When "antithyroid drugs" "encounter" 7 kinds of adverse reactions, this is the right way to deal with it | International Thyroid Awareness Week

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 "Graves disease hyperthyroidism" is a common clinical endocrine disease.
There are three classic treatment methods: oral medication, iodine 131 treatment and surgical treatment.

At present, in my country, most Graves disease hyperthyroidism is still the first choice for the treatment of antithyroid drugs (ATD).
Its advantages are that it is convenient and non-invasive, has a relatively positive effect, and does not cause permanent hypothyroidism.
However, drug treatment also has its problems, that is, the side effects of drugs.
, And occasionally cause more serious adverse drug reactions, so when we encounter adverse reactions of antithyroid drugs in clinical practice, how should we deal with it? It coincides with the International Thyroid Knowledge Promotion Week in 2021.
The author refers to the literature and makes a summary for readers.

 There are three main types of antithyroid drugs (ATD): methimazole (MMI), propylthiouracil (PTU), and carbimazole (CMZ, namely hyperthyroidism).
They are currently an important weapon in the clinical treatment of hyperthyroidism.
The main applications are the first two: methimazole and propylthiouracil.

 1.
ATD and liver damage Liver damage is the most common adverse reaction of ATD treatment.
The exact mechanism has not been fully elucidated.
The incidence of PTU is 2.
7% and MMI is 0.
4%, which mostly occur within 4 months after treatment.

However, when diagnosing, it is necessary to determine whether liver damage occurred before or after medication.
Because hyperthyroidism itself, viral hepatitis, autoimmune liver disease, and other drugs can cause liver damage, it is recommended to routinely test liver function before ATD treatment.
Identify and inform the patient of the adverse reactions of ATD.
According to the situation, the medicine can be used after the liver function is normal.

 1.
Liver damage caused by MMI usually manifests as cholestatic hepatotoxicity, manifested by jaundice and toxic hepatitis with elevated liver enzymes.
It mostly occurs in patients over 40 years old, but in most cases it is mild and rarely causes liver necrosis.

According to literature reports, there are no reports of deaths from liver toxicity related to MMI.

Studies have suggested that there seems to be a dose-dependent relationship between MMI and the risk of liver toxicity.

Liver function improved or recovered after stopping ATD.

Pathological examination often finds: inflammatory infiltration of monocytes and lymphocytes in liver lobules, and re-administration can still cause liver damage.

 Treatment: The liver damage caused by MMI needs to be discontinued or reduced.

If the patient has subclinical liver damage, or only has mild liver function abnormalities, it is generally not necessary to stop the drug, but combined with liver protection treatment; if the liver damage is significant, signs of liver toxicity and/or symptoms appear, baseline transaminase>3-5 The drug should be discontinued immediately and the treatment plan should be changed, such as radioactive iodine or surgery.

MMI liver damage is mainly cholestatic liver damage, so treatments for reversing cholestasis (such as the use of ursodeoxycholic acid) are needed for hepatoprotective treatment.

 2.
PTU-induced hepatotoxicity may be related to autoimmune or specific reactions that cause liver cell damage, manifested as increased serum AST and ALT, about 8.
3% of patients with transaminase 3 times higher than ULN, moderately elevated bilirubin, and Accompanied by nausea, vomiting, and other physical discomforts, in most cases, these abnormalities will alleviate spontaneously.
Occasionally, fatal fulminant hepatocellular injury and liver failure may be seen.
In severe cases, liver transplantation is required.

The liver damage caused by PTU seems to have nothing to do with the dose, and the re-use of PTU may lead to recurrence of liver damage.
In addition, it has been found that children with hyperthyroidism are more likely to develop liver damage after PTU is administered than adults.

 Treatment: When PTU causes liver damage, it is necessary to stop the drug (if the transaminase level reaches more than 3 times the upper limit of normal, or if the treatment starts to increase further, PTU should be stopped), and the treatment plan for hyperthyroidism should be changed, such as radioactive iodine treatment, surgery Or MMI, liver protection and nutritional support treatment should be carried out at the same time.

