-
Expert Review of Endocrinology &... Jan 2023The thionamide anti-thyroid drugs namely carbimazole, methimazole, and propylthiouracil, have been the predominant therapy modality for Graves' hyperthyroidism for over... (Review)
Review
INTRODUCTION
The thionamide anti-thyroid drugs namely carbimazole, methimazole, and propylthiouracil, have been the predominant therapy modality for Graves' hyperthyroidism for over 60 years. Although these agents have proven efficacy and favorable side-effect profiles, non-thionamide alternatives are occasionally indicated in patients who are intolerant or unresponsive to thionamides alone. This review examines the available non-thionamide drug options for the control of Graves' hyperthyroidism and summarizes their clinical utility, efficacy, and limitations.
AREAS COVERED
We reviewed existing literature on mechanisms, therapeutic utility, and side-effect profiles of non-thionamide anti-thyroid drugs. Established non-thionamide agents act on various phases of the synthesis, release, and metabolism of thyroid hormones and comprise historical agents such as iodine compounds and potassium perchlorate as well as drug repurposing candidates like lithium, glucocorticoids, beta-blockers, and cholestyramine. Novel experimental agents in development target key players in Graves' disease pathogenesis including B-cell depletors (Rituximab), CD40 blockers (Iscalimab), TSH-receptor antagonists, blocking antibodies, and immune-modifying peptides.
EXPERT OPINION
Non-thionamide anti-thyroid drugs are useful alternatives in Graves' hyperthyroidism and more clinical trials are needed to establish their safety and long-term efficacy in hyperthyroidism control. Ultimately, the promise for a cure will lie in novel approaches that target the well-established immunopathogenesis of Graves' disease.
Topics: Humans; Antithyroid Agents; Hyperthyroidism; Propylthiouracil; Methimazole; Graves Disease
PubMed: 36740774
DOI: 10.1080/17446651.2023.2167709 -
Current Opinion in Endocrinology,... Oct 2019Graves' hyperthyroidism is associated with significant obstetric, maternal, fetal, and neonatal complications. Early diagnosis and an understanding of the management of... (Review)
Review
PURPOSE OF REVIEW
Graves' hyperthyroidism is associated with significant obstetric, maternal, fetal, and neonatal complications. Early diagnosis and an understanding of the management of Graves' hyperthyroidism in pregnancy can help to prevent these complications. Antithyroid drugs (ATD) should be avoided in early pregnancy, given their association with congenital malformations.
RECENT FINDINGS
TSH-receptor antibodies (TRAb) are integral in the management of Graves' hyperthyroidism in pregnancy and in the preconception period. TRAb are indicative of the current activity of Graves' hyperthyroidism and the likelihood of relapse. Furthermore, TRAb predicts the risk of fetal and neonatal hyperthyroidism.The incidence of congenital malformations is roughly the same for propylthiouracil (PTU) and methimazole (MMZ). Exposure to both ATDs in early pregnancy has been associated with increased incidence of congenital malformations compared with exposure to either ATD alone.
SUMMARY
The goal of the physician is maintaining euthyroidism throughout pregnancy and delivery of a healthy, euthyroid baby. An understanding of the natural progression of Graves' hyperthyroidism in pregnancy and the proper utilization of TRAb enables the physician to minimize the risks associated with Graves' hyperthyroidism and side effects of ATDs unique to pregnancy. The physician should prioritize preconception counseling in women with Graves' hyperthyroidism in order to avoid hyperthyroidism and having to use ATDs in pregnancy.
Topics: Antithyroid Agents; Female; Graves Disease; Humans; Hyperthyroidism; Pregnancy; Pregnancy Complications
PubMed: 31389810
DOI: 10.1097/MED.0000000000000492 -
Best Practice & Research. Clinical... Jul 2020Thyrotoxicosis during pregnancy should be adequately managed and controlled to prevent maternal and fetal complications. The evaluation of thyroid function in pregnant... (Review)
Review
Thyrotoxicosis during pregnancy should be adequately managed and controlled to prevent maternal and fetal complications. The evaluation of thyroid function in pregnant women is challenged by the physiological adaptations associated with pregnancy, and the treatment with antithyroid drugs (ATD) raises concerns for the pregnant woman and the fetus. Thyrotoxicosis in pregnant women is mainly of autoimmune origin, and the measurement of thyroid stimulating hormone-receptor antibodies (TRAb) plays a key role. TRAb helps to distinguish the hyperthyroidism of Graves' disease from gestational hyperthyroidism in early pregnancy, and to evaluate the risk of fetal and neonatal hyperthyroidism in late pregnancy. Furthermore, the measurement of TRAb in early pregnancy is recommended to evaluate the need for ATD during the teratogenic period of pregnancy. Observational studies have raised concern about the risk of birth defects associated with the use of ATD in early pregnancy and challenged the clinical management and choice of treatment.
