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At present, oral medicine is still the most basic and common treatment for hyperthyroidism.

It is suitable for patients with mild to moderate thyroid enlargement.

Both propylthiouracil (PTU) and methimazole (MMI) are the mainstream antithyroid drugs (ATD) used in clinics, but how do we choose between those two?

They have similar mechanisms of action:

They can inhibit the peroxidase system in the thyroid and block the oxidation of ionic iodine concentrated to active iodine so that tyrosine cannot be iodinated to hinder the condensation of iodinated tyrosine, then inhibit the synthesis of triiodothyronine (T3) and thyroxine (T4), exerting an anti-thyroid effect.

However, the two have their characteristics in terms of clinical efficacy and adverse reactions.

#1. Clinical efficacy

The dose of MMI 5mg and PTU 50mg are equivalent.

But related studies have found that although the dose is the same, the efficacy is different when it is applied to patients with hyperthyroidism clinically.

Studies have shown that the therapeutic effect of MMI is better than that of PTU.

This may be explained by the following two aspects:

1.1 Methimazole (MMI) contains sulfhydryl groups

Studies have found that untreated patients with Graves’ hyperthyroidism have increased serum lipid peroxidation activity, decreased plasma sulfhydryl and sulfhydryl lysate levels, increased intracellular antioxidant enzyme activity, and insufficient activity of the extracellular free radical scavenging system. Thiimidazole treatment can reverse these abnormalities.

1.2 Propylthiouracil (PTU) has a larger molecular weight

The molecular weight of PTU is 170.24, while MMI is only 114.16.

The high molecular weight makes it difficult for propylthiouracil to pass through the placental tissue, and its concentration in breast milk is also very low.

This is its advantage; but at the same time, it also affects it.

Absorption in the body and through the thyroid follicular cell membrane to function.

Although large doses of propylthiouracil also inhibit the activity of deiodinase in the thyroid and peripheral tissues, reduce the conversion of thyroxine to triiodothyronine, and reduce the blood triiodothyronine, it cannot completely offset it. Due to the short plasma half-life and large molecular weight.

#2 Adverse reactions

In general, antithyroid drugs are safe and effective, but their clinical adverse reactions are also common, generally mild, and can recover on their own if the drug can be stopped in time.

However, rare and serious side effects can also occur during the treatment, which may be potentially fatal, so attention should be paid.

The adverse reaction of MMI is significantly lower than that of PTU, and the adverse reaction of MMI is dose-dependent, while PTU has no clear correlation with drug dose.

2.1 Agranulocytosis

The absolute count of peripheral blood granulocytes below 0.5 x 109/L is defined as agranulocytosis.

The incidence of agranulocytosis caused by antithyroid drugs is 0.1%-0.5%.

The incidence of PTU and MMI treatment was 0.37% and 0.35%, respectively.

Most agranulocytosis occurs in the first 3 months of treatment, and some appear 1 year or longer after treatment.

It should be noted that agranulocytosis did not occur in the initial treatment, and it may still occur during retreatment.

The most typical clinical manifestations of agranulocytosis are fever and sore throat and may have infections of the respiratory tract, digestive tract, genitourinary tract, or severe sepsis and sepsis.

If it is determined clinically to use antithyroid drugs, the patient should undergo routine blood tests before medication to make sure that the patient has no other problems, and it can also be compared with the blood routine after medication.

During antithyroid drug treatment, white blood cells should be tested regularly to detect asymptomatic agranulocytosis as early as possible.

If the neutrophils are less than 1.5×109/L, the drug should be stopped immediately.

In the treatment of agranulocytosis, the infection should be actively controlled, combined with granulocyte colony-stimulating factor, glucocorticoid, or lithium carbonate.

It should be pointed out that MMI and PTU have cross-reactions in the adverse reaction of agranulocytosis, so it is not recommended to replace the two.

2.2 Liver damage

The clinical manifestations of liver damage caused by antithyroid drugs lack specificity, such as abdominal distension, nausea, vomiting, yellow urine, yellowish skin, sclera, etc.

