Experience sharing: Precautions and special case treatment of "radioactive iodine" in the treatment of Graves' disease

There are currently three treatment options: RAI therapy, antithyroid drugs (ATD) and surgery
.
RAI has been used to treat thyroid diseases for more than 80 years
since 1941.
Compared with the other two treatments, RAI has the advantages
of good efficacy, fewer adverse effects, and rapid onset of action, except for complications related to eye disease.

Before RAI treatment: 9 precautions, one is indispensable

1.
Informed consent

Before RAI treatment, an informed consent form for treatment should be signed to fully inform patients of the advantages and disadvantages of common treatments for GD, possible short-term and long-term outcomes and management methods, and the possibility that repeated RAI treatment may be required
.

2.
Food restrictions

Before RAI treatment, some iodine-containing foods, drugs and contrast agents should be strictly restricted, and the specific time should be referred to the table below
.

Table 1 Factors affecting thyroid 131 I rate measurement and ¹³¹I treatment and discontinuation time

3.
Female patients of childbearing age

A pregnancy test is required within 48 hours prior to RAI treatment, and RAI treatment can only be performed after a negative pregnancy test result is confirmed
.

4.
Lactating women

RAI therapy
should be performed at least 6-8 weeks after stopping breastfeeding and ensuring that RAI no longer accumulates in breast tissue.
A 3-month delay period further ensures that increased sodium-iodine transporter (NIS) activity in lactating breasts returns to normal levels
.
Breastfeeding
should not be performed after RAI treatment.

5.
Patients with serious underlying diseases

Before treatment, patients should receive standardized and adequate medical treatment for serious underlying diseases (atrial fibrillation, heart failure, pulmonary hypertension and associated renal failure, infection, trauma, poorly controlled diabetes, cerebrovascular disease or lung disease, liver failure, agranulocytosis, etc.
) and/or complications, and try to cooperate with relevant disciplines to maximize the patient's condition
before RAI treatment.

6.
ATD pre-treatment before RAI treatment

Thyroid storm rarely occurs
after RAI treatment.
In one study of RAI as the only treatment for hyperthyroid heart disease, no cardiac clinical worsening
due to thyrotoxicosis was found.
However, RAI therapy can cause transient increases in thyroid hormone levels, so patients with severe hyperthyroidism, older people, and patients with underlying comorbidities may be at increased risk of complications due to worsening hyperthyroidism symptoms before and after RAI treatment, and patients with a significant increase in FT 4 (2 to 3 times the upper limit of normal) can be given
to patients who are pre-treated with RAI therapy and significantly increased FT₄ (2 to 3 times the upper limit of normal).
。 In randomized controlled trials, MMI (methimazole) and carbimazole showed an effect
on reducing thyroid hormone levels after RAI therapy.
There is no carbimazole in China, so MMI
is recommended.

For the time to stop taking the drug before RAI treatment, our guidelines recommend 3-5 days before, the ATA (American Thyroid Association) recommends 2-3 days before, and the 2019ETA (European Thyroid Association) guidelines recommend that ATD drugs should be suspended for one week
before and after RAI treatment.
Meta-analysis has found that the use of ATD (including MMI, carpimezole, and PTU) within one week before and after treatment may reduce the success rate of
RAI treatment.
This effect can be counteracted
by appropriately increasing the therapeutic dose of RAI.
Therefore, the dose
of RAI can be appropriately increased for patients who require ATD therapy before and after treatment.

For young and middle-aged GD patients with inconspicuous clinical symptoms, even if the FT₄ level is high, RAI treatment
can be directly selected without pretreatment.

7.
β the application of adrenergic receptor blockers

β adrenergic receptor blockers include non-selective β receptor blockers (representative drug: propranolol) and selective beta-1 blockers (representative drugs: metoprolol, atenolol, bisoprolol, etc.
), which help control heart rate and systolic blood pressure, relieve muscle weakness and muscle tremor, and improve symptoms such as irritability, emotional instability and exercise intolerance of GD
.
If there is no contraindication, it is recommended that all GD patients should use β adrenergic receptor blockers before ¹³¹I treatment, especially elderly patients, or those with a heart rate of more than 90 beats / min at rest, or those with
systemic diseases such as cardiovascular disease.
Patients with bronchial asthma should not use propranolol.

