应该放弃甲状腺素诱导的肝毒性理论吗?
Yahya Al-Hammada1, Sinan Sharba1, Samer Al-Dury2,3,4
1Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Vastra Gotaland, Sweden.
World journal of hepatology
|March 11, 2026
概括
甲甲酸 (MTX) 不像以前想象的那样会导致肝纤维化,特别是与叶酸一起. 专注于代谢因素,而不仅仅是MTX剂量,以指导监测并避免早期停药.
科学领域:
- 风湿病学和免疫学
- 肝病学 肝病学是一种肝病学.
- 药理学 药理学是指药理学的学科.
背景情况:
- 甲基 (MTX) 是慢性炎症性疾病的重要治疗方法,如类风湿性关节炎和牛皮.
- 由于对MTX肝毒性,特别是肝纤维化的历史担忧,导致了保守的监测和侵入性肝活检.
- 这些做法往往导致MTX的过早停用.
研究的目的:
- 根据目前的证据,重新评估MTX诱导的肝纤维化风险.
- 倡导从基于剂量的监测转向基于风险的非侵入性策略.
- 通过纠正关于其肝毒性的历史假设,防止不必要的MTX停止.
主要方法:
- 对MTX肝毒性和肝纤维化的当代数据的综述.
- 对最近的大型队列研究和非侵入性纤维化评估方法的分析.
- 考虑代谢并发症在MTX相关肝脏结果中的作用.
主要成果:
- 在接受MTX治疗的患者中,晚期肝纤维化不常见,并且通常与代谢因素 (肥胖,胰岛素抵抗) 相关.
- 标准剂量的MTX与叶酸补充剂很少独立导致严重的肝纤维化.
- 历史上的担忧很可能受到对高剂量MTX的研究的影响,而没有充分考虑代谢风险.
结论:
- MTX的肝毒性低于历史上所认为的,尤其是在标准剂量与叶酸一起使用时.
- 监测策略应该从例行活检过渡到针对个体代谢风险因素的非侵入性评估.
- 这种方法可以优化患者管理,防止不必要的MTX中止,并改善治疗坚持.
相关概念视频
01:27Pharmacogenetics of Phase II Enzymes: N-acetyltransferase, Thiopurine S-methyltransferase, UDP-glucuronosyltransferase
55
Phase II biotransformation reactions are essential for detoxifying and eliminating xenobiotics, including many pharmaceutical compounds. These reactions typically involve conjugation, the covalent attachment of polar endogenous groups such as glucuronic acid, sulfate, methyl, or acetyl moieties to functional groups introduced during Phase I metabolism. The resulting conjugates are more water-soluble, enabling efficient renal or biliary excretion.The major classes of Phase II enzymes include...
55
01:25Bioactivation and Tissue Toxicity
75
Bioactivation is a metabolic process that transforms less reactive substances into highly reactive metabolites, initiating tissue toxicity. This transformation can lead to various toxic effects, including carcinogenesis and teratogenesis. Reactive metabolites are classified into two main types: electrophiles and free radicals.Electrophiles are electron-deficient species and are produced primarily by the enzyme cytochrome P-450 during the metabolism of compounds containing carbon, nitrogen, or...
75
01:17Phase II Reactions: Methylation Reactions
842
Methylation is a phase II biotransformation process involving the attachment of a methyl group to a substrate. Enzymes known as methyltransferases orchestrate this reaction.
The mechanism of methylation unfolds in two stages. The first stage sees a methyltransferase enzyme facilitating the transfer of a methyl group from S-adenosylmethionine (SAM) to the substrate, forming S-adenosylhomocysteine (SAH). The second stage involves further metabolism of SAH into homocysteine, which can be recycled...
The mechanism of methylation unfolds in two stages. The first stage sees a methyltransferase enzyme facilitating the transfer of a methyl group from S-adenosylmethionine (SAM) to the substrate, forming S-adenosylhomocysteine (SAH). The second stage involves further metabolism of SAH into homocysteine, which can be recycled...
842
01:24Drug Toxicity: Dose-Dependent Reactions
99
Drug toxicities can be stratified into pharmacological, pathological, or genotoxic based on their mechanisms. The incidence and severity of these toxicities generally increase with the drug's concentration in the body and exposure time.Pharmacological toxicity is evident when the therapeutic effects of drugs overshoot into adverse reactions in a predictable, dose-dependent manner. Central nervous system (CNS) depression from barbiturates is a classic example, with effects escalating from...
99
01:22Phase II Reactions: Glutathione Conjugation and Mercapturic Acid Formation
1.1K
Glutathione, a tripeptide made up of glutamate, cysteine, and glycine, is a critical player in the detoxification of drugs and xenobiotics via a process known as glutathione conjugation or mercapturic acid formation. This phase II biotransformation reaction involves the covalent binding of glutathione to a drug or its metabolite, enhancing the compound's water solubility and enabling its excretion.
Several distinctive characteristics distinguish glutathione conjugation from other phase II...
Several distinctive characteristics distinguish glutathione conjugation from other phase II...
1.1K
01:26Toxic Reactions: Overview
3.3K
When toxic substances penetrate the human body, they disseminate to various tissues, undergoing metabolic changes. This process yields reactive metabolites that may covalently bind with specific target molecules, resulting in toxicity.
Toxicity falls into two primary categories: local and systemic.
Local toxicity appears at the exposure site, such as protein denaturation caused by caustic substances.
In contrast, systemic toxicity requires the toxic agent's absorption and distribution,...
Toxicity falls into two primary categories: local and systemic.
Local toxicity appears at the exposure site, such as protein denaturation caused by caustic substances.
In contrast, systemic toxicity requires the toxic agent's absorption and distribution,...
3.3K