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The American Thyroid Association and American Association of Clinical

Endocrinologists’ Guidelines for Hyperthyroidism and Other Causes of

Thyrotoxicosis: An Appraisal.

Gilbert H. Daniels M.D.

Gilbert H. Daniels M.D.

Thyroid Unit and Department of Medicine, Massachusetts General Hospital

Harvard Medical School

Address

Thyroid Unit ACC 730

Massachusetts General Hospital ACC 730

Boston, MA 02114

Email: gdaniels@partners.org

Phone: 617-726-8430

Fax: 617-726-5905

DOI:10.4158/EP11120.ED

© 2011 AACE.

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The American Thyroid Association and American Association of Clinical

Endocrinologists’ Guidelines for Hyperthyroidism and Other Causes of

Thyrotoxicosis: An Appraisal.

The new ATA/AACE Guidelines took more than three years to prepare but are

well worth the wait (1). Like all good guidelines they provide a handy reference

on an important subject. The information is up-to-date, evidence-based,

educational, thoughtfully presented, practical, and useful as a stimulus for

further research. Of course, the guidelines are also controversial.

Why do good guidelines tend to be controversial? To answer that question, we

must first understand what guidelines are and are not. We will begin with what

they are not, since it is actually more important. In the absence of randomized

controlled trials, guidelines are not gospel and should never be considered as

such. They are not rigid rules to be applied in every clinical situation. They are

not a substitute for common sense and good clinical judgment. They are not

designed to be a handy reference for malpractice lawyers seeking to understand

“the standard of care”.

Good guidelines are actually a set of expert opinions, the emphasis being on

both expert and opinions. Since they are based upon a highly imperfect

literature, guidelines are usually formulated after extensive discussions and

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debates among experts, all of whom have different training, experience, and

approaches. In the case of the new ATA/AACE guidelines, the authors are North

American and European clinicians with great expertise in adult and pediatric

thyroidology, thyroid surgery, nuclear medicine, statistics and evidence-based

medicine/guidelines. There were undoubtedly differences of opinion, approach

and practice among these international experts, but they ultimately had to be

submerged in the interest of conciliation and consensus.

Who will read these guidelines and what purpose do they serve? Primary care

physicians will occasionally consult them for an overview and to learn what is

new in the care of hyperthyroid patients. Endocrine fellows will read them to

see how the opinions of their mentors compare with these new standards.

Novice practitioners will use them for guidance and reassurance. More

experienced practitioners will use them to discover new literature, keep up-to-

date and compare their own approach with those of the experts. In some cases

they will be surprised by some of the recommendations, but will usually

acknowledge that “it can also be done that way.” They may find themselves in

genuine disagreement with some of the recommendations or perhaps they may

think that certain recommendations go beyond the available evidence. In my

own case, I find that reading guidelines leads me to review the literature so that I

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can evaluate the quality of the data on which recommendations are based, and in

the process I tend to discover papers that I had either overlooked or forgotten.

These new ATA/AACE guidelines have many strengths. The authors provide

100 evidence-weighted recommendations detailing specific and practical

suggestions for clinicians. Most of these recommendations are devoted to

Graves’ Disease and toxic nodular goiter in adults and to hyperthyroidism in

children. The listing of these recommendations seriatim in Appendix A and the

Guide to Organization of Recommendations (Table 2) is particularly user-

friendly. The new guidelines also make a clear and very important distinction

between the treatment of Graves’ disease and toxic nodular goiter. The 15

recommendations devoted to pediatric hyperthyroidism as well as the scholarly

discussion about these recommendations are unique among guidelines and are

to be applauded. The authors grappled with and came up with helpful advice

concerning several difficult and controversial issues, e.g., is anti-thyroid drug

pre-treatment necessary prior to radioactive therapy? What is the role of

thyrotropin receptor antibodies (TRAb) in Graves’ diagnosis and therapy as well

as pregnancy? When are glucocorticoids necessary after radioactive iodine to

protect against the development or exacerbation of Graves’ opthalmopathy? The

authors firmly, definitively, and appropriately enthrone methimazole as the anti-

thyroid drug of choice and discuss the limited roles of propythiouracil. The

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authors acknowledge that hypothyroidism is the desired goal of radioactive

iodine therapy for Graves’ disease. The authors do not neglect less common or

less controversial disorders characterized by an excess of thyroid hormone.