8.
Adjuvant treatment of compound iodine solution

Compound iodine solution is most commonly used in the treatment of hyperthyroid crisis in clinical practice, and it is also used in China for GD and has complex or serious comorbidities, complications, taking ATD with liver damage or abnormal blood picture in patients
.
However, this drug can affect thyroid ¹³¹I and reduce its efficacy
.
Stopping 4-7 days before RAI treatment will not cause aggravation or rebound of GD symptoms, and can restore the iodine intake function of the thyroid gland to ensure the efficacy
of RAI.
There are few studies on ^{the treatment of} GD assisted by combined iodine solutions, and more high-quality studies are needed to validate
them.

9.
Adjuvant therapy of lithium carbonate

Lithium carbonate can inhibit the release of thyroid hormones, reduce serum_FT4 levels, short-term application helps to control GD symptoms, and does not affect the uptake
of ¹³¹I by the thyroid gland.
For decades, it has been reported that lithium before RAI treatment reduces the dose of ^131I, improves cure rates and safety, and prevents thyroid
hormone levels from increasing after ATD is stopped.
There is currently a lack of sufficient evidence-based medical research, so the treatment of lithium carbonate-assisted RAI is neither recommended nor opposed
.

RAI treatment: early precautions and management

1.
In order to ensure full absorption, fasting for at least 2h before oral administration ^{of 131}I, drinking water in an appropriate amount after taking ¹³¹I, eating after 2 h, paying attention not to rub the thyroid gland, paying attention to rest, avoiding infection, fatigue and mental stimulation, so as not to aggravate
the condition.

2.
When treated with low-dose RAI, it has less
effect on the thyroid gland and other tissues concentrated in iodide (such as salivary glands, gastric glands and breast).

3.
During high-dose RAI treatment, some patients can have neck pain, swelling, or sialadenitis due to radiation thyroiditis within the first week of treatment, and the symptoms can last for several weeks
.
The thyroid gland presents with epithelial swelling and necrosis, destruction of follicular structures, edema, and monocytic infiltration
.
Resolution of the acute phase is followed by fibrosis, narrowing of blood vessels, and further lymphocytic infiltration
.
Nonsteroidal anti-inflammatory drugs, glucocorticoids can be used to relieve pain, and vitamin C tablets or some acidic substances in the mouth can promote saliva secretion
.
If necessary, some protective agents
of the gastric mucosa can be used.

In addition, some patients may have symptoms such as fatigue, poor nutrition, nausea, and itchy skin in the short term, which can be observed or given symptomatic treatment
.
RAI treatment generally does not affect the blood picture, and individual patients have temporary leukopenia, and leukocyte drugs
can be given if necessary.

4
.
Transient thyroid hormone levels after RAI treatment can aggravate hypermetabolic symptoms, but hyperthyroid crises are rare.
In the absence of contraindications, β adrenergic blockers are effective in reducing symptoms and complications and can be used in all patients
.

5.
For elderly patients, patients with underlying cardiovascular disease, or patients with an increased risk of complications due to worsening hyperthyroidism, consider resuming MMI 3-7 days after RAI
treatment.
FT ₄ tends to be normal and gradually tapered and discontinued for 4 to 6 weeks
.
In patients who have not been pre-treated with ATD, thyroid hormone levels usually do not rise after RAI treatment, but decrease
after a few days.
ATD is taken before radioactive iodine therapy, but only if it is accompanied by ATD therapy after RAI treatment, which can prevent transient thyrotoxicosis
.
It has been reported that FT 4 levels decrease by about 6% at 3 weeks after RAI treatment if MMI is reused 7 days after RAI treatment, and FT₄ levels increase by about 36%
if MMI is not used 7 days after RAI treatment.

6.
Iodine: In some patients who should use ATD due to comorbidities or severe symptoms but do not use it due to allergies, the use of iodine (such as saturated potassium iodide solution) one week after RAI treatment may shorten the course of
hyperthyroidism.

Follow-up after RAI treatment: 6 points to focus on

1.
RAI follow-up content

Follow-up is a very important part of the treatment process, and the adverse reactions of RAI treatment and early or severe hypothyroidism can be detected in time through planned follow-up, and measures can be taken as soon as possible to avoid serious adverse reactions
.