Topics: Antithyroid Agents; Female; Fetal Diseases; Graves Disease; Humans; Hyperthyroidism; Immunoglobulins, Thyroid-Stimulating; Infant, Newborn; Infant, Newborn, Diseases; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prenatal Exposure Delayed Effects; Thyrotoxicosis
PubMed: 32199749
DOI: 10.1016/j.beem.2020.101414 -
Thyroid Research 2020Antithyroid drugs (ATDs) are preferred for the treatment of hyperthyroidism caused by Graves' disease in pregnant women. The drugs have been a recognized treatment for... (Review)
Review
Antithyroid drugs (ATDs) are preferred for the treatment of hyperthyroidism caused by Graves' disease in pregnant women. The drugs have been a recognized treatment for decades, and a general risk of side effects is known. For the use of ATDs in pregnancy, a concern about teratogenic side effects has been brought forward since the 1970s. In more recent years, a number of large observational studies have added new evidence and quantified the risk of birth defects associated with different types of ATDs. The findings that both Methimazole (MMI) and Propylthiouracil (PTU) are associated with birth defects have challenged the clinical recommendations on the treatment of hyperthyroidism in pregnancy, and certain aspects remain unclarified. In this review, the current evidence on the risk of birth defects associated with the use of ATDs in early pregnancy is described, and determinants of causality are discussed. This includes the current evidence of a biological gradient and the role of maternal thyroid function per se Finally, clinical aspects of the timing and type of treatment is discussed, and future perspectives are addressed. Current evidence corroborates a risk of birth defects associated with MMI while more evidence is needed to determine the teratogenic potential of PTU. Detailed assessment of type and timing of exposure in large cohorts are needed. Moreover, studies investigating alternative or new treatments are warranted.
PubMed: 32607131
DOI: 10.1186/s13044-020-00085-8 -
Clinical Rheumatology Dec 2021Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have a two- to threefold greater risk of developing venous as well as arterial... (Review)
Review
Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have a two- to threefold greater risk of developing venous as well as arterial thrombotic events. Although such thrombotic events are more commonly seen during phases of active AAV, they are also recognized to occur during AAV in remission. Endothelial injury is a key pathogenic event in AAV. Endothelial injury can be caused by neutrophil activation and release of thrombogenic tissue factor into the circulation. Neutrophil activation further results in the formation of neutrophil extracellular traps (NETs). NETs contribute to thrombosis by expressing tissue factor. NETs have also been detected in cutaneous thrombi from patients with AAV induced by hydralazine. Activated neutrophils in AAV patients release thrombogenic microparticles loaded with tissue factor which further enhances clotting of blood. Antiphospholipid antibodies (APLs) have been detected in up to a third of AAV and might also be induced by drugs such as cocaine adulterated with levamisole and propylthiouracil, which are known to trigger AAV. Such APLs further drive the thrombosis in AAV. Once thrombogenesis occurs, the homeostatic mechanisms resulting in clot dissolution are further impaired in AAV due to anti-plasminogen antibodies. The ongoing pandemic of coronavirus disease 2019 (COVID-19) is associated with endothelial injury and NETosis, mechanisms which are in common with AAV. Reports of new-onset AAV following COVID-19 have been described in the literature, and there could be shared mechanisms driving these processes that require further evaluation.
Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; COVID-19; Extracellular Traps; Humans; Neutrophils; SARS-CoV-2; Thrombosis
PubMed: 34109491
DOI: 10.1007/s10067-021-05790-9 -
Cureus Jul 2022The use of propylthiouracil (PTU) is associated with the development of autoantibodies, namely, antineutrophil cytoplasmic antibodies (ANCAs), which are associated with...
The use of propylthiouracil (PTU) is associated with the development of autoantibodies, namely, antineutrophil cytoplasmic antibodies (ANCAs), which are associated with the pathogenesis of ANCA-associated systemic vasculitis, most often related to the myeloperoxidase subtype (ANCA-MPO). The authors report the case of a 61-year-old woman on PTU for one year who was referred to Internal Medicine for a three-month evolution of painless non-blanching purple patches, non-pruriginous, involving the chest and legs. The autoimmunity revealed ANCA antibody positivity, with a cutaneous biopsy compatible with leukocytoclastic vasculitis/necrotizing vasculitis with involvement of small and medium-sized vessels. Clinical improvement was noted after the drug was discontinued, with the resolution of the analytical changes.
