Graves’ disease, or diffuse toxic goiter, is the most common type of hyperthyroidism in clinical practice, accounting for about 80% to 85% of hyperthyroidism and occurring in young and middle-aged women between the ages of 20 and 40. There are three main treatments for this disease: antithyroid drugs, radioactive iodine 131 therapy and subtotal thyroidectomy. Among them, drug therapy is the most widely used in clinical practice because of its efficacy, simplicity, non-invasiveness, few complications and no permanent “hypothyroidism”. The disadvantage is that this method has a long course of treatment and is prone to relapse after stopping medication. Some of the key issues involved in drug therapy are briefly described below.
Which patients with hyperthyroidism are suitable for drug treatment?
The indications for drug treatment of hyperthyroidism are.
① Those with mild disease and mild to moderate enlargement of the thyroid gland.
②Patients under 20 years of age, pregnant women, elderly and frail patients or those with severe combined heart, liver and kidney disease who are not suitable for surgery.
③pre-operative preparation.
④ those who have relapsed after surgery and are not suitable for treatment with radioactive iodine 131
⑤ Those with adjuvant therapy after radioactive iodine 131 treatment.
Characteristics of the action and usage of antithyroid drugs
Methimazole (MMI) and propylthiouracil (PTU) are commonly used antithyroid drugs. Their mechanism of action is to inhibit the synthesis of thyroid hormone, but they do not work on the already synthesized thyroid hormone and cannot prevent the release of thyroid hormone.
Therefore, antithyroid drugs need to be taken for 1 to 2 weeks until most of the thyroid hormones previously stored in the thyroid follicles are consumed, while it takes 4 to 8 weeks to reduce the patient’s hypermetabolic state to normal levels.
The half-life of methimazole is 4-6 hours and the effect can be maintained for 24 hours, so the whole day’s dose can be taken in one dose in the morning and the effect is equivalent to 3 oral doses per day, while the half-life of propylthiouracil is only 2 hours and the effect is short, so 3 doses per day are required.
In addition, propylthiouracil is the drug of choice for the treatment of hyperthyroidism because of its rapid onset of action and its ability to inhibit the conversion of T4 to the more active T3 in peripheral tissues.
What are the common side effects of antithyroid drugs?
The side effects of antithyroid drugs mainly include leukopenia and drug rash, and others include liver function impairment, etc. These side effects mostly occur within 1 to 2 months after starting the medication.
When the white blood cells are <4×109/L and neutrophils are <2×109/L, additional leukocyte-raising drugs (such as reserpine, shark liver alcohol, vitamin B4) are required. If, after the above treatment, leukocytes are still <3×109/L and neutrophils <1.5×109/L, along with fever, sore throat, arthralgia and other symptoms of granulocyte deficiency, the patient should immediately discontinue the drug and give granulocyte colony-stimulating factor, plus symptomatic treatment with effective broad-spectrum antibacterial agents.
If the rash is severe and deteriorates into “exfoliative dermatitis”, the medication should be stopped immediately and glucocorticoid therapy should be given.
Rational selection of antithyroid drugs
Methimazole is internationally recommended as the first choice for the treatment of hyperthyroidism because of its relatively good safety profile, smooth efficacy and high patient compliance. However, the following three conditions are excluded: ① hyperthyroidism crisis; ② T3?-type hyperthyroidism; ③ hyperthyroidism in early pregnancy. Clinically, propylthiouracil is the drug of choice for these three conditions.
How to adjust the dosage of anti-thyroid drugs at the right time?
The treatment of hyperthyroidism can be divided into three phases: “control”, “dose reduction” and “maintenance”.
In the “control phase”, methimazole 10-15mg 3 times a day or propylthiouracil 100-150mg 3 times a day can be given depending on the severity of the patient’s condition. The effect usually starts after 1 to 2 weeks, and after 4 to 8 weeks, the symptoms of hyperthyroidism can be relieved and T3 and T4 can be normalized.
”After 2 to 3 months, when the patient’s condition is well controlled and the daily methimazole dosage is 2.5 to 10 mg or the daily propylthiouracil dosage is 25 to 100 mg, the patient can be transferred to the “maintenance phase”.
The “maintenance phase” should last at least 1.5 to 2 years. It is important to note that the dosage should be increased during any phase of treatment, especially when the patient is suffering from infection or mental trauma, and then gradually reduced after the condition has stabilized.
Adjuvant medications for hyperthyroidism
The adjuvant drugs for hyperthyroidism mainly include beta-blockers (such as “Tretinoin”), thyroxine preparations and iodine, among which iodine is mainly used for the preoperative preparation of hyperthyroidism and rescue of hyperthyroidism crisis. Here we focus on the application of the first two drugs.