Follow-up includes: questioning of symptoms and examination of signs; thyroid function, thyroid-associated antibodies (it should be noted that TRAB can be temporarily elevated after RAI treatment); Patients with complications should pay attention to evaluating the control of symptoms and signs of related diseases and changes
in indicators.

Follow-up time combined with Chinese and ATA guidelines:

➤It is recommended that patients with mild or moderate disease without serious comorbidities can be followed up 1-2 months after RAI treatment, and the efficacy is preliminarily evaluated;

➤ For patients with invasive exophthalmos, thyroid function testing should be performed 4 weeks after RAI treatment to avoid early onset of hypothyroidism and aggravation of eye disease;

➤Patients with more severe disease or large changes in clinical manifestations should be closely observed and followed up
as necessary.

From the current clinical data and patient uncertainty, even if there are no serious comorbidities, it is possible to find early more serious hypothyroidism and avoid serious reactions caused by hypothyroidism, so it is recommended that all patients with conditions recheck every 4-6 weeks within half a year after treatment, or until hypothyroidism occurs and thyroid hormone replacement therapy reaches a stable state
.
If a complete response is confirmed, the follow-up interval may be extended at least once a
year.

2.
Treatment of hypothyroidism

Fatigue, drowsiness, increased body mass, chills, constipation, and menstrual abnormalities in women after RAI treatment suggest the possibility of hypothyroidism and should be reviewed in time
.
Most patients gradually recover thyroid hormone levels within 4-8 weeks after RAI treatment.

Hypothyroidism can begin as early as 4 weeks after RAI treatment, with 2 to 6 months being more common, with 40% of patients occurring
after 8 weeks.
If FT₄ is below the normal range and TSH is still suppressed, hypothyroidism
should be considered.

In some patients, hypothyroidism is temporary, and thyroid function may return to normal
.
Early return to normal thyroid function after RAI treatment and subsequent onset of hypothyroidism are the result
of radiation-induced destruction of the thyroid parenchyma.
Levothyroxine tablets are preferred for the treatment of hypothyroidism
.
Patients with normal FT₄ and persistent TSH depression require close monitoring to prevent transition to clinical hyperthyroidism
.

The incidence of hypothyroidism is 5%-50% within 1 year after RAI treatment, which is positively correlated with the therapeutic dose of RAI, and the larger the dose, the higher the one-time response rate and the higher the
incidence of early hypothyroidism.
Due to the delayed effect of radiation and the destruction of thyroid tissue by lymphocyte infiltration, thyroid function and thyroid volume are reduced, and the size of the thyroid gland basically returns to normal
after one year.

In patients with concurrent TPOAb-positive GD, the subsequent incidence of hypothyroidism is 3% to 5% per year, even if thyroid function returns to normal after RAI therapy, which is largely independent
of RAI dose.
Even with low-dose RAI therapy, which increases the chance of persistence or recurrence of GD, hypothyroidism is inevitable
.

3.
Actively prevent thyroid eye disease

Approximately 15% to 33% of patients with RAI have new or transient GO.

This effect may be associated with a significant increase in serum TSHRAb after RAI treatment, compared to a decrease
in TSHRAb after thyroidectomy or ATD treatment.

It should be noted that even in patients whose thyrotoxicosis does not resolve after 3 months of treatment, indicating treatment failure, 3% to 20% of patients may develop early-onset hypothyroidism that does not necessarily develop permanent hypothyroidism, and thyroid hormone therapy is required in time to avoid exacerbation of thyroid-related eye disease (GO) or transient exophthalmos
.
Prophylactic glucocorticoids prevent GO without affecting the final function
of the thyroid gland.

4.
Evaluation of the efficacy of RAI treatment

For the treatment of GD, there is basically no absolute ideal dose
that can correct hyperthyroidism without causing hypothyroidism.
Non-hyperthyroidism after treatment, including normal thyroid function and hypothyroidism, is considered a treatment success
.

