Hyperthyroidism (hyperthyroidism) is an ancient disease, and there has been a gradual process of understanding the dangers of hyperthyroidism. Since 1883, when Wamer discovered that Graves’ disease affected the eyes of patients, scholars have gradually discovered over the next 100 years that Graves’ disease causes serious damage to the psychoneurological, cardiovascular, cutaneous, hematological, and hepatic systems. These findings have led scholars to explore better and safer treatment methods.
It is well known that there are three main methods of treatment for hyperthyroidism, namely surgery, nuclear therapy and medication. in 1908, it was mentioned in the literature that surgical treatment of Graves’ disease may cause thyroid crisis leading to death. in 1957 and 1967, it was reported in the literature that patients with hyperthyroidism treated with radioactive iodine may suffer from hematologic and bone marrow system damage. These have alerted clinicians to the adverse effects of surgery and nuclear therapy and to guard against them.
Anti-thyroid drugs (ATD) have been around for 60 years and are still the mainstay of treatment for hyperthyroidism, especially for Graves’ disease, and ATD therapy has been of great concern to scholars because of its long duration and adverse effects. In the 1940s and 1970s, scholars discovered that both methimazole and thiourea drugs may cause adverse effects/events such as leukopenia or granulocyte deficiency, liver function damage, vasculitis and teratogenicity. At the same time, to better guide clinical drug selection, scholars conducted a series of studies comparing the differences in safety between the two drugs.
The commonly used drugs for ATD are propylthiouracil (PTU) and methimazole (MMI). In general, ATD therapy is safe and effective, but clinical adverse effects are common, usually mild, and can be recovered on their own if ATD is discontinued promptly. However, rare and serious side effects can occur in ATD therapy, which may be potentially fatal and therefore require the attention of clinicians. In recent years, some reports and review studies have provided updated information on the side effects of ATD, so that we have a new understanding of the adverse effects of ATD and can better guide our clinical practice.
I. Toxic effects in the liver
The liver damage caused by ATD is not uncommon, but it is generally mild and can recover on its own after discontinuing ATD. liver damage caused by MMI is mostly related to the drug dose, while PTU is not significantly related to the dose. liver damage can occur at any stage of drug administration, mostly within 3 months after drug administration, and can occur as early as within 1 day of drug administration and as long as 1 year afterwards. It can occur at any age, and is more common in women.
Fatal hepatic injury or liver failure due to ATD is rare, but it is a potentially fatal and serious adverse reaction in KI therapy, with a significantly higher incidence of hepatotoxicity than MMI. PTU-induced hepatitis or liver failure is not dose-dependent, with a mean dose of 426 mg/d and a mean duration of treatment of 3.6 months. The etiology is unknown and may be related to a heterogeneous response of the organism. It is currently believed that the drug forms metabolically active substances during biotransformation in the liver and binds to various hepatic proteins, which then react immunologically with semi-antigen-modified egg self, causing liver damage. In PTU-induced hepatitis, there is evidence of immune abnormalities, mainly through lymphocyte sensitivity to PTU, but also through positive autoantibodies including anti-nuclear antibodies (ANA) and positive anti-smooth muscle and anti-mitochondrial antibodies. Another characteristic of the immune response is the recurrence and more rapid development when re-exposed to the same drug. The nature of the hepatic target antigen protein and the risk factors for hepatitis are not known, but it is relatively clear that the liver damage is secondary and the susceptibility factors are not clear, and it is possible that, as with other drugs, genetic variants in drug metabolism and immune responses play a key role, but liver damage due to antithyroid drugs is rare and no data are available. Clinically, patients present with signs and symptoms of hepatitis: peripheral discomfort, anorexia, right upper abdominal pain and jaundice, and in some patients, rash, fever and granulocyte deficiency or granulocytopenia. Laboratory tests are consistent with hepatocellular injury, with significant increases in transaminases, bilirubin and alkaline phosphatase. Liver biopsy shows hepatocellular damage with scattered or large necrosis. Some cases were accompanied by cholestasis and intra-biliary obstruction. Animal studies have found that PTU inhibits the production of murine hepatic cytochrome P450, possibly forming a PTU active metabolite that interacts with macromolecules in the endoplasmic reticulum and causes hepatocyte necrosis. However, no metabolites of direct hepatotoxicity of PTU or tabazol have been identified.