Upper abdominal pain and hepatomegaly are rare;

laboratory tests usually have a significant increase in ALT, and pathology suggests non-specific hepatocyte necrosis.

Both MMI and PTU can cause liver damage, but the liver damage caused by MMI is relatively mild, mainly intrahepatic cholestasis, which usually occurs about 2 weeks after medication;

The main manifestations are elevated bilirubin and jaundice, and laboratory examination.

It can be seen that serum bilirubin is elevated, liver enzymes are mildly elevated, and liver biopsy shows the presence of hepatocyte structure, accompanied by cholestasis in the tubules and mild periportal inflammation.

Liver damage caused by PTU is more serious than MMI, and liver damage mainly occurs in patients treated with PTU, with a general incidence of 0.1%-0.2%, mainly liver cell damage.

Most of which appear in the initial stage of PTU treatment, after taking the drug for 1-2 months.

It should be noted that 30% of patients treated with PTU will have a short-term acute increase in ALT, which can be as high as 1.1-6.0 times the upper limit of normal.

This increase in ALT can subside while continuing the medication.

The mechanism of liver damage is unclear, and it is generally believed to be related to the body’s heterogeneous reactions.

The incidence of severe liver damage caused by antithyroid drugs is very low, and there is no predictor.

It is recommended to test liver function before treatment with antithyroid drugs.

If ALT or serum bilirubin is slightly elevated, it is recommended to use hepatoprotective or anti-jaundice drugs at the same time as antithyroid drug treatment;

if ALT or serum bilirubin is significantly elevated, it is recommended to treat liver protection or anti-jaundice first. 

After the indicators improve and become slightly elevated, anti-thyroid medication is performed, and the liver function should be continuously observed.

If liver damage occurs after antithyroid drug treatment, the drug should be discontinued immediately, and symptomatic hepatoprotective treatment should be used.

At present, there is no report of liver toxicity between MMI and PTU.

Therefore, when liver damage occurs with one of these drugs, the other drug can be carefully selected.

2.3 Vasculitis

Vasculitis is generally rare, and PTU causes more than MMI.

Anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis is more common in middle-aged women.

The clinical manifestations mainly include fever, rash, joint muscle pain, acute renal insufficiency, and upper respiratory tract involvement (such as pharyngitis, rhinitis, nasopharyngeal Ulcer, nose bleeding, etc.) and lower respiratory tract involvement (such as cough, hemoptysis, pulmonary hemorrhage, non-infectious lung shadows, and severe respiratory failure, etc.).

Once vasculitis occurs, the drug should be discontinued immediately, and most patients can recover, but in some severe cases, whether to apply glucocorticoids, immunosuppressive agents, hemodialysis or plasma should be determined based on their clinical manifestations, organ involvement, and antibody titer Replacement and other treatments.

2.4 Adverse skin reactions

Mainly skin rash and skin itching, the incidence rate is 10% and can be corrected with antihistamine drugs.

If the rash is severe, the drug should be stopped to avoid exfoliative dermatitis.

2.5 Joint pain

The incidence of joint pain is 1%-5%. When joint pain occurs, it should be considered a sign of antithyroid arthritis syndrome.

It usually appears within 2 months of antithyroid drug treatment and can be relieved after stopping the drug.

It is recommended to switch to other therapies to treat hyperthyroidism and use non-steroid Symptomatic treatment with anti-inflammatory drugs or glucocorticoids.

2.6 Gastrointestinal reactions

The gastrointestinal reaction is one of the minor adverse reactions of antithyroid drugs, and its incidence is between 1% and 5%.

It usually manifests as an upset stomach, loss of appetite, and nausea. Generally, it does not cause serious harm, and only symptomatic treatment is enough.

2.7 Hypoglycemia syndrome

Hypoglycemia syndrome is also known as insulin autoimmune syndrome or Hirata disease.

