Interpretation of the 2022 version of the hyperthyroidism guidelines - how to carry out standardized drug treatment for hyperthyroidism? And listen to the in-depth analysis of the big coffee

The main methods of treatment of hyperthyroidism (referred to as hyperthyroidism) are drug therapy, ¹³¹I treatment and surgical treatment, among which antithyroid drugs (ATDs) have positive efficacy, do not cause permanent hypothyroidism, and have high economic applicability, which is the most commonly used regimen
in the treatment of hyperthyroidism.

Recently, the "Guidelines for the Diagnosis and Treatment of Thyrotoxicosis Caused by Hyperthyroidism and Other Causes in China" ¹ (hereinafter referred to as the "Guidelines") was released, which has good reference significance for the standardized diagnosis and treatment of hyperthyroidism, and specially invited Professor Gao Ying of Peking University First Hospital to give a wonderful interpretation of the relevant content of ATDs treatment in the guidelines for readers.

MMI: the general drug of choice for the treatment of ATDs

ATDs have been introduced into clinical application since the 40s of the 20th century and are still one of the main methods for the treatment of hyperthyroidism, which can improve the state of hyperthyroidism and promote the normalization of dysregulated immune function by reducing thyroid hormone levels
.
ATDs are suitable for a wide range of patients with new-onset Graves disease (GD), before hyperthyroidism surgery, and ^{in the pre- and post-treatment stages of 131}I
.
This update of the hyperthyroidism guidelines provides a detailed description of the preference for ATDs and adds contraindications to ATDs

➤Priority is given to ATDs for treatment: GD patients with mild hyperthyroidism, insignificant goiter, negative thyroid-stimulating hormone receptor antibody (TRAb) or mildly elevated titers; Those who are elderly or in poor physical condition due to other diseases and cannot tolerate surgery, or have a short expected survival time; Patients with recurrence after surgery or a history of neck surgery who are not suitable for ¹³¹I treatment; Amiodarone-induced thyrotoxicosis type 1 patients; Those
who need rapid control of thyroid function in the short term.

➤ATDs contraindications: the total number of white blood cells before the application of ATDs < 3.
0×10 9/L, the absolute neutrophil count <1.
5×10⁹/L or the level of liver transaminases exceeds the upper limit of the reference value 3 times with caution, and try to avoid the use of ATDs
when it exceeds 5 times.

ATDs include imidazoles and thioureas, representing drugs such as methimidazole (MMI) and propylthiouracil (PTU), both of which inhibit thyroid hormone synthesis
by inhibiting thyroid peroxidase.
Compared with PTU, MMI is clinically equivalent to the dose, but MMI has a longer half-life, the actual clinical effect is stronger than PTU, and it can be taken once a day, which is more convenient
.

Both the 2016 American Thyroid Association (ATA) ^guidelines2 and the 2018 European Thyroid Association (ETA) ^guidelines3 recommend MMI
as the first choice for ATDs in GD patients, except in exceptional circumstances.
The 2022 version of the Chinese hyperthyroidism guidelines emphasizes for the first time in this update that MMI is generally preferred when using ATDs, except for the first trimester, when treating thyroid storm, poor response to MMI and unwilling to accept ¹³¹I and PTU is recommended for surgical treatment
.
In addition, the new hyperthyroidism guidelines add management of GD patients in children and adolescents, and indicate that ATD therapy is the first-line treatment for patients with GD in newly diagnosed children and adolescents, and MMI
is the drug of choice.
  