These guidelines also have several weaknesses. I acknowledge that some of my

criticisms are a matter of opinion (that word again) and style and that some

might be considered minor. As a regular reader of guidelines, I should add that

many of these same weaknesses are commonly found in other guidelines.

1) The authors of the ATA/AACE guidelines provide admirably thorough

discussions of thorny and controversial dilemmas but often give more

perfunctory treatment to less controversial and more traditional subjects.

2) In their attempt to provide helpful recommendations for clinicians, the authors

sometimes go too far and provide highly specific recommendations in the

absence of supporting evidence. For other recommendations, the authors apply

their expertise and logical thinking to direct clinical practice despite the fact that

these recommendations have not been clinically tested in rigorous trials or even

in clinical practice. One must never forget the immutable law of unintended

consequences when recommending untested remedies.

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3) While the guidelines do not explicitly forbid some (uncommon) clinical

practices, the discussions tend to restrict and narrow the range of therapeutic

options for the clinician.

4) I feel that certain recommendations and their discussions could be more

precise or scholarly.

The following are specific examples of some of the strengths and weakness of

these guidelines. I present my ideas in the hope that they will provide food for

thought, suggest areas for further study, and help strengthen both these and

future guidelines.

Antithyroid Drugs

It is interesting to observe how the debate about the necessity of anti-thyroid

drug (ATD) pre-treatment prior to radioactive iodine therapy has evolved over

the past forty years. For many years, clinicians argued that such treatment was

essential for safety purposes. Yet in my own experience, pre-treatment most

often seemed unnecessary. It also seemed peculiar to me that some patients

chose radioactive iodine in order to avoid the potential toxicity of ATDs only to

have those same agents prescribed for several months prior to radioactive iodine

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therapy. The question now seems to have shifted to: “is pre-treatment ever

necessary?” One of the authors of the new guidelines has maintained that pre-

treatment is never necessary.

To some extent the question of whether ATD pre-treatment is ever necessary is

beside the point, since the very sickest hospitalized hyperthyroid patients cannot

be treated with radioactive iodine in the hospital and are almost invariably

started on ATD. I continue to pre-treat severely ill hyperthyroid patients when I

am concerned they cannot tolerate worsening hyperthyroidism, but I

acknowledge that making that distinction is a judgment call. The authors agree

(#5), recommending pretreatment of “extremely symptomatic” patients who are

at increased risk for complications due to worsening of hyperthyroidism. But I

think that the authors go too far by including in the population requiring pre-

treatment both adults who have free T4 estimates 2 – 3 times the upper limits of

normal and children who have a free T4 > 5 ng/dl. They give this a rating of 1,

the highest level of assurity, despite the fact that there is really no evidence to

support this arbitrary number. It is interesting that the guidelines provide no

numerical free T4 value for pre-treatment of patients with toxic nodular goiter,

perhaps because these patients are usually not as hyperthyroid. In my

experience pre-treatment is never based on arbitrary fT4 or T3 concentrations,

and I usually follow the simple rule of “pre-treat if you are seriously worried.”

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It is important to review the history of the choice of ATD here. For many years

PTU was considered the ATD of choice. It was thought to provide an advantage

over methimazole because it inhibited T4 to T3 conversion yet I suspect, that the

major reason for its use during those years was that most senior mentors and

clinicians in the USA both felt most comfortable using PTU. I was fortunate to

have a mentor (Dr. Farahe Maloof) who preferred methimazole. The most recent

evidence clearly shows that methimazole should be the drug of choice based on

its greater efficacy, greater convenience, and greater safety. The new guidelines

strongly favor the use of methimazole.

The authors note (# 7) that methimazole may be unsafe during the first trimester

of pregnancy and that PTU is preferable at that time. They recommend that

methimazole should be used when therapy is initiated after the first trimester.