MMI and PTU-induced liver toxicity have some similarities, but compared with MMI, severe liver injury events are more likely to occur in patients who use PTU, especially in children.

Therefore, MMI is currently the first choice in the treatment of ATD, and PTU is generally used as a second-line choice, and short-term medication is recommended to avoid use by children.

Except for special circumstances, such as patients in the first trimester of pregnancy (because MMI has a higher risk of fetal malformations), patients with thyroid crisis (because PTU can play a special role in inhibiting the conversion of T4 to T3), and there are contraindications to MMI or Insensitive patients need to choose PTU treatment.

 2.
ATD and skin allergies The common clinical manifestations of ATD skin allergies are mild and severe, the former such as skin itching, urticaria, drug fever, etc.
, and the latter such as exfoliative dermatitis.

The rash can be generalized or localized, and the localized rash usually occurs on the trunk.

The incidence is about 5% (MMI is 6%, PTU is 3%).
The symptoms caused by MMI are often dose-related.
PTU or high-dose MMI (>30mg) is more common and usually occurs in the first month of medication.
The average appearance time reported in the literature is 18-22 days.

 Treatment: There is no need to stop ATD for patients with mild symptoms, and antihistamines can be used in combination, such as loratadine tablets, ebastine tablets, etc.
; if the rash continues to progress and the patient is intolerant, switch to another ATD+ Antihistamines; patients with severe allergic reactions such as exfoliative dermatitis should stop using ATD drugs and take radioactive iodine and surgery.

In addition, some skin reactions caused by PTU may be manifestations of vasculitis, and attention needs to be paid to distinguish them.

 3.
ATD and the reduction of peripheral blood white blood cell count.
ATD can cause leukopenia and agranulocytosis.
It usually occurs 1 to 3 months after treatment, with an incidence of about 0.
2% to 0.
5%.
MMI may be related to the dose.
The MMI dose exceeds 40 mg.
/d, it is more common in older persons; PTU has nothing to do with dose, any dose of PTU may cause neutropenia or deficiency.

 Since Graves disease itself can also cause leukopenia, routine blood tests should be performed before treatment, and ATD should be carefully considered for neutrophils <1.
0×10^9/L.

 Treatment: At the beginning of ATD treatment, it may be necessary to check blood routine every 1 to 2 weeks.
When the WBC is 3.
0-4.
0×10^9/L, the dose of ATD is reduced, and at the same time, oral white blood cell-increasing drugs such as Licordone and Shark are given.
Liver alcohol, etc.
; WBC<3.
0×10^9/L, NEU<1.
5×10^9/L, stop the drug immediately.

Granulocytopenia can cause fatigue, fever, sore throat, etc.
, and agranulocytosis (<0.
5×10^9/L) is even life-threatening.
Therefore, during medication, patients should be advised to see a doctor promptly if they have sore throat or fever, and beware of agranulocytosis.

When agranulocytosis occurs, all antithyroid drugs should be stopped immediately, and patients with fever should undergo hematuria culture, throat swab, sputum culture and other pathogenic examinations in time to find and remove the infection foci, adopt sterile isolation measures, support treatment, and apply a broad spectrum Antibiotics can be given to recombinant human granulocyte colony stimulating factor, and the daily dose is subcutaneous injection of 3 to 5ug/kg.

 4.
PTU and small vasculitis PTU can cause anti-neutrophil cytoplasmic antibody-positive small vasculitis, the incidence is very low, only 0.
1% to 0.
5%, and its risk increases with the prolonged medication time.

Multiple system involvement, such as fever, muscle and joint pain, cough, blood in sputum or hemoptysis, respiratory failure, proteinuria, hematuria, anemia and other lung and kidney damage manifestations.

Children are more likely to cause PTU-related small vasculitis than adults.
Therefore, PTU treatment is not recommended for children with hyperthyroidism.

 Treatment: Once the disease is suspected, PTU should be stopped.

Diagnosis first depends on the diagnosis of vasculitis by kidney and other pathological biopsy and the detection of anti-neutrophil cytoplasmic antibodies (ANCA) and other related antibodies, and at the same time, combined with past history (if there is kidney disease) to determine the correlation with drugs.