Therapeutic dose: individualized and dynamic adjustment is the key

The initial high dose, then reduction and maintenance are the basic principles followed by the treatment of ATDs, but in the process of clinical practical application, due to individual differences, it is difficult to unify and standardize
the starting dose, reduction speed, maintenance dose and total course of ATDs.
Compared with the 2007 version of the hyperthyroidism guidelines, the new version of the guidelines puts forward more specific suggestions for the therapeutic dose and adjustment timing of ATDs based on the principles of practicality and advanced clinical problems:

➤ Initial dose

The initial dose of ATDs recommended by the new guidelines is lower, of which MMI is generally 10~30 mg/d (the old guideline is 30~45 mg/d), which can be taken single or divided doses; PTU is generally 100~300 mg/d (300~450 mg/d in the old guidelines), taken in divided doses
.
The specific initial dose of ATDs needs to be further determined according to the severity of the patient's hyperthyroidism, and the initial dose of MMI can refer to the US ATA guidelines: FT₄ exceeds the upper limit of normal value by 1~1.
5 times: 5~10 mg; 1.
5~2 times: 10~20 mg; 2~3 times: 30~40 mg
.

➤ Dose reduction period

Thyroid function is usually measured 1 month after initial treatment, and if FT₃ and FT₄ drop to near or reach the normal range into the tapering period, MMI can be reduced by 5~10 mg/d, or PTU can be reduced by 50~100 mg/d
.

➤ Maintenance period dose

Compared with the 2007 version of the guidelines, the new version of the guidelines clarifies the timing of the maintenance period, that is, when TSH, FT₃, FT₄ are normal
.
MMI is reduced to 5 mg/d, PTU is reduced to 50~100 mg/d, the follow-up time can be extended, and the dose is reduced until thyroid function is maintained to maintain normal minimum dose maintenance therapy
.

Note: If TSH is reduced or FT₃ or_{FT 4} is elevated during follow-up, treatment can be extended or the dose of ATDs increased, or treatment can be restarted
.

Treatment course: long course, small dose maintenance effect is good

Patients with GD hyperthyroidism are treated with systematic ATDs and maintain serum TSH, FT ₃ and FT₄ at normal levels for more than 1 year after discontinuation of the drug, which is called GD remission; After the disease is relieved, hyperthyroidism has recurred, which is called relapse
.
The biggest disadvantage of ATDs is the high recurrence rate after stopping the drug, and almost all the relapses after short-term treatment of normal thyroid function, but after a certain period of systematic treatment, a considerable number of patients with hyperthyroidism can be relieved
after stopping the drug.

A prospective ^study4 in China, aimed to evaluate the long-term response rate after the second ATD treatment, included 128 patients with recurrent GD who had completed the first conventional ATD treatment, and were given MMI treatment
.
When the MMI was reduced to 2.
5 mg/day, patients were randomized into two groups: Group 1 discontinued after 5 months of treatment; Group 2 was given a dose of 2.
5 mg every other day after 5 months of treatment, and discontinued after 5 months of treatment (median duration of treatment 20 months).

After 48 months of follow-up after discontinuation of the drug, the remission rate of hyperthyroidism in group 2 was 84.
62%, which was significantly higher than that in group 1 (66.
67%), suggesting that low-dose, long-course systematic therapy can improve the remission rate
of GD.

The old version of the hyperthyroidism guideline suggests that the total course of treatment for ATDs is generally 12~18 months, which is the same as the 2016 ATA guideline and the
2018 ETA guideline.
In recent years, with the accumulation of clinical evidence, the 2022 version of the Chinese hyperthyroidism guidelines has been updated, and for the first time the standard course of ATDs can reach 24 months, emphasizing the long course
of ATDs treatment.

The guidelines suggest that the treatment course of ATDs is generally 18~24 months, and continuous low-dose MMI treatment can improve the remission rate
of hyperthyroidism.
(strongly recommended, low-certainty evidence).

