,000 nmol/24 h (624-1250 microgram). The uptake of 131I in the thyroid glands were low, none had goitre. Their iodine intake was interrupted, urinary iodine excretion gradually decreased, and T3 and T4 in serum concomitantly normalized. They were clinically and biochemically euthyroid 9 and 11 weeks after withdrawal. After 14 and 22 weeks they had normal thyroid uptake of 131I, and thyroid scans showed glands of normal size and configuration. TRH-stimulation and a T3-suppression tests became normal. ESR was not elevated in any of the cases, thyroid antibodies against thyroglobulin and follicular cell microsomes were absent and TSAb was undetectable durng the thyrotoxic stage. Thus no evidence of any pre-existing and/or pre-disposing pathological condition in the thyroid glands were found. The mechanism for the iodine-induced thyrotoxicosis in such cases remains obscure.

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Four cases of painful thyroid enlargement accutely after iodine load. No thyrotoxicosis though, Perhaps allergic reaction?

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On the other hand, the present findings seem clearly to indicate that the thyroid does respond with hyperfunction to procedures that acutely lower plasma iodide concentration…For the foregoing reasons, it would appear that acute depletion of extracellular iodide in man is associated with an intrinsic, autoregulatory increase in thyroid function, which tends to minimize the decreased hormonal synthesis that would otherwise occur.

87) Bonnema, Steen Joop, and Laszlo Hegedüs. “Radioiodine therapy in benign thyroid diseases: effects, side effects, and factors affecting therapeutic outcome.” Endocrine reviews 33.6 (2012): 920-980.

A recent systematic review based on eight studies concluded that a low-iodine diet appears to increase the thyroid RAIU and possibly the efficacy of 131I therapy of thyroid cancer patients, but the impact on the long-term recurrence rate is unknown

88) Sawka, Anna M., et al. “Dietary iodine restriction in preparation for radioactive iodine treatment or scanning in well-differentiated thyroid cancer: a systematic review.” Thyroid 20.10 (2010): 1129-1138.

Given that LIDs reduce urinary iodine measurements, increase I-131 uptake, and possibly improve efficacy of I-131 treatment, we currently favor the use of a 1-2-week LID before I-131 therapy or scanning.

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92) Léger, Aubéne, et al. “Thyroid iodine content measured by x-ray fluorescence in amiodarone-induced thyrotoxicosis: concise communication.” Journal of Nuclear Medicine 24.7 (1983): 582-585.

93) Trohman, Richard G., et al. “Amiodarone and thyroid physiology, pathophysiology, diagnosis and management.” Trends in cardiovascular medicine 29.5 (2019): 285-295.

94) Pitsiavas, Vicki, Peter Smerdely, and Steven C. Boyages. “Amiodarone compared with iodine exhibits a potent and persistent inhibitory effect on TSH-stimulated cAMP production in vitro: a possible mechanism to explain amiodarone-induced hypothyroidism.” European journal of endocrinology 140.3 (1999): 241-249.

95) Yamazaki, Kazuko, et al. “Amiodarone reversibly decreases sodium-iodide symporter mRNA expression at therapeutic concentrations and induces antioxidant responses at supraphysiological concentrations in cultured human thyroid follicles.” Thyroid 17.12 (2007): 1189-1200.

96) Vanderpas, Jean B., et al. “Iodine and selenium deficiency associated with cretinism in northern Zaire.” The American journal of clinical nutrition 52.6 (1990): 1087-1093.

97) Eskes, Silvia A., and Wilmar M. Wiersinga. “Amiodarone and thyroid.” Best Practice & Research Clinical Endocrinology & Metabolism 23.6 (2009): 735-751.

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

99) Sato, Kanji, et al. “Differential diagnosis and appropriate treatment of four thyrotoxic patients with Graves’ disease required to take amiodarone due to life-threatening arrhythmia.” Internal medicine 47.8 (2008): 757-762.

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101) Yamamoto, M., et al. “Effect of prednisolone and salicylate on serum thyroglobulin level in patients with subacute thyroiditis.” Clinical endocrinology 27.3 (1987): 339-344.

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Last updated on by Jeffrey Dach MD

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