Antineutrophil cytoplasmic antibody positive alveolar haemorrhage during propylthiouracil therapy for hyperthyroidism

Recently, propylthiouracil (PTU) has been thought to be one of the possible causes of antineutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis syndrome, resulting in glomerulonephritis and, infrequently, diffuse alveolar haemorrhage (DAH). The mechanism of ANCA-positive vasculitis during PTU therapy is still unknown. Herein, we describe the case of a 59-year-old woman who developed myeloperoxidase (MPO)- and proteinase 3 (PR3)-ANCA positive DAH, without any other organ system involvement, during PTU therapy. Diminution and discontinuation of PTU resulted in a positive response. To our knowledge, this is the first documentation of both MPO- and PR3-ANCA-positive DAH, without systemic manifestations, developing during PTU therapy.     

UPLC-MS/MS法测定人血浆中丙硫氧嘧啶的含量

目的 建立UPLC-MS/MS法测定人血浆中丙硫氧嘧啶的含量,为临床治疗药物监测（TDM）和生物等效性试验（BE）提供方法学基础。方法 采用Agilent SB-C₁₈柱（4.6 mm×150 mm,5 μm）,流动相为甲醇-0.1%甲酸水溶液（80∶20,V/V）,等度洗脱。质谱采用AJS-ESI源,多反应监测（MRM）正离子模式,检测离子对为：丙硫氧嘧啶m/z 171.1→112.1、内标（丙硫氧嘧啶-D5）m/z 176.1→117.0。结果 血浆中丙硫氧嘧啶在10~5 000 ng/ml范围内线性关系良好,r=0.999 3;批内和批间的精密度和准确度良好（RSD<10%,RE<±10%）;不同浓度的基质效应均<110%,变异系数<5%;不同浓度的平均回收率为101.60%~113.56%,符合方法学要求。结论 该方法快速简便、灵敏准确,适用于血浆中丙硫氧嘧啶的含量测定。     

Propylthiouracil-Induced Vasculitis Associated with ANCA: A Case Report

Propylthiouracil is a drug used in the treatment of hyperthyroidism for more than 60 years. Adverse side effects are seen in 1–5% of patients. Renal complications of the drug including glomerulonephritis and vasculitis are rarely seen. Cases of propylthiouracil-induced rapidly progressive glomerulonephritis and vasculitis are reported in association with antineutrophil cytoplasmic autoantibodies. Here we report a case of positive antineutrophil cytoplasmic autoantibodies rapidly progressive glomerulonephritis (RPGN) associated with propylthiouracil treatment.     

不同剂量丙硫氧嘧啶对妊娠期甲亢患者甲状腺功能及妊娠结局的影响

目的探讨不同剂量丙硫氧嘧啶对妊娠期甲亢患者甲状腺功能及妊娠结局的影响。方法选取我院2017年3月至2018年3月收治的125例妊娠期甲亢患者作为研究对象,按治疗方案将其分为对照组(60例,常规剂量丙硫氧嘧啶)与观察组(65例,低剂量丙硫氧嘧啶)。比较两组患者治疗前、后的甲状腺功能指标及肝功能指标;比较两组患者的治疗效果及妊娠不良事件发生情况。结果治疗后,两组患者TSH水平均显著升高,FT3、FT4、T3、T4水平均显著降低(P<0.05)。治疗后,两组的ALP、GGT、TBIL水平均无显著变化(P>0.05);对照组的ALT、AST水平均升高,且显著高于观察组(P<0.05)。两组甲亢治疗的总有效率比较,差异无统计学意义(P>0.05)。观察组的妊娠不良事件总发生率明显低于对照组(P<0.05)。结论常规剂量、低丙硫氧嘧啶用于妊娠期甲亢患者的治疗,均可获得良好的治疗效果,但低剂量可明显减轻患者肝功能损伤和妊娠不良事件的发生风险。     

Thyrotoxicosis: Diagnosis and Management

Thyrotoxicosis is the clinical manifestation of excess thyroid hormone action at the tissue level due to inappropriately high circulating thyroid hormone concentrations. Hyperthyroidism, a subset of thyrotoxicosis, refers specifically to excess thyroid hormone synthesis and secretion by the thyroid gland. We performed a review of the literature on these topics utilizing published data in PubMed and MEDLINE. In this review, we discuss the more common etiologies of thyrotoxicosis, focusing on the current approach to diagnosis and management, new trends in those directions, and potential upcoming changes in the field.     

Inhibition of Na+,K+-ATPase in the hypothalamus,pons and cerebellum of the offspring rat due to experimentally-induced maternal hypothyroidism

Neurodevelopment is known to be particularly susceptible to thyroid hormone insufficiency and can result in extensive structural and functional deficits within the central nervous system (CNS), subsequently leading to the establishment of cognitive impairment and neuropsychiatric symptomatology. The current study evaluated the effects of gestational and/or lactational maternal exposure to propylthiouracil (PTU)-induced hypothyroidism (as a suggestive multilevel experimental approach to the study of hypothyroidism-induced changes that has been developed and characterized by the authors) on crucial brain enzyme activities of 21-day-old Wistar rat offspring in a CNS region-specific manner. The activities of acetylcholinesterase (AChE), Na⁺,K⁺-ATPase and Mg²⁺-ATPase in the offspring hypothalamus, cerebellum and pons were assessed. The study demonstrated that maternal exposure to PTU (0.05% w/v in the drinking water) during the critical periods of neurodevelopment can result in an inhibition of hypothalamic, pontine and cerebellar Na⁺,K⁺-ATPase; a major marker of neuronal excitability and metabolic energy production as well as an important regulator of important systems of neurotransmission. On the other hand, no significant changes in the activities of the herein offspring CNS regions’ AChE and Mg²⁺-ATPase were recorded. The observed Na⁺,K⁺-ATPase inhibition: (i) is region-specific (and non-detectable in whole brain homogenetes), (ii) could constitute a central event in the pathophysiology of clinically-relevant hypothyroidism-associated developmental neurotoxicity, (iii) occurs under all examined experimental schemes, and (iv) certainly deserves further clarification at a molecular and histopathological level. As these findings are analyzed and compared to the available literature, they also underline the need for the adoption and further study of Na⁺,K⁺-ATPase activity as a consistent neurochemical marker within the context of a systematic comparative study of existing (and novel) simulation approaches to congenital and early age hypothyroidism.     

甲巯咪唑和丙硫氧嘧啶治疗甲亢安全性的回顾性分析

目的:系统评价甲巯咪唑和丙硫氧嘧啶治疗甲状腺功能亢进症的安全性。方法:检索中外文数据库,比较1994-2014年关于甲巯咪唑和丙硫氧嘧啶治疗甲亢出现粒细胞减少、肝损伤、皮疹主要不良反应的RCT,对结果进行Meta分析。结果:共纳入11个研究,涉及病例数1 660,Meta分析显示甲巯咪唑在治疗甲亢时引起粒细胞减少和皮疹的发生率与丙硫氧嘧啶无差别 [RR=0.61,95% CI (0.25,1.51),P=0.28;RR=0.88,95% CI (0.66,1.17),P=0.38],但肝损伤的发生率比丙硫氧嘧啶低 [RR=2.21,95% CI (1.27,3.83),P=0.005]。结论:甲巯咪唑治疗甲亢引起粒细胞减少和皮疹的风险与丙硫氧嘧啶相当,但肝损伤的风险比丙硫氧嘧啶低。     

Preliminary pharmacokinetic studies of propylthiouracil in humans

Previous analytical procedures for the analysis of propylthiouracil (PTU) in blood and urine samples are questionable on several points. Therefore, a gas-liquid chromatography method has been developed which is both more sensitive and more specific. Application of this procedure confirmed that the drug was rapidly absorbed and eliminated. The mean terminal half-life in euthyroids was found to be 63 min. One hyperthyroid subject showed a far higher plasma clearance than seen with euthyroids, which requires further study.Supported in part by Grant GM 16496 from the National Institutes of Health.This paper was submitted to a Consulting Editor who served as the Journal Editor during its review process.     

Propylthiouracil attenuates acetaminophen-induced renal damage in the rat

BACKGROUND: To date, there is no specific antidote to acetaminophen poisoning. Propylthiouracil (PTU) has been shown to be protective against acetaminophen (APAP)-induced liver damage in rats; however, the nephroprotective effect of propylthiouracil has not been studied yet. METHODS: In order to verify this, rats were given different doses of PTU (100, 200 or 400 mg/kg per body weight, orally) 1 h before a nephrotoxic dose of APAP (1,000 mg/kg per body weight, intraperitoneally (i.p.)). RESULTS: Propylthiouracil pretreatment significantly reduced APAP-induced nephrotoxicity in a dose-dependant manner, as evidenced by reduction in plasma creatinine and by amelioration of renal pathology (interstitial congestion, tubular cell degeneration and necrosis). CONCLUSION: The mechanism of protection by PTU is probably not due to the sparing effect of non-protein thiol (approximately 95% of which is reduced glutathione), as similar depletion of renal glutathione was observed regardless of PTU pretreatment; other mechanisms are suggested.     

Anti-endothelial cell antibodies (AECA) in patients with propylthiouracil (PTU)-induced ANCA positive vasculitis are associated with disease activity

Increasing evidence has demonstrated that propylthiouracil (PTU) could induce ANCA positive vasculitis. However, our previous work has suggested that only one-fifth of the PTU-induced ANCA positive patients had clinical vasculitis and so the mechanism is not clear. Anti-endothelial cell antibodies (AECA) have been implicated in the pathogenesis of various vasculitides, including primary ANCA positive systemic vasculitis. The purpose of this study is to investigate the prevalence of AECA and their possible role in the pathogenesis of patients with PTU-induced ANCA positive vasculitis. Sera from 11 patients with PTU-induced ANCA positive vasculitis at both active and quiescent phases, and sera from 10 patients with PTU-induced ANCA but without clinical vasculitis, were studied. Sera from 30 healthy blood donors were collected as normal controls. Soluble proteins from 1% Triton-100 extracted in vitro cultured human umbilical vein endothelial cells were used as antigens and an immunoblotting technique was performed to determine the presence of AECA, and their specific target antigens were identified. In patients with PTU-induced ANCA positive vasculitis, 10 of the 11 patients in an active phase of disease were serum IgG-AECA positive and six protein bands of endothelial antigens could be blotted (61 kD, 69 kD, 77 kD, 85 kD, 91 kD and 97 kD). However, in the quiescent phase, seven of the 10 positive sera turned negative. None of the ANCA positive but vasculitis negative patients or normal controls were AECA positive. In conclusion, AECA could be found in sera from patients with PTU-induced ANCA positive vasculitis and were associated more closely with vasculitic disease activity.