Tabazol is significantly different from the potentially fatal hepatocellular damage caused by PTU, which usually causes cholestatic liver disease, and no fatal hepatitis or liver failure has been reported in the literature to date.
The diagnosis of drug-related liver damage is usually made by the exclusion method, with a chronological sequence of drug use and liver damage. In subclinical liver damage, patients mostly have no corresponding symptoms, only mild abnormalities of liver function, which last for a short period of time, and generally do not need to stop the drug, but can reduce the dose to continue treatment, or add liver-protective therapy, but should closely observe the liver function. If liver damage is significant, discontinue the drug immediately. Most patients have a humble recovery of liver function after discontinuation. The incidence of significant liver damage is low, about 0.5% to l%, and patients often have corresponding symptoms, such as anorexia, nausea, vomiting, right upper abdominal pain with jaundice, etc. Laboratory tests for liver function continue to be significantly abnormal, mostly progressive aggravation, requiring immediate discontinuation of the drug and liver-protective therapy. A small number of patients may continue to progress even after discontinuation of the drug due to late discontinuation or excessive liver damage, and eventually die of liver failure.
Toxic effects on the hematological system
ATD can lead to damage and toxic effects on the blood system, including leukopenia, anemia, thrombocytopenia, and in severe cases, granulocyte deficiency and even severe bone marrow suppression, leading to aplastic anemia, which is life-threatening. The mechanism has not been fully clarified, and is currently believed to be mainly related to the toxic effects of drugs on the bone marrow and immune mechanisms. The cause of the immune side effects of the drug is not well understood and may be related to the intrinsic immune deficiency of the patients with Graves’ disease itself. Secondly, ATD and its metabolites can act as semi-antigens and induce the body to produce autoantibodies. In fact, insulin antibodies, anti-neutrophil antibodies, anti-granulocyte progenitor cell antibodies and anti-glucagon antibodies can be detected in patients who develop immune side effects of ATD. In addition, the metabolites of PTU can inhibit DNA synthesis by competing for ATP. Once such metabolites are integrated into DNA molecules, they can cause abnormal immunomodulatory functions and produce immune side effects. Genetic defects in individual drug metabolizing enzymes may be responsible for the susceptibility of some patients to immune side effects.
The incidence of granulocyte deficiency (absolute peripheral blood neutrophil count <0.5×109/L) is approximately 0.3% to 0.6% and usually occurs within 2-3 months of initial high-dose treatment with ATD or within 1-2 months of re-dosing, but can occur at any time of drug administration. Regular monitoring of leukocytes has been advocated and discontinuation should be considered if leukocytes are less than 2.5 x 109/L and neutrophils are less than 1.0 x 109/L. If neutrophils are between 1.0 and 1.5 x 109/L, very close monitoring is required. In addition, patients need to be reminded that if symptoms such as sore throat, fever, and general malaise occur during the course of drug administration they should be quickly examined at a hospital. It is worth noting that some patients whose initial use of ATD did not affect the white blood cell count can develop granulocyte deficiency when the drug is used again in a relapse of hyperthyroidism. Once granulocyte deficiency occurs anti-thyroid drugs should be immediately discontinued and other anti-thyroid drugs should be prohibited, sterilization and isolation measures should be taken, and broad-spectrum antibiotics should be used. At the same time, glucocorticoid therapy needs to be given, which has a clear efficacy in most patients. If necessary, recombinant human granulocyte colony-stimulating factor (rhG-cSF) or recombinant human granulocyte-macrophage colony-stimulating factor (rhGMcsF) can be administered subcutaneously at a dose of 2-10ug?kg-1?d-1 and discontinued once leukocytes return to normal. The latter therapeutic measure can be used alone or in combination with glucocorticoids.