They also recommend switching from PTU to methimazole at the mid-point of

pregnancy if therapy is still required. While making this switch might seem

logical I would hesitate to follow such an approach routinely, until prospective

studies or clinical experience confirm that it is both safe and effective. Indeed,

switching might cause a new allergic reaction or lead to over- or under-control of

the hyperthyroidism. The authors do acknowledge in the discussion that not

switching is also an alternative.

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To be sure, one cannot ignore the 1 in 2000 – 4000 risk of potentially lethal

hepatic failure in children and adults exposed to PTU. Yet I wonder whether

the pendulum has now swung too far in demonizing PTU? For example, how

should a clinician deal with a 4 year old with a minor allergic reaction to

methimazole? Since these guidelines recommend that radioactive iodine not be

used under age 5, surgery would be the only recommended alternative. But

surgery would expose the young child to the very high risks of surgical

hypoparathyroidism, vocal cord paralysis and stridor, especially if a world-class

thyroid surgeon were not available. In other words, the case against longer-term

use of PTU is not as cut and dry as one might think.

TRAb

The authors accept the measurement of TRAb as an alternative to a readioactive

iodine uptake for the diagnosis of Graves’ disease when a radioactive iodine

uptake is either unavailable or contraindicated. I would take this

recommendation several steps further. I believe it is time to acknowledge that

TRAb is a reasonable alternative to a radioactive iodine uptake for diagnosing

Graves’ disease in many cases. I would also encourage performing a radioactive

iodine scan when an initial radiodine uptake is done for hyperthyroidism and

not, as recommended by these guidelines, only when nodular disease is

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suspected. I acknowledge that this is a personal preference. The authors note,

quite appropriately, that patients with high titers of TRAb are unlikely to be in a

remission and that stopping their ATDs is unlikely to be successful.

The authors have taken an important first step in acknowledging the importance

of TRAb measurements during Graves’ pregnancy, but I would like more

precision in their actual recommendations. European guidelines make three

recommendations which I find particularly helpful: 1) in a euthyroid pregnant

woman with a prior history of anti-thyroid drug therapy for Graves’ disease,

TRAb measurements are unnecessary; 2) in a euthyroid pregnant woman with

prior radioactive iodine therapy or surgery for Graves’ disease, TRAb should be

measured early in pregnancy to assess risk for fetal hyperthyroidism and late in

pregnancy to assess risk for neonatal hyperthyroidism; 3) in a pregnant woman

on ATD for Graves, TRAb should be measured in the last trimester to assess for

neonatal hyperthyroidism

(2).

The current ATA/AACE guidelines do not define a titer of TRAb where the fetus

or newborn is at risk for hyperthyroidism. I would recommend a titer of at least 3

times the upper limits of normal. The earliest case of fetal hyperthyroidism has

been reported at 20 weeks; therefore I would recommend measuring TRAb prior

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to that date. The current guidelines suggest measuring TRAb either at 22 -26

weeks initially or at 22-26 weeks if initially elevated (#75). I would recommend

measuring TRAb by 20 weeks. The current guidelines recommend measuring

TRAb by 22-26 weeks in a woman diagnosed with GD during pregnancy, but

such measurements are unnecessary until late in pregnancy if the mother is

being treated with ATD. The reason that early TRAb measurements are

unnecessary when ATDs are prescribed is that the risk of fetal hyperthyroidism

is essentially nil if the mother is being effectively treated with ATD. Measuring

TRAb near the end of pregnancy in patients being treated with ATD may help

predict neonatal Graves’ disease. Late measurement of TRAb is not suggested in

these guidelines. I would therefore encourage revision of Table 9 and the

corresponding recommendations to be consistent with the European guidelines.

Glucocorticoids and Graves’ Ophthalmopathy (GO)

Of all the topics considered in these guidelines, probably the most difficult and

controversial one is the role of glucocorticoids after radioactive iodine in the

prevention of Graves’ ophthalmopathy. We all struggle with this issue,and it is

to the credit of the authors that they tackle it head-on. They recommend against

concomitant glucocorticoid therapy in non-smokers with either no GO or mild

GO. They are uncertain about using glucocorticoids for smokers without

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ophthalmopathy but recommend glucocorticoids in smokers with mild

ophthalmopathy. They recommend that active moderate to severe as well as

sight-threatening ophthalmopathy be treated with either MMI or surgery but

note in Table 12 that there is insufficient evidence to recommend either for or

against the use of radioactive iodine with glucocorticoids in this particular group

of patients.