Treatment outcomes can be divided into 4 categories:

➤ Complete remission or clinical recovery (complete disappearance of hyperthyroidism and return to normal serum FT₄ after more than half a year of follow-up);

➤ presence of signs and symptoms of hypothyroidism (serum FT₄ below normal, TSH above normal);

➤ Partial remission (symptoms of hyperthyroidism are reduced, signs are partially disappeared, serum FT₄ is reduced than before, but does not return to normal);

➤ Ineffective (no improvement or worsening of symptoms and signs, no significant change in serum FT₄).

The recurrence rate after RAI treatment is about 1% to 4%.

Relapse is defined as the reappearance of signs and symptoms of hyperthyroidism and the re-elevation
of thyroid hormone levels after complete remission of RAI therapy.

5.
Re-treatment after RAI treatment

Patients who follow up after 3 to 6 months of RAI and confirm that symptoms and signs do not resolve or do not respond to treatment can be re-treated
with RAI.
When re-treating, the dose of ¹³¹I can be appropriately increased for patients who are ineffective with the previous treatment and who are accompanied by complications; A small number of patients with large, stiff GD require multiple RAI treatments to achieve complete remission
.
Surgery should be recommended in patients who do not respond to multiple RAI treatments or relapse
.

Precautions for adverse reactions after RAI treatment

¹³¹ I has little distribution and short residence time in extrathyroidal tissues, and the amount of ¹³¹I used in conventional treatment of GD produces very limited radiation to the bone marrow, gonads, liver, and heart, and there is no evidence that it will cause damage to the function of the corresponding organ tissue, even the nearest parathyroid gland damage is very limited
.

In some men, there is a moderate decrease
in subclinical and reversible testosterone and luteinizing hormone after RAI therapy.
Therefore, male patients need to postpone fertilization after 3-4 months to allow sperm regeneration, and ETA recommends extending this time to 6 months
.
Female patients should postpone pregnancy until stable normal thyroid function is established (for patients undergoing thyroid hormone replacement therapy after thyroidectomy), which usually takes 6 months or more
.
However, once thyroid function is normal in both men and women, there is no evidence of reduced fertility and congenital anomalies
in offspring compared to the general population.

RAI treatment alone does not increase mortality
from GD.
Studies have found an increase in long-term cardiovascular and cerebrovascular death in patients treated with RAI without hypothyroidism, reflecting the role of persistent hyperthyroidism, while there is no change
in mortality in patients treated with hypothyroidism LT₄ after RAI treatment.

Whether RAI treatment will increase the incidence of cancer has been a hot topic
.
Most studies found no significant increase
in the prevalence of thyroid cancer or secondary malignancies in adult patients treated with RAI.
However, meta-analyses have shown that RAI does not increase the overall risk of cancer in hyperthyroidism, although there is a trend towards increased risk of thyroid, gastric and kidney cancer, and further research
is needed.

In addition, the frequency of genetic damage does not appear to increase in the offspring of patients who received radioactive iodine treatment early
.
Given that there is no evidence of serious toxicity of RAI at doses commonly used to treat hyperthyroidism in adults, the age limit for the use of RAI (in some major international countries) has been gradually lowered from the initial lower limit of 40 years to 10 years or younger
.
However, in 5-year-olds, the theoretical lifetime cancer risk after 15^{mCi 131}I is 4%, so very young children should consider ATD
.

summary

GD is a very common disease of the endocrine system, according to the patient's condition at different times to choose the appropriate treatment method has a great impact on the patient's life treatment and prognosis, and RAI treatment plan is an important treatment guarantee
for both patients and endocrinologists.
How to make patients aware and proactive before and after treatment is also an important factor affecting the efficacy of treatment, so it is undoubtedly necessary
for doctors or patients to fully understand and grasp some issues before and after RAI treatment.

References:

1.
Nuclear Medicine Branch of Chinese Medical Association.
131I guidelines for the treatment of Graves' hyperthyroidism (2021 edition)[J].
Chinese Journal of Nuclear Medicine and Molecular Imaging, 2021, 41(4):12.

2.
Ross D S , Burch H B , Cooper D S , et al.
2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis.
[J].
Thyroid, 2016, 26（10）.

3.
George J.
K ,  Luigi B ,  Lazlo H , et al.
2018 European Thyroid Association Guideline for the Management of Graves' Hyperthyroidism[J].
European Thyroid Journal, 2018, 7（4）:1-20.

Williams Textbook of Endocrinology, 14th edition