It is important to note that some ATD-induced granulocyte deficiencies may not be due to autoimmunity, but rather to the toxicity of ATD, and are dose-dependent adverse reactions, with patients experiencing myelosuppression, which is slower to respond to glucocorticoid and colony-stimulating factor therapy and often takes longer to raise leukocytes to normal levels.
In controlled studies of MMI and PTU for Graves’ disease, leukopenia events occurred significantly more with PTU than with MMI. dose-related side effects have been reported with MMI, whereas there was no significant dose-related effect with PTU.
III. Anti-neutrophil cytoplasmic antibody (ANCA)-associated pulmonary small vessel vasculitis
PTU can induce the production of ANCA. Most patients have no clinical manifestations, and only some present with ANCA-associated small-vessel vasculitis with multi-system involvement such as fever, muscle and joint pain, and lung and kidney damage, mostly in young and middle-aged women. The majority of patients have a good prognosis as their symptoms resolve quickly after discontinuation of antithyroid drugs and treatment with hormones and immunosuppressants. Very few patients may develop renal failure. Therefore, before using PTU, urinary routine should be checked, and ANCA antibodies can be routinely checked if available.
Overseas reports show that the rate of ANCA positivity in patients with initial untreated hyperthyroidism is low, and 25% of them appear positive during PTU treatment. In China, Guo Xiaohui et al. reported 14 cases (22.6%) of ANCA positivity among 66 cases taking PTU, and none of the 77 cases in the group taking tabazol were positive for ANCA. Small-vessel vasculitis is mainly associated with renal involvement (crescentic nephritis), resulting in severe proteinuria and progressive renal function impairment. Other manifestations were fever, rash, joint and muscle pain, anemia, cough, blood in sputum or hemoptysis, and respiratory failure. Vasculitis has been observed in cases where it occurred during all periods of drug administration and was non-dose dependent. It is currently believed that PTU-induced ANCA-associated small vessel vasculitis is an autoimmune disease caused by a polyclonal immune response. Currently known target antigens of PTU-ANCA include: myeloperoxidase (hep O), protease 3 (PR3), lactoferrin (LF), human elastase (HLE), and bactericidal/permeability-enhancing protein (BPI). In ANCA-associated vasculitis, neutrophils can mediate vascular endothelial cell injury. For one, ANCA activates neutrophils to release cytoplasmic proteases that cause endothelial damage, and for another, it mediates free radical production that damages the vascular endothelium. In addition, neutrophil cytoplasmic proteases have direct cytotoxic effects and can induce a variety of cell damage, necrosis or apoptosis.
Clinical diagnosis of drug-induced small vessel vasculitis: (1) non-specific symptoms: fever, malaise and weight loss; (2) arthralgia and muscle pain; (3) skin damage: rash and skin ulcers; (4) damage to the five senses: oral ulcers, sclerositis, tinnitus and deafness, rhinitis; (5) mononeuritis. The clinical manifestations of ANcA-related small vessel vasculitis were diagnosed when any three of the above five clinical manifestations newly appeared after the application of antithyroid drugs (PTU/MMI); or when only the lungs were involved as hemoptysis and respiratory failure; or when only the kidneys were involved as hematuria, proteinuria and impaired renal function.
IV. Hypoglycemia
ATD can cause hypoglycemia, also known as insulin autoimmune syndromes (IAs). This disease was first reported by Harital, a Japanese scholar, in 1970. Its clinical features are spontaneous hypoglycemia, high level of insulin and high titer of insulin autoantibodies (IAA). It is mostly seen in people who use MMI. The mechanism of its occurrence is currently thought to be related to genetic immunodeficiency.