Many of the seminal studies about glucocorticoids after radioactive iodine to

prevent GO have been done by European investigators. The EUGOGO

consensus publication in particular considers this subject in great detail (3). The

EUGOGO group reports that 15% of patients in these studies either develop new

eye disease or experience the progression of pre-existing GO within 6 months

after radioactive iodine therapy. They note that this risk is almost entirely

eliminated by giving a short course of oral glucorticoids after radioactive iodine

and by avoiding post-treatment hypothyroidism. As a result, they recommend

that patients with active (not otherwise defined) GO “be offered” prophylactic

steroid coverage after radioactive iodine.

In 2008 the chairperson of the new ATA/AACE guidelines wrote: “… while the

EUGOGO group can be credited with having performed the majority of

randomized controlled trials in [the field of glucocorticoids and Graves’

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ophthalmopathy]… they are not of sufficient scope to support formal practice

guidelines” (4). To provide this necessary scope it will be important to conduct

initial-risk-stratified randomized controlled trials of radioactive iodine both with

and without glucocorticoids with avoidance of hypothyroidism. It will be

especially important to run trials in which careful attention is paid to the less

commonly reported toxicities of glucocorticoids that may occur, e.g. behavioral

changes, insomnia, aseptic necrosis, and not focus exclusively on the more

commonly reported toxicities.

Tables

Tables can be an extremely helpful way to organize and summarize the many

thoughtful discussions in the text of guidelines. Unfortunately, some of the tables

in the new guidelines are not as helpful as they might be.

While Table 13 includes several drugs which have been associated with

thyrotoxicosis, it neglects many others which are also important. The authors

refer to and presumably use a 1995 reference but they should certainly have

included a more recent reference for the sake of completeness (5). Although

alumtuzemab is not approved for therapy of multiple sclerosis, it is worth

including because it causes Graves’ disease in 10 % of patients and destructive

thyroiditis in other patients. Highly active antiretroviral therapy (HAART) has

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also been associated with Graves’ disease. Denileukin diftitox, tyrosine kinase

inhibitors, etanercept and other drugs have also been associated with destructive

thyroiditis. Thyrotropin alpha should also be included in the list of drugs

causing hyperthyroidism.

Table 3 (Causes of Thyrotoxicosis) and Table 14 (Unusual Causes of

Thyrotoxicosis) omit important information, overlap unnecessarily, and would

from being organized differently. In the the text accompanying these tables

the authors use the terms subacute thyroidtis and painful subacute thyroiditis

(DeQuervain’s thyroiditis) interchangeably. The two terms were considered

synonymous at one time, but more recent studies routinely distinguish

between painful and painless subacute thyroiditis. A better way of

organizing this topic might be to use the general term destructive thyroiditis,

and to subdivide it into the painful or painless type (6). Painless subacute

(or destructive) thyroiditis includes: autoimmune, drug-induced (including

amiodarone), palpation thyroiditis, , external radiation-induced, amyloidosis,

pneumocystis and other infections, and others rare causes. Painful subacute

(destructive) thyroiditis includes not only DeQuervain’s but also malignant

pseudothyroiditis and post-radioactive iodine thyroiditis. To make the list of

rare causes comprehensive, one would have to add germ-line activating TSH

receptor mutations (7), thyroid cancer which hyperconverts T4 to T3 (8), and

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other rare causes of destructive thyroiditis listed above. Table 3 notes quite

properly that “patients with thyroid hormone resistance are not uniformly

clinically hyperthyroid.” The problem with the wording of this statement is that

one could easily infer that most patients in this group are actually clinically

hyperthyroid, and that point is debatable.

The discussion of thyroid storm in Table 6 would look familiar to readers

perusing the literature of the 1970s, except for its references to the inhibition of

T4 to T3 conversion by high doses of propranolol, glucocorticoids and PTU.