Glucocorticoid therapy is given after diagnosis, and immunosuppressive agents are added if necessary, but there is no need to maintain glucocorticoid or immunosuppressive therapy for a long time.

Those who are only positive for ANCA without system damage should be followed up closely.

At the same time, consider radioactive iodine or surgery to treat hyperthyroidism, but it should be noted that the application of radioactive iodine may trigger or aggravate the manifestations of vasculitis.

 5.
ATD and drug-induced lupus (DIL) It is reported that both MMI and PTU induce DIL.

Different from common lupus erythematosus (SLE), DIL is more common in youth and old age; facial rash, oral ulcers, and photosensitivity often appear in SLE, but rarely in DIL.
DIL may have rash (mostly distributed on the limbs) and joint pain ; Although the three major systems of the kidney, nervous system, and blood system can also be affected, the probability of damage to the kidney and nervous system is generally far less than that of SLE.

Most prognosis is good.

 Treatment: Once suspected of the disease, stop ATD as soon as possible, and consider radioactive iodine or surgery to treat hyperthyroidism.
The symptoms of most patients can disappear within a few weeks; those with joint and muscle symptoms can be improved by the application of non-steroidal anti-inflammatory drugs; In some serious cases, such as kidney and blood system damage and serositis changes, glucocorticoids and immunosuppressive agents such as hydroxychloroquine and cyclophosphamide should be given.

 6.
ATD and arthritis syndrome PTU and MMI can cause joint/muscle pain, the so-called arthritis syndrome, with an incidence of 1% to 2%.

The patient was diagnosed with hyperthyroidism and had no history of joint pain.
After taking ATD, the joint pain appeared migratory in 2-3 months, and it mostly affected the large joints of both lower extremities.
Generally, there was no fever and no joint swelling.
Such as gout and rheumatoid arthritis are being ruled out.
On the basis of joint pain caused by allergic purpura, systemic lupus erythematosus, etc.
, this situation needs to be considered.

It is more common in women and can occur at all ages; joint damage is more likely to occur when the MMI dose is larger.

 Treatment: Symptoms are relieved after drug withdrawal, and the prognosis is good.

Patients with obvious pain or no obvious pain relief after stopping the drug and those with systemic symptoms can use non-steroidal anti-inflammatory drugs or glucocorticoids for anti-inflammatory and pain relief.

When muscle enzymes increase, ATD is reduced, supplemented with fructose, inosine, adenosine triphosphate and other treatments.

Patients with significantly elevated muscle enzymes generally no longer continue to take ATD and can be treated with iodine 131.

 7.
MMI and hypoglycemia.
MMI can cause insulin autoimmune syndrome, but it is very rare.
It manifests spontaneous hypoglycemia, high levels of insulin and high titers of insulin autoantibodies; digestive tract reactions, such as gastrointestinal discomfort, mild abdominal pain , A very small number of oral odor and decreased taste.

 Treatment principle: Treat symptomatically, reduce the dose of ATD or add prednisone in a short period of time to gradually relieve it, and stop the drug if necessary.

 Reference materials: [1] Pharmaceutical Hepatology Group of the Chinese Medical Association Hepatology Branch.
Guidelines for the diagnosis and treatment of drug-induced liver injury (2015 edition)[J].
Journal of Practical Hepatology, 2017, 20 (2): Ⅰ-ⅩⅧ.
[2 ]Li Li,Shi Rui,Lu Shan,Pan Dan.
Liver injury, rash and arthritis syndrome caused by methimazole[J].
Adverse Drug Reactions Journal,2017,19(06):473-474.
[3]China The Medical Association, the Journal of the Chinese Medical Association, the Chinese General Practice Branch of the Chinese Medical Association, the Chinese Journal of General Practitioners, the editorial board of the Chinese Medical Association, the expert group for the preparation of guidelines for the primary diagnosis and treatment of endocrine system diseases.
Guidelines for the primary diagnosis and treatment of hyperthyroidism[J].
Chinese Journal of General Practitioners, 2019, 18 (12): 1129-1135.