Timing of discontinuation: considered when TRAb is negative or there is an adverse drug reaction

The old guidelines believe that patients with negative thyroid-stimulating antibodies (TSAb) at the time of discontinuation have a low recurrence rate after discontinuation of the drug, but TSAb measurement conditions are complex and have not been widely used
in clinical practice.
At present, there is no good clinical predictor of remission when
discontinued.
A 2006 study5 from Italy to analyze the association between serum TRAb concentrations and hyperthyroid recurrence during and after MMI treatment and discontinuation of MMI showed a retrospective quantitative analysis of serum TRAb levels in 58 GD patients and found a significant positive correlation between serum TRAb concentrations at the end of MMI treatment and the percentage of patients with hyperthyroidism (r:0.
56;P < 0.
001), there was a significant negative correlation with the time to recurrence of hyperthyroidism (r: -0.
38; P = 0.
03), in which four patients with low-titer TRAb (TRAb<0.
9 UI/L) maintained normal thyroid function throughout the follow-up period, suggesting that TRAb may be a predictor
of MMI outcomes.

With the accumulation of clinical evidence, the idea of TRAb as a predictor of remission when discontinued is gradually recognized
.
The 2016 version of the ATA guidelines and the 2018 version of the ETA guidelines both believe that MMI should be continued for 12~18 months, and when TRAb and TSH levels are normal, discontinuation can be considered
.
The 2022 version of the Chinese hyperthyroidism guidelines makes clear recommendations in this regard: adequate treatment, negative TRAb, and low-dose ATDs to maintain normal TSH, which is often an indication for discontinuation and indicates that remission may be large
.
(strong recommendation, low-certainty evidence)

In addition, in addition to considering discontinuation of the drug when the condition improves, ATDs should also be discontinued when there is a severe skin allergic reaction caused by ATDs, agranulocytosis (total number of white blood cells< 3.
0× 10 9/L or absolute neutrophil count <1.
5×10⁹/L), severe liver injury, and vasculitis, ATDs should also be discontinued to avoid further damage
to the patient.

Referral treatment recommendation ⁶

Primary medical and health institutions can undertake the initial diagnosis, treatment and long-term follow-up management of hyperthyroidism, and can identify patients with hyperthyroidism who are not suitable for diagnosis and treatment at the primary level and refer them
in time.

Critical conditions such as severe adverse effects of ATDs, thyroid storm, and hypokalemic periodic paralysis require urgent referral to a higher hospital
.
Before transfer, the corresponding emergency medical treatment should be completed, the patient's vital signs should be closely monitored, and the patient's condition should be transferred after the condition is stable to prevent adverse consequences
.

General referral
is required in patients who cannot confirm the etiology of the diagnosis, who do not respond well to ATDs that require treatment adjustment, who require ¹³¹I therapy/surgery, who have hyperthyroidism in pregnancy, hyperthyroid heart disease, thyroid nodules that require definite nature, worsening symptoms of hyperthyroidism, or other conditions.

summary

In the 2022 new version of the hyperthyroidism guidelines, the key points of drug treatment update emphasize that MMI is the general drug of choice for the treatment of ATDs, and the standard course of ATDs can reach 18-24 months for the first time, and further elaborates on the therapeutic dose adjustment and discontinuation timing of ATDs, which provides practical reference value
for the clinical work of doctors.
It is believed that the standardized use of ATDs will benefit more patients
with hyperthyroidism.

References:

1.
Guidelines for the diagnosis and treatment of thyrotoxicosis caused by hyperthyroidism and other causes in China[J].
Chinese Journal of Endocrinology and Metabolism,2022,38(08):58-106.
)

2.
Ross DS, et al.
Thyroid.
2016 Oct; 26(10):1343-1421.

3.
Kahaly GJ, et al.
Eur Thyroid J.
2018; 7(4):167-186.

4.
Liu X, et al.
Eur J Endocrinol.
2015 Mar; 172(3):321-6.

5.
Carella C, et al.
Thyroid.
2006 Mar; 16(3):295-302.

6.
Guidelines for primary diagnosis and treatment of hyperthyroidism (2019)[J].
Chinese Journal of General Practitioners, 2019, 18(12):1118-1128.

Source: Thyroid Academy

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