PubMed: 36000132
DOI: 10.7759/cureus.27073 -
Birth Defects Research Sep 2020Thyroid disorders including hyperthyroidism are common during pregnancy. Untreated hyperthyroidism can result in adverse outcomes for pregnancy. (Review)
Review
OBJECTIVE
Thyroid disorders including hyperthyroidism are common during pregnancy. Untreated hyperthyroidism can result in adverse outcomes for pregnancy.
METHODS
Iodine, propylthiouracil (PTU), carbimazole (CMZ), and methimazole (MMI) are common medications for hyperthyroidism treatment. The literature regarding antithyroid medication use in pregnancy and breastfeeding is reviewed.
RESULTS
Animal studies for PTU have suggested congenital anomalies while animal studies for MMI have only indicated adverse outcomes at higher doses than used in humans. Epidemiological studies have noted an increased risk of congenital anomalies for PTU less often than CMZ or MMI but the epidemiological evidence remains mixed. A pattern of anomalies has been described for CMZ and MMI, from both case and epidemiological studies, including choanal atresia, aplasia cutis congenita, and other facial, heart, gastrointestinal, and skin anomalies. Closer examination of cases indicates that a few cases of the anomalies have occurred without exposure to CMZ or MMI and outside of the proposed critical period. PTU has a small risk of hepatotoxicity which rarely results in liver transplantation and death. Some authors have suggested that PTU be prescribed in early pregnancy and switched to MMI in late pregnancy. Untreated hyperthyroidism, from either a lack of medications or switching medications during the first trimester, may also increase the chance of congenital anomalies. Multiple case studies and larger epidemiological studies have failed to provide clear, consistent outcomes for the use of PTU, CMZ, and MMI in pregnancy. MMI and PTU both enter the breastmilk in small amounts.
CONCLUSION
Additional research is needed to assist in the medical management and exposure counseling of pregnant and breastfeeding women with hyperthyroidism.
Topics: Abnormalities, Drug-Induced; Animals; Antithyroid Agents; Female; Humans; Methimazole; Pregnancy; Propylthiouracil; Teratogens
PubMed: 32738035
DOI: 10.1002/bdr2.1771 -
Journal Der Deutschen Dermatologischen... Feb 2022
Topics: Antibodies, Antineutrophil Cytoplasmic; Humans; Propylthiouracil; Vasculitis
PubMed: 34951512
DOI: 10.1111/ddg.14654 -
Journal of Endocrinological... Aug 2022To review the pathophysiology, diagnosis and management of postpartum thyroid dysfunction, and related management of thyroid disorders during lactation. (Review)
Review
PURPOSE
To review the pathophysiology, diagnosis and management of postpartum thyroid dysfunction, and related management of thyroid disorders during lactation.
METHODS
We reviewed the literature on postpartum thyroid dysfunction and management of thyroid disorders during lactation.
RESULTS
The postpartum period is characterized by a rebound from the immunotolerance induced by pregnancy. Routine thyroid function screening is not recommended for asymptomatic women in the postpartum period. Testing thyroid function should be considered at 6-12-week postpartum for high-risk populations, including women with a previous episode of postpartum thyroiditis, Graves' disease, or those with Hashimoto's thyroiditis on thyroid hormone replacement, known thyroid peroxidase antibody positivity, type 1 diabetes mellitus, other nonthyroidal autoimmune disease, or chronic hepatitis C. A serum TSH should also be checked in the setting of postpartum depression or difficulty lactating. If patients have thyrotoxicosis, new-onset or recurrent Graves' disease must be differentiated from postpartum thyroiditis, because the management differs. Periodic thyroid function testing is recommended following recovery from postpartum thyroiditis due to high lifetime risk of developing permanent hypothyroidism. Levothyroxine, and the lowest effective dose of antithyroid drugs, (propylthiouracil, methimazole, and carbimazole) can be safely used in lactating women. The use of radiopharmaceutical scanning is avoided during lactation and radioactive iodine treatment is contraindicated.
CONCLUSIONS
Diagnosing postpartum thyroid dysfunction is challenging, because symptoms may be subtle. A team approach involving primary care providers, endocrinologists, and obstetricians is essential for transitioning thyroid care from the gestational to the postpartum setting.
Topics: Female; Graves Disease; Humans; Iodine Radioisotopes; Lactation; Postpartum Period; Postpartum Thyroiditis; Pregnancy; Puerperal Disorders; Thyroid Diseases; Thyroid Neoplasms
PubMed: 35181848
DOI: 10.1007/s40618-022-01762-1