The chemical structure of MMI contains SH group, which can bind to the S-S bond of insulin and change its space structure, triggering autoimmune reaction and producing large amount of IAA. After a large amount of IAA binds to insulin, it is dissociated again by some mechanism, and a large amount of insulin bound to antibody is released leading to the occurrence of hypoglycemia. After the occurrence of IAS, the syndrome disappears within a few months after the discontinuation of MMI, and glucocorticoids can be added if necessary.
V. Muscle injury
There are reports of patients with varying degrees of muscle and joint pain and creatine phosphokinase (cPK) increase gradually during treatment with ATD, and muscle spasms and convulsions may occur in severe cases, mostly in patients using PTu. Myalgia is mostly seen in the extremity muscle groups, and serum cPK is increased, mostly about two times the normal value. Intravenous administration of calcium gluconate or symptomatic treatment with analgesic and anti-inflammatory drugs is mostly ineffective. The mechanism is unknown and may be related to the inhibition of thyroid hormone synthesis by ATD and the rapid decrease in thyroid hormone levels. Although FT3 and FT4 are normal, the drastic decrease of thyroid hormone in muscle tissue can cause cPK to escape from skeletal muscle, which may be accompanied by muscle pain or spasm. In addition, the direct effect of the drug on the muscle or immunosuppressive effect may be involved in muscle injury.
If muscle damage occurs, ATD can be reduced and thyroxine preparation can be added, and supplemented with fructose, inosine, adenosine triphosphate and coenzyme A. Symptoms can gradually be relieved and disappear, and CPK can return to normal.
VI. Classic allergic side effects
ATD can cause allergic side effects such as pruritus, urticaria, allergic erythema, drug fever, acute necrotizing gingivitis, etc. In severe cases, it can cause pulmonary vasculitis and exfoliative dermatitis, which are related to drug immune side effects.
VII. Gastrointestinal reactions
Some patients may experience gastrointestinal discomfort and mild abdominal pain after using ATD, and very few may experience oral odor and loss of taste.
VIII. Other adverse effects
Other rare side effects of ATD include alopecia, congenital epidermal dysplasia, goiter, skin dysplasia, hypergammaglobulinemia, periarteritis, nephritis, myositis and cavitary pulmonary infiltration, etc. Very few patients may develop hypoprothrombinemia or polyarteritis, etc.
IX. Difference between PTU and MMI adverse reactions
Since then, people have been studying the similarities and differences in adverse reactions caused by PTU and MMI, and the recent data on the safety of the two drugs have some clear and accepted conclusions. First, the adverse effects of MMI are significantly lower than those of PTU, and most of the adverse effects of the former are dose-dependent, whereas those of PTU are not significantly related to the dose of the drug. ; MMI 15 mg: 13.9%; MMl30 mg: 30.0%).
In the 1980s, numerous studies comparing the hepatotoxicity of these two drugs showed that the incidence of hepatotoxicity was significantly higher with PTU than with MMI. In 20lO, the US Food and Drug Administration (FDA) concluded, based on the number of cases of severe liver damage reported between 1969 and 2009, that “Shan was more hepatotoxic than MMI. . Medical professionals should be careful in selecting initial treatment drugs for newly diagnosed patients, and if PTU is chosen for treatment, patients should be closely monitored for signs and symptoms of liver damage, especially during the first 6 months of drug administration.” And a black box warning was added for PTU liver damage: “Application of PTU in adult or pediatric patients may increase the risk of serious liver damage, including leading to acute liver failure or even death.” In light of this, the current regulations state that patients should prefer MMI whenever possible, especially in pediatric and adolescent patients. At this point, the dust has settled on a comparison of the two drugs in terms of hepatotoxic damage.