Although hydrocortisone has been used for decades in thyroid storm, there is

little firm evidence that it is either necessary or beneficial, despite the fact that

thyrotoxicosis accelerates the production and metabolism of glucocorticoids. One

study suggests that the adrenal response to ACTH (after dexamethasone

administration) is less vigorous in severely hyperthyroid individuals than in the

same patients, when euthyroid (9). But there is still no evidence that thyroid

storm is quantitatively or qualitatively different from severe thyrotoxicosis in

this regard, or that glucocorticoids make a difference in its therapy. Although

glucocorticoids inhibit T4 to T3 conversion it is uncertain whether this adds to

the inhibition of T4 to T3 produced by high dose PTU. If the

authors wish to continue recommending glucocorticoid therapy, they might also

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discuss the evidence for and against its benefits.

Table 6 and the text which accompanies this table, do not discuss the use of other

potent inhibitors of T4 to T3 conversion. The text does mention that ipodate and

iopanoic acid, the most potent inhibitors of T4 to T3 conversion, are no longer

available in the U.S.A. Nevertheless, it fails to mention that amiodarone is

readily available and that it is a potent inhibitor of T4 to T3 conversion.

Although clinicians are justifiably hesitant to use amiodarone for fear of causing

hyperthyroidism, the drug has proved effective when added to ATDs in order to

accelerate the return to euthyroidism (10).

Cholecystyramine also shortens the return to euthyroidism when added to ATD

therapy of hyperthyroidism (11). If critically ill thyrotoxic patients are able to

take PO medications, it would seem reasonable to add cholestyramine to the mix.

The guidelines do not mention either amiodarone or cholestyramine for the

treatment of thyroid storm. Reference to the use of rectal PTU or methimazole for

those unable to take medications P.O. is also missing. There are anecdotal reports

of resin hemoperfusion and exchange transfusion being used to treat thyroid

storm, and these therapies merit discussion even if they are not recommended.

An important problem is how to define and diagnose thyroid storm. After 40

years of practice, I am still not certain what constitutes thyroid storm. Janet

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McArthur’s description of thyroid storm from 1947 continues to provide a

reasonable working definition for the clinician: “[Thyroid storm is] a life-

endangering augmentation of the symptoms of thyrotoxicosis in which the

patients’ response is out of proportion to the exciting stimulus (12).” In 1993

Burch and Wartofsky (13) attempted to make the diagnosis of thyroid storm by

basing it on a scoring system. This quantitative system was validated by

accurately diagnosing 59 of 61 cases of thyroid storm in the literature and by

reclassifying the remaining two as impending thyroid storm. The authors of the

current guidelines lend implicit support to the Burch-Wartofsky scoring system

by presenting it as Table 5. I consider this scoring system a clinically unvalidated

approach to the problem of thyroid storm and would thus prefer it to be

presented in a critique rather than in a table. We simply do not know how many

patients whose scores reach the “thyroid storm” threshold would actually get

into clinical trouble or how many patients with “impending storm” would

actually develop thyroid storm. For example, a patient with a temperature of

99.5 (5points), mild agitation (10 points), and atrial fibrillation (10 points) would

be considered “suggestive of impending storm”. If a pulse of 110 (10 points) and

diarrhea (10 points) were added, then the score of 45 or more points would be

suggestive of thyroid storm. I doubt whether the authors of these guidelines

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would recommend therapy for thyroid storm for all patients with a score of 45 or

more.

Table 7 presents a comprehensive summary of the theoretical risks of cancer

incidence and cancer mortality after radioactive iodine therapy. I question

whether this hypothetical information belongs in clinical guidelines and whether

a simple reference would not be preferable.

Expanding Clinical Options

It is important for an expert clinician to have many possible options to treat

difficult diseases. Although these guidelines do not specifically forbid certain

options, they tend to narrow the clinician’s therapeutic horizons.

The following are several examples of therapies which merit discussion even if

they do not yet reach the level of a recommendation:

• The authors discuss the benefits of lithium use after radioactive iodine to

return thyroid function to normal, but they do not generally recommend

it. On the other hand, they make no mention of using iodide (SSKI and

others) after radioactive iodine despite its similar benefit. It could be that

the authors omit iodide because its use has not been studied in

randomized controlled trials. But we know that during the decades after

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the discovery of radioactive iodine, iodide was used routinely and safely

after radioactive iodine. It has also been shown to be effective in two

retrospective trials (14,15). I have already mentioned the potential roles of

amiodarone and cholestyramine in thyroid storm.