1. β-blockers
These drugs can improve the symptoms of sympathetic excitation and reduce the hypermetabolic manifestations (palpitations, excitability, shivering, etc.) caused by thyroid hormone overload. However, these drugs are not the only treatment for hyperthyroidism. However, these drugs are not the fundamental treatment for hyperthyroidism and cannot correct the cause of the disease, so they are not used as long-term treatment. It should be noted that these drugs should not be used in patients with hyperthyroidism combined with bronchial asthma or severe heart failure.
2.Thyroid hormone preparation
The purpose is to stabilize the function of hypothalamic-pituitary-thyroid axis and to suppress the secretion of thyroid stimulating hormone (TSH), so as to avoid “pharmacological hypothyroidism” that may lead to The enlarged thyroid gland and proptosis are aggravated. In addition, the recurrence rate of hyperthyroidism can be significantly reduced. The dose used is 50-100 μg/d of levothyroxine (eugenol) or 20-60 mg/d of thyroid tablets, which can be taken for a long time until it is discontinued together with antithyroid drugs.
Medication for hyperthyroidism during pregnancy and lactation
Most scholars believe that pregnancy does not worsen hyperthyroidism. Therefore, hyperthyroidism is not an absolute contraindication to pregnancy. However, there are differences in medication use compared to non-pregnant hyperthyroidism.
In early pregnancy, propylthiouracil is preferred. It is less likely to cross the placental barrier (only 1/3 as much as methimazole) and therefore has little effect on the fetus; in mid- and late pregnancy, methimazole is recommended instead.
In addition, the dose of methimazole should be reduced in pregnant patients with hyperthyroidism because the basal metabolic rate of women is inherently high during pregnancy, and their basal heart rate and thyroid hormone levels are slightly higher than before pregnancy.
Therefore, it is advisable to choose the smallest effective dose so that the thyroid function can be maintained at a normal high level to avoid causing hypothyroidism in the mother and child and affecting the normal development of the fetus.
The question of whether or not you can breastfeed while taking anti-thyroid medication is also an issue. Currently, it is considered safe for mothers to breastfeed as long as the dosage of antithyroid drugs is not too high (methimazole <20mg/d and propylthiouracil <450mg/d).
Since methimazole peaks in breast milk two hours after administration, breastfeeding should be avoided at this time, and you can choose to take the medication immediately after breastfeeding so that there is a gap of more than 2 to 4 hours until the next feeding.
How to grasp the indications for stopping anti-thyroid drugs?
Hyperthyroidism is an autoimmune disease in which thyroid-stimulating antibodies (TSAb) are the main cause. Although antithyroid medication can normalize thyroid function in a short period of time (2-3 months), it takes a long time to turn the blood TSAb negative.
Indications for discontinuation of hyperthyroidism include the following.
(i) relief of hyperthyroid symptoms, shrinking of the thyroid gland, disappearance of vascular murmurs, and improvement of proptosis.
(ii) Normalization of T3, T4 and TSH, return of TRH excitation test to normal and TSAb turning negative.
(iii) The course of treatment reaches more than 2 years.
④The drug maintenance dose is small.
If the above requirements are not met, the course of anti-thyroid drugs should be extended or even lifelong medication should be used, or radioactive iodine 131 or surgery should be used instead. Those who relapse after stopping medication can be treated with anti-thyroid drugs again, or switched to radioactive iodine 131 or surgery.
Indicators that need to be monitored during hyperthyroidism treatment
During the treatment of hyperthyroidism, thyroid function tests (T3, T4, TSH) should be done every 2 to 4 weeks, and the dose of medication should be adjusted according to the changes in the enlarged thyroid gland and proptosis of the patient. Antithyroid drugs can cause leukopenia and, in severe cases, granulocyte deficiency. This mostly occurs 2 to 3 months after the patient’s initial dose or 1 to 2 weeks after a second dose. Therefore, during the beginning “control phase”, patients should have blood tests at least once a week to ensure safety.
In addition, liver function tests should be done both before and after treatment. If a patient has abnormal liver function before medication, it is most likely due to hyperthyroidism itself, so there is no need to stop medication at this time.
Factors affecting the recovery and recurrence of hyperthyroidism
Factors affecting the recovery and relapse of hyperthyroidism are summarized in the following two points.
1. Inappropriate medication and inadequate course of treatment: too rapid reduction of medication, intermittent medication or premature discontinuation of medication are the most common reasons for recurrence of the disease. At present, it is advocated to continue the maintenance treatment for 1.5 to 2 years after the thyroid function has returned to normal, and to stop the medication only after the TSAb has turned negative. If TSAb is positive, the course of treatment should be extended until it is completely negative, so that it is less likely to recur. It is observed that the cure rate of hyperthyroidism is 60% for “long course” treatment of more than one and a half years and only 40% for “short course” treatment of less than six months.
2. Strong mental stimulation, severe infection, overwork, pregnancy and other stressful conditions, as well as a diet high in iodine, are also important factors that cause the recurrence of hyperthyroidism.
In addition, the recurrence of hyperthyroidism is also related to age and gender. Generally speaking, young patients and male patients are more likely to relapse than older patients and female patients.