In 2007, the Japanese scholar Nakarnura published data from his study confirming that leukopenic events occurring with PTU were significantly higher than with MMI. a 1984 review reviewed vasculitis and lupus-like syndrome reported during previous antithyroid drug therapy and found a higher incidence associated with PTU than with MMI. and, as noted earlier, the incidence of ANcA positivity with PTU was significantly This was also confirmed in the Chinese population by a 2004 article by Associate Professor Ying Gao of Peking University Hospital. For comparison of skin adverse reactions, it was found that the incidence of maculopapular/urticarial events with PTU 300 mg was similar to that of the MMI 30 mg group, but significantly higher than that of MMI 15 mg, mainly due to the dose-related adverse effects of MMI.
X. ATD and pregnancy and lactation
MMI does not bind to plasma proteins and is a fat-soluble drug that can freely pass through the placenta and breast epithelial cells into breast milk. On the contrary, PTU has a high binding rate to plasma proteins and can be ionized at physiological PH, and generally does not pass through the placenta and breast epithelial cells into breast milk.
Some studies have reported that the use of MMI during pregnancy may lead to reduced mental function in children, and in addition, MMI has been associated with possible skin dysplasia, esophageal or anal atresia, and posterior nasal foramen atresia. However, the incidence of these side effects is extremely low. Therefore, MMI is not absolutely contraindicated in pregnant women and can be used as a second-line agent for the treatment of Graves’ disease in pregnancy. In addition, there have been case reports of anal atresia caused by PTU.
Therefore, we recommend that PTU be used as the first choice for ATD in pregnant patients, followed by MMI, and that PTU at doses below 150 mg/d is generally safe for the fetus, while doses above 200 mg may lead to fetal hypothyroidism and goitre.
MMI is 4-7 times more likely than PTU to be excreted in breast milk, so PTU should be the first choice for treating hyperthyroidism during lactation, and the infant’s thyroid function should be monitored.
There are recent reports in the literature that MMI at doses below 20 mg/d does not affect the thyroid function of the infant, so it is safe to use MMI during lactation, but the thyroid function of the infant should also be monitored regularly.
XI. Use of ATD in children
ATD has long been the first-line drug for hyperthyroidism in children, and many children are even treated with ATD for a long time. The duration of treatment of hyperthyroidism with ATD in children needs to be longer, and the relapse rate after discontinuation of the drug is higher than that in adults. MMI has been shown to be safer than PTU in children, so it is preferred for the treatment of Graves’ disease in children.
In the clinical course of ATD in children with hyperthyroidism, the incidence of adverse events including rash, leukopenia, arthritis, vasculitis, liver injury, and death caused by PTU was significantly higher than that of MMI, and PTU was more hepatotoxic, even causing severe toxic hepatitis and liver failure, independent of the dose. In addition, three cases of vasculitis and renal failure due to PTU in children have been reported. The adverse effects caused by MMI were much less frequent and milder, generally dose-related, with no reported cases of liver failure.
Therefore, PTU should not be used as a first-line agent in children with hyperthyroidism, except in certain special circumstances, such as allergy to MMI, preparation of the patient for surgery, or during pregnancy with hyperthyroidism, and children who are currently using PTU should be advised to discontinue it to prevent drug-related liver failure. If the patient has had a toxic reaction to MMI and there is no indication for surgery or iodine therapy, and pharmacological therapy is necessary, then short-term use of PTU may be considered; however, in this case, the child and his or her parents must be informed in advance of the possible risk of liver damage or even liver failure associated with PTU use. If the child develops fatigue, nausea, dizziness, or fever during PTU application, PTU should be stopped immediately and blood counts, liver function, etc. should be checked.
In view of the fact that there are no reports of liver failure in children using PTU in China and that most Chinese physicians are accustomed to using these drugs, some experts still advocate that PTU is preferred for pediatric hyperthyroidism. however, there is no comprehensive monitoring and reporting system for adverse drug reactions in China, and there is a lack of systematic prospective studies. therefore, we believe that it is appropriate to follow the principles of international guidelines in China and use MMI is preferred.