• Although long-term high-dose iodide is clearly contraindicated during

pregnancy because of the risk of obstructive goiter in the fetus, the use of

low-dose iodide (35 mg) is a safe and potentially important therapeutic

alternative for pregnant hyperthyroid women who are allergic to

antithyroid drugs (16).

• I have found the block-replace regimen particularly effective for a limited

number of patients with Graves’ disease, particularly for those who have

yo-yo’d between high and low thyroid function, for those going away to

school where variations in thyroid function may be particularly

troublesome, and for those without access to laboratory monitoring. The

authors discount the block-replace regimen because they feel that

methimazole toxicity is dose-related. However most of the literature on

increased toxicity with high-dose methimazole involves patients receiving

doses upwards of 30 mg, and agranulocytosis has also been reported with

doses of methimazole as low as 5 to 10 mg. At least one reference quoted

in these guidelines supports the block-replace regimen and the risks of

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high dose MMI being primarily for doses upwards of 30 mg (17). If

clinicians are concerned about using 30 mg of MMI, 20-25 mg also works

in this regimen.

• I have seen many patients who are told that they are not “allowed” to

take anti-thyroid drugs for more than two years. Although I am a great

fan of radioactive iodine, there is often an implicit prejudice against long-

term ATD therapy. I think it is important to distinguish between therapy

designed to increase the possibility of remission (which does not seem to

increase with long-term use) and therapy designed simply to provide

long-term control of Graves’ hyperthyroidism. The guidelines make a

reasonable recommendation to consider alternative therapy after two

years of ATDs. It is also important for clinicians to acknowledge patient

autonomy and to avoid insisting upon alternative therapies if the patient

does not want radioactive iodine or surgery. It is critical for patients to feel

comfortable with the therapy that is used and for them to be the ones who

make the final choice of therapy. When adults are treated with ATD, most

of the complications occur early in the course of therapy, and long-term

allergic reactions are rare. I was interested to learn that children are more

likely than adults to have late allergic complications to ATD. I was also

surprised to read that is more difficult to control toxic multinodular goiter

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with ATD than it is to control Graves’ disease with these agents. That has

not been my experience when using adequate doses of MMI.

Logical But Unproven Recommendations

There are several recommendations put forth by the authors which seem entirely

logical but which are still untested and unproven. It would seem that the

previous recommendations in favor of estrogen for menopausal women and PTU

for Graves’ disease should militate against making strong recommendations

without clinical validation.

• Does every 19-year-old with a pulse of 91 and hyperthyroidism need

a beta blocker?

• Do all hyperthyroid patients really need to have their respiratory

rates measured and recorded or should that be reserved for

individuals with a history of dyspnea? What do the authors mean in

recommending that pulmonary function be monitored?

• Is there any evidence that avoiding iodine containing vitamins is

necessary prior to receiving radioactive iodine?

• What are the potential unintended consequences of measuring a WBC

and differential and liver function tests (LFTs) prior to starting anti-

thyroid drugs? Will the finding of a low WBC or slight elevations of

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LFTs frighten many primary care physicians and some

endocrinologists and prevent therapy with ATDs? This

recommendation requires further study.

• Is there really an arbitrary threshold of fT4 concentrations above

which ATDs must be prescribed prior to radioactive iodine?

• I have already discussed switching from PTU to MMI in mid-

pregnancy.

Areas Where Additional or More Nuanced Advice Might Be Helpful

There are a number of areas where additional discussion/advice would be

invaluable.

• The authors recommend retreatment with radioactive iodine if the Graves’

patient is not euthyroid after 6 months. I would encourage basing the

decision to retreat on the severity of residual hyperthyroidism and the size

of the thyroid rather than on an arbitrary date. The milder the

hyperthyroidism and the smaller the thyroid, the longer one can wait. In

some cases, the addition of MMI or SSKI could be utilized while waiting

for continued radioactive iodine effect.