At present, more than 200 cases of this syndrome have been reported worldwide, and they are more common in Asian populations, especially Japanese.

The syndrome can be seen in patients taking MMI treatment, and there is no report that PTU causes this syndrome.

After stopping MMI in most patients, the condition resolved spontaneously within 3 months.

The treatment method is to eat multiple times a day and avoid high-sugar foods (except when hypoglycemia occurs).

Studies have shown that the application of α-glycosidase inhibitors may reduce the immune response to insulin in the serum after a meal.

Glucocorticoids, azathioprine, 6-mercaptopurine, and other immunosuppressive agents can also be used or plasma exchange to remove antibodies in the serum.

2.8 Hypocalcemia

Studies have found that it may be the result of T3emia inhibiting the release of bone calcium, or it may be related to changes in the function of parafollicular cells secreting calcitonin in the thyroid tissue.

2.9 Other adverse reactions

In addition to the above-mentioned adverse reactions, antithyroid drugs can also cause abnormal taste or smell, sialadenitis, thrombocytopenia, aplastic anemia, hypothrombinemia, hair loss, drug fever, acute necrotizing gingivitis, pancreatitis.

Side effects such as methimazole dependence are rare.

Among them, abnormal taste or smell and sialadenitis are only seen in patients receiving MMI treatment.

#3 Special circumstances

3.1 Patients during pregnancy

The goal of antithyroid drugs in the treatment of hyperthyroidism during pregnancy is to use the smallest effective dose of antithyroid drugs to reach and maintain the upper limit of serum FT4 in the shortest possible time and to prevent antithyroid drugs from affecting the fetal brain development through the placenta.

PTU preferred in early pregnancy

PTU is preferred, MMI is the second-line choice.

Because of the high ratio of PTU to plasma protein binding, the placental passage rate is lower than MMI, and the amount of PTU passing through the placenta is only 1/4 of the MMI.

MMI may cause fetal skin hypoplasia and methimazole-induced embryonic diseases (including posterior nares), atresia of the esophagus, facial deformities), and other congenital malformations.

MMI preferred in the second and third trimesters

MMI is recommended as the first choice, because PTU has the risk of severe liver damage, including liver failure and death.

The starting dose is PTU 50-100mg, orally 3 times a day, or MMI 10-20mg, once a day.

Monitor thyroid functions and reduces the drug dose in time.

Check the thyroid function every 2-4 weeks at the beginning of treatment, and then extend it to 4-6 weeks.

3.2 Patients with hyperthyroidism during lactation

The choice of drugs for breastfeeding hyperthyroidism is still controversial.

The 2008 “Guidelines for the Diagnosis and Treatment of Thyroid Diseases in China” pointed out that PTU should be the first choice for the treatment of hyperthyroidism during lactation.

Studies in the past 20 years have shown that the use of antithyroid drugs during lactation is safe for offspring.

The use of PTU 150mg/d or MMI 10mg/d has no significant effect on infant brain development, but the infant’s thyroid function should be monitored.

Antithyroid drugs should be used during lactation.

The mothers who were treated with drugs did not find any complications such as neutropenia and liver damage in their offspring.

Mothers should take antithyroid drugs after breastfeeding, and then take the next breastfeeding at an interval of 3 to 4 hours.

The milk output of MMI is 7 times that of PTU.

The 2012 “Guidelines for the Diagnosis and Treatment of Thyroid Diseases in Pregnancy and Postpartum” pointed out that MMI should be the first choice for breastfeeding antithyroid drugs.

The dose of 20-30mg/d is safe, and PTU is used as a second-line drug.

3.3 Patients with hyperthyroidism crisis

PTU is preferred.

Compared with MMI, in addition to inhibiting the synthesis of thyroid hormone, PTU can also inhibit the conversion of T4 into T3 with higher biological activity in peripheral tissues, so it has a faster onset and can quickly control the symptoms of hyperthyroidism.

Therefore, PTU is the first choice for the rescue of hyperthyroidism, but MMI can be completely replaced when there is no PTU.