• The authors recommend (#70) ATDs for hyperthyroidism due to GD that

requires treatment during pregnancy. It would be helpful to have some

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guidance about when treatment is actually required. With many South

American immigrants now in the USA, we are seeing more toxic nodular

goiters in young pregnant women. It would be helpful to provide advice

about treating this condition in pregnant women.

• In the initial discussion of toxicity of ATDs, it might be helpful to list the

prevalence of each side effect.

• There is evidence that subclinical hyperthyroidism is more likely to

progress to overt hyperthyroidism in patients with toxic adenomas and

toxic nodular goiters. A reader would undoubtedly find this information

helpful.

• The authors recommend beta blockers and/or methimazole for overt

iodine-induced hyperthyroidism (#88). Should not methimazole always be

added for severe hyperthyroidism? Perchlorate may be useful in selected

cases of iodine –induced hyperthyroidism. Although perchlorate is not

readily available in the USA, it can be compounded from reagent grade

perchlorate.

• The authors recommend testing to distinguish Type 1 and Type 2

amiodarone- induced thyrotoxicosis (AIT). Additional guidance on how to

make this difficult distinction would be helpful and should include a

discussion of the diagnostic utility of glucocorticoid responsivity. It would

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also be helpful to point out that 90% of AIT is now Type 2 and that Type 2

tends to occur with longer duration of amiodarone therapy. The authors

recommend that the decision to stop amiodraone in the setting of

thyrotoxicoiss should be made on an individual basis in consultation with

a cardiologist. The discussion makes it clear that although there is some

debate about stopping amiodarone in Type 1, there is no real benefit to

stopping it in Type 2. I would say that this is a situation where the

endocrinologist should educate the cardiologist rather than consult the

cardiologist for advice. Additional guidance about how long to use

combination therapy with ATD and glucocorticoids and when to pull the

trigger on surgery would be helpful to all clinicians.

• The recommendation which deals with patients who are allergic to

antithyroid drugs and require beta blockade for surgery is appropriate,

but it would be helpful to have additional guidance about how to use this

pre-operative regimen (18).

• The authors describe the “rapid” decline in TFTs in individuals with

methimazole and iodide, but they fail to define what constitutes this

“rapid” decline. In most studies, normalization of T4 and T3 in patients

on this regimen takes weeks rather than days (19). How quickly TFTs

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normalize in the intensive care unit, is clearly a very important

consideration.

• Post-operative phosphate measurement, in addition to calcium or PTH

measurement, may be a less expensive alternative to PTH measurements

in determining whether a patient needs post-operative calcium and

calcitriol (20).

• Should hyperparathyroidism be included among the possible long-term

consequences of radioactive iodine therapy (21)?

• A low-iodine diet is mentioned for patients with a low radioiodine uptake

prior to radioactive iodine therapy for Graves’ disease but not for patients

with toxic nodular goiter, where a low uptake is a much more common

occurrence.

• The authors strongly oppose “routine” monitoring of WBC and

differential in patients taking anti-thyroid drugs but then cite a study that

strongly supports routine WBC monitoring (22). It would be helpful for

the authors to provide a more careful evaluation of that study.

• When discussing gestational hyperthyroidism and hyperemesis,

thyrotoxic vomiting might also be mentioned.

• While the authors mention the potential for iodine-induced

hyperthyroidism in individuals with nodular autonomy, they do not

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weigh in on the role of anti-thyroid drug prophylaxis in individuals with

nodular thyroid glands and low or borderline low TSH who must be

exposed to iodine (e.g. CT scan with contrast, cardiac catheterization or

amiodarone) (23).

• The authors note that the risk of thyroid cancer in Graves’ disease is 2 %

but fail to mention that there is also evidence that the risk is much higher.

• The authors recommend restricting the dose of radioactive iodine (131-I)

to less than 10 mCi for children between 5 and 10 years of age, yet they

quote a study which recommends a dose of 15 mCi for all pediatric

patients. The authors should discuss this discrepancy in dosage.

• A persistent SGOT 2 – 3 times the upper limits of normal is presented as

an indication to discontinue PTU. But what should the clinician do when

the SGOT is in this range prior to administering antithyroid drugs?

• The authors recommend measurement of free T4 four weeks after starting

ATD and note that T3 can also be monitored. I would encourage a much

stronger recommendation about T3 measurement. Many clinicians wait 6

weeks after starting ATD before re-testing thyroid function. Perhaps a

range of time would be more helpful.

Additional Editing

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Minor inconsistencies and errors inevitably show up in comprehensive

guidelines such as this one:

• The authors first note that a decreased TSH in early pregnancy does not

indicate abnormal thyroid function and later state that it is

hyperthyroidism but that it does not require treatment. I would agree

with second statement.

• The authors initially comment that “there is evidence that MMI

pretreatment may reduce the efficacy of subsequent radioactive iodine

therapy” (although the quoted references do not seem to address the

subject) and then subsequently say “Whether MMI may have the same

effect is unclear” (the reference here is appropriate).

• The authors consider 10 – 20 mg of MMI to be a “higher” dose. I would

consider 30 mg to be a high dose and 10 – 20 mg to be low to medium

doses. I am concerned that 10 mg would not be a sufficiently high initial

dose for many patients with hyperthyroidism. Even 20 mg would not be

sufficient for some of them. The dilemma of ATD administration is that it

takes 4 – 8 weeks to judge the result of a given dose and months can be

wasted if the initial dose is too low. There are studies that demonstrate

much more rapid normalization of thyroid function when the T4 is > 20

with a 30 mg dose of MMI than with a 15 mg dose (24).

28

• For recommendation #14 I think the authors mean “pruritis and rash”

(rather than pruritic rash). This is correctly stated in recommendation #56.

• The authors say that glucocorticoids may be used in preparing patients for

surgery who are allergic to ATD. However, the accompanying reference

uses iopanoic acid plus glucocorticoids rather than glucocorticoids alone.

Future Studies Stimulated by these Guidelines.

Important guidelines such as these help us understand not only how much we

know, but even more importantly, how much remains to be learned. It might be

helpful for future guidelines to include a list of potential research/clinical

questions that need to be answered.

The following are some possibilities:

• Is the HPA axis impaired in severe thyrotoxicosis?

• What is the benefit of monitoring respiratory rate in hyperthyroidism?

• Will measuring WBC and diff and LFTs prior to starting ATDs prevent

some patients from starting on this therapy?

29

• What information leads a patient to select a particular therapy for

hyperthyroidism? The authors suggest some possibilities, but it would be

interesting to actually know why.

• What is the complication rate following radioactive iodine therapy

without ATD pre-treatment when the free T4 is 2-3 times the upper limits

of normal in adults and > 5ng/dl in children?

• If serum calcium and phosphate are measured post-thyroidectomy, what

additional information does PTH monitoring provide?

• What is the risk of operating on patients with TMNG without pre-

operative antithyroid drugs? There is unpublished experience at some

centers, and it would be interesting to review it.

• What is the risk of prolonged glucocorticoid therapy for AIT 2 compared

with surgery? How often is prolonged glucocorticoid therapy required for

AIT 2 ?

• What is the true complication rate for thyroid surgery for Graves’ disease

in the second trimester of pregnancy when surgery is performed by expert

surgeons? What is the true complication rate for Graves’ surgery in

infants when surgery is performed by expert surgeons?

• What are the risks and benefits of glucorticoids added to radioactive

iodine in a randomized controlled trial of patients with GO who are

30

randomized after risk stratification, e.g., smokers with no opthalmopathy,

smokers with mild ophthalmopathy, non-smokers with mild

ophthalmopathy?

• What are the consequences of switching from PTU in the first trimester of

pregnancy to methimazole in later trimesters?

• How often does a thyroid scan add additional information to the

radioactive iodine uptake in hyperthyroid patients?

• Would it be helpful to apply the thyroid storm scoring system to all

patients with hyperthyroidism in order to determine how accurate this

system actually is in predicting outcome?

I am certain that you will be as stimulated and educated by these guidelines

as I was.

31

Disclosure:

I have no conflicts